DARWIN'S BLACK BOX

THE BIOCHEMICAL CHALLENGE TO EVOLUTIONMICHAEL J. ВЕНЕFREE PRESSNew York London Toronto SydneyTO CELESTE

CONTENTSPREFACEIX

THE BOX IS OPENED
1. LILIPUTIAN BIOLOGY
2. NUTS AND BOLTS

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EXAMINING THE CONTENTS OF THE BOX
3.
4.
5.
6.
7.

ROW, ROW, ROW YOUR BOAT
RUBE GOLDBERG IN THE BLOOD
FROM HERE TO THEREA DANGEROUS WORLDROAD KILL

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74
98
117
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WHAT DOES THE BOX TELL US?
8. PUBLISH OR PERISH
9. INTELLIGENT DESIGN
10. QUESTIONS ABOUT DESIGN
11. SCIENCE, PHILOSOPHY, RELIGION
AFTERWORD
APPENDIXNOTESACKNOWLEDGMENTS

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313

PREFACE IX

PREFACEA MOLECULAR PHENOMENON

It is commonplace, almost banal, to say that science has made great
strides in understanding nature. The laws of physics are now so wellunderstood that space probes fly unerringly to photograph worlds billionsof miles from earth. Computers, telephones, electric lights, and untold
other examples testify to the mastery of science and technology over theforces of nature. Vaccines and high-yield crops have stayed the ancientenemies of mankind, disease and hunger—at least in parts of the world.
Almost weekly, announcements of discoveries in molecular biology
encourage the hope of cures for genetic diseases and more.
Yet understanding how something works is not the same asunderstanding how it came to be. For example, the motions of the planetsin the solar system can be predicted with tremendous accuracy; however,
the origin of the solar system (the question of how the sun, planets, andtheir moons formed in the first place) is still controversial.1 Science may
eventually solve the riddle. Still, the point remains that understanding
the origin of something is different from understanding its day-to-day
workings.
Science's mastery of nature has led many people to presume that it
can—indeed, must—also explain the origin of nature and life. Dar-

X  X﻿
win's proposal that life can be explained by natural selection acting on
variation has been overwhelmingly accepted in educated circles for morethan a century, even though the basic mechanisms of life remained utterly
mysterious until several decades ago.
Modem science has learned that, ultimately, life is a molecular
phenomenon: All organisms are made of molecules that act as the nuts
and bolts, gears and pulleys of biological systems. Certainly there arecomplex biological features (such as the circulation of blood) that emerge at
higher levels, but the gritty details of life are the province of biomolecules.
Therefore the science of biochemistry, which studies those molecules, has
as its mission the exploration of the very foundation of life.
Since the mid-1950s biochemistry has painstakingly elucidated theworkings of life at the molecular level. Darwin was ignorant of the reason
for variation within a species (one of the requirements of his theory), butbiochemistry has identified the molecular basis for it. Nineteenth-century
science could not even guess at the mechanism of vision, immunity, or
movement, but modern biochemistry has identified the molecules thatallow those and other functions.
It was once expected that the basis of life would be exceedingly simple.
That expectation has been smashed. Vision, motion, and other biological
functions have proven to be no less sophisticated than television cameras
and automobiles. Science has made enormous progress in understanding
how the chemistry of life works, but the elegance and complexity of
biological systems at the molecular level have paralyzed science's attempt to
explain their origins. There has been virtually no attempt to account for theorigin of specific, complex biomolecular systems, much less any progress.
Many scientists have gamely asserted that explanations are already in
hand, or will be sooner or later; but no support for such assertions can befound in the professional science literature. More importantly, there arecompelling reasons—based on the structure of the systems themselves—to think that a Darwinian explanation for the mechanisms of life will
forever prove elusive.
Evolution is a flexible word.2 It can be used by one person to meansomething as simple as change over time, or by another person to mean thedescent of all life forms from a common ancestor, leaving the mechanismof change unspecified. In its full-throated, biologicalPREFACE XI
sense, however, evolution means a process whereby life arose from
nonliving matter and subsequently developed entirely by natural means.
That is the sense that Darwin gave to the word, and the meaning that it
holds in the scientific community. And that is the sense in which I use theword evolution throughout this book.

APOLOGIA FOR DETAILS

Several years ago, Santa Claus gave my oldest son a plastic tricycle for
Christmas. Unfortunately, busy man that he is, Santa had no time to takeit out of the box and assemble it before heading off. The task fell to Dad.
I took the parts out of the box, unfolded the assembly instructions, andsighed. There were six pages of detailed instructions: line up the eight
different types of screws, insert two 1½-inch screws through the handle
into the shaft, stick the shaft through the square hole in the body of thebike, and so on. I didn't want to even read the instructions, because I knew
they couldn't be skimmed like a newspaper—the whole purpose is in thedetails. But I rolled up my sleeves, opened a can of beer, and set to work.
After several hours the tricycle was assembled. In the process I had indeed
read every single instruction in the booklet several times (to drill them into
my head) and performed the exact actions that the instructions required.
My aversion to instructions seems to be widespread. Although mosthouseholds own a videocassette recorder (VCR), most folks cannot
program them. These technological wonders come with complete operating
instructions, but the very thought of tediously studying each sentence ofthe booklet makes most people delegate the job to the nearest ten-year-old.
Unfortunately, much of biochemistry is like an instruction booklet, inthe sense that the importance is in the details. A student of biochemistry
who merely skims through a biochemistry textbook is virtually certain
to spend much of the next exam staring at the ceiling as drops of sweat
trickle down his or her forehead. Skimming the textbook does not preparea student for questions such as «Outline in detail the mechanism ofhydrolysis of a peptide bond by trypsin, paying special attention to the roleof transition state binding energy.» Although there are broad principles
of biochemistry that help a mortal comprehend the general picture of thechemistry of life, broad princi-

XII  XII﻿
ples only take you so far. A degree in engineering does not substitute forthe tricycle instruction booklet, nor does it directly help you to program
your VCR.
Many people, unfortunately, are all too aware of the pickiness ofbiochemistry. People who suffer with sickle cell anemia, enduring muchpain in their shortened lives, know the importance of the little detailthat changed one out of 146 amino acid residues in one out of the tens of
thousands of proteins in their body. The parents of children who die of
Tay-Sachs or cystic fibrosis, or who suffer from diabetes or hemophilia,
know more than they want to about the importance of biochemical details.
So, as a writer who wants people to read my work, I face a dilemma:
people hate to read details, yet the story of the impact of biochemistry on
evolutionary theory rests solely in the details. Therefore I have to write
the kind of book people don't like to read in order to persuade them of theideas that push me to write. Nonetheless, complexity must be experienced
to be appreciated. So, gentle reader, I beg your patience; there are going to
be a lot of details in this book.
The book is divided into three parts. Part I gives some backgroundand shows why evolution must now be argued at the molecular level—the
domain of the science of biochemistry. This portion is largely free fromtechnical details, although some do creep in during a discussion of theeye. Part II contains the «example chapters,» where most of the complexity
is found. Part III is a nontechnical discussion of the implications ofbiochemistry's discoveries.
So the hard stuff is confined mostly to Part II. In that section, however, I
liberally use analogies to familiar, everyday objects to get the ideas across,and even in that section detailed descriptions of biochemical systems areminimized. Paragraphs that contain the heaviest doses of details—repletewith eye-glazing technical terms—are set off from the regular text with theornament  to brace the reader. Some readers may plow right through Part
II. Others, however, may wish to skim the section or even skip parts, thenreturn when they're ready to absorb more. For those who want a deeper
understanding of biochemistry, I have included an Appendix outliningsome general biochemical principles. I encourage those who want all thedetails to borrow an introductory biochemistry text from the library.

DARWIN'S BLACK BOX

PART I

THE BOX IS OPENEDCHAPTER 1

LILIPUTIAN BIOLOGY
THE LIMITS OF AN IDEAThis book is about an idea—Darwinian evolution—that is being pushed
to its limits by discoveries in biochemistry. Biochemistry is the study ofthe very basis of life: the molecules that make up cells and tissues, thatcatalyze the chemical reactions of digestion, photosynthesis, immunity,and more.1 The astonishing progress made by biochemistry since the mid1950s is a monumental tribute to science's power to understand the world.
It has brought many practical benefits in medicine and agriculture. We
may have to pay a price, though, for our knowledge. When foundations
are unearthed, the structures that rest on them are shaken; sometimes
they collapse. When sciences such as physics finally uncovered theirfoundations, old ways of understanding the world had to be tossed out,
extensively revised, or restricted to a limited part of nature. Will thishappen to the theory of evolution by natural selection?
Like many great ideas, Darwin's is elegantly simple. He observed that
there is variation in all species: some members are bigger, some smaller,
some faster, some lighter in color, and so forth. He reasoned that sincelimited food supplies could not support all organisms that3

4 THE BOX IS OPENED
are born, the ones whose chance variation gave them an advantage in the
struggle for life would tend to survive and reproduce, outcompet-ing theless favored ones. If the variation were inherited, then the characteristicsof the species would change over time; over great periods, great changes
might occur.
For more than a century most scientists have thought that virtually allof life, or at least all of its most interesting features, resulted from natural
selection working on random variation. Darwin's idea has been used to
explain finch beaks and horse hoofs, moth coloration and insect slaves,and the distribution of life around the globe and through the ages. The
theory has even been stretched by some scientists to interpret humanbehavior: why desperate people commit suicide, why teenagers have babies
out of wedlock, why some groups do better on intelligence tests than othergroups, and why religious missionaries forgo marriage and children. Thereis nothing—no organ or idea, no sense or thought—that has not been thesubject of evolutionary rumination.
Almost a century and a half after Darwin proposed his theory,
evolutionary biology has had much success in accounting for patterns oflife we see around us. To many, its triumph seems complete. But the real
work of life does not happen at the level of the whole animal or organ; themost important parts of living things are too small to be seen. Life is lived
in the details, and it is molecules that handle life's details. Darwin's idea
might explain horse hoofs, but can it explain life's foundation?
Shortly after 1950 science advanced to the point where it could
determine the shapes and properties of a few of the molecules that makeup living organisms. Slowly, painstakingly, the structures of more andmore biological molecules were elucidated, and the way they work inferredfrom countless experiments. The cumulative results show with piercing
clarity that life is based on machines—machines made of molecules!
Molecular machines haul cargo from one place in the cell to another along«highways» made of other molecules, while still others act as cables, ropes,
and pulleys to hold the cell in shape. Machines turn cellular switches on
and off, sometimes killing the cell or causing it to grow. Solar-poweredmachines capture the energy of photons and store it in chemicals. Electricalmachines

LILIPUTIAN BIOLOGY 5
allow current to flow through nerves. Manufacturing machines build
other molecular machines, as well as themselves. Cells swim using
machines, copy themselves with machinery, ingest food with machinery.
In short, highly sophisticated molecular machines control every cellular
process. Thus the details of life are finely calibrated, and the machinery oflife enormously complex.
Can all of life be fit into Darwin's theory of evolution? Because thepopular media likes to publish exciting stories, and because some scientists
enjoy speculating about how far their discoveries might go, it has beendifficult for the public to separate fact from conjecture. To find the real
evidence you have to dig into the journals and books published by thescientific community itself. The scientific literature reports experiments
firsthand, and the reports are generally free of the flights of fancy thatmake their way into the spinoffs that follow. But as I will note later, if you
search the scientific literature on evolution, and if you focus your searchon the question of how molecular machines— the basis of life—developed,
you find an eerie and complete silence. The complexity of life's foundation
has paralyzed science's attempt to account for it; molecular machines raise
an as-yet-impenetrable barrier to Darwinism's universal reach. To find out
why, in this book I will examine several fascinating molecular machines,
then ask whether they can ever be explained by random mutation/natural
selection.
Evolution is a controversial topic, so it is necessary to address a few
basic questions at the beginning of the book. Many people think thatquestioning Darwinian evolution must be equivalent to espousing
creationism. As commonly understood, creationism involves belief in an
earth formed only about ten thousand years ago, an interpretation of the
Bible that is still very popular. For the record, I have no reason to doubtthat the universe is the billions of years old that physicists say it is. Further,
I find the idea of common descent (that all organisms share a common
ancestor) fairly convincing, and have no particular reason to doubt it. I
greatly respect the work of my colleagues who study the development andbehavior of organisms within an evolutionary framework, and I think thatevolutionary biologists have contributed enormously to our understandingof the world. Although Darwin's mechanism—natural selection working
on variation—might explain many things, however, I do not believe it
explains molecular life. I also do6 THE BOX IS OPENED
not think it surprising that the new science of the very small mightchange the way we view the less small.

A VERY BRIEF HISTORY OF BIOLOGYWhen things are going smoothly in our lives most of us tend to thinkthat the society we live in is «natural,» and that our ideas about the world
are self-evidently true. It's hard to imagine how other people in othertimes and places lived as they did or why they believed the things theydid. During periods of upheaval, however, when apparently solid verities
are questioned, it can seem as if nothing in the world makes sense. During
those times history can remind us that the search for reliable knowledge isa long, difficult process that has not yet reached an end. In order to develop
a perspective from which we can view the idea of Darwinian evolution,over the next few pages I will very briefly outline the history of biology.
In a way, this history has been a chain of black boxes; as one is opened,
another is revealed.
Black box is a whimsical term for a device that does something, butwhose inner workings are mysterious—sometimes because the workings
can't be seen, and sometimes because they just aren't comprehensible.
Computers are a good example of a black box. Most of us use these marvelous
machines without the vaguest idea of how they work, processing words orplotting graphs or playing games in contented ignorance of what is goingon underneath the outer case. Even if we were to remove the cover, though,few of us could make heads or tails of the jumble of pieces inside. There isno simple, observable connection between the parts of the computer andthe things that it does.
Imagine that a computer with a long-lasting battery was transported
back in time a thousand years to King Arthur's court. How would peopleof that era react to a computer in action? Most would be in awe, but withluck someone might want to understand the thing. Someone might noticethat letters appeared on the screen as he or she touched the keys. Some
combinations of letters—corresponding to computer commands—mightmake the screen change; after a while, many commands would be figuredout. Our medieval Englishmen might believe they had unlocked thesecrets of the computer. But eventually somebody would remove the coverand gaze on the computer's inner workings. Suddenly the theory of «howa computer works» would be revealed as profoundly naive. The black box
that had been slowly decoded would have exposed another black box.

LILIPUTIAN BIOLOGY 7
In ancient times all of biology was a black box, because no one
understood on even the broadest level how living things worked. The
ancients who gaped at a plant or animal and wondered just how the thingworked were in the presence of unfathomable technology. They were truly
in the dark.
The earliest biological investigations began in the only way they could—
with the naked eye.2 A number of books from about 400 B.C. (attributed
to Hippocrates, the «father of medicine») describe the symptoms ofsome common diseases and attribute sickness to diet and other physicalcauses, rather than to the work of the gods. Although the writings were abeginning, the ancients were still lost when it came to the composition ofliving things. They believed that all matter was made up of four elements:
earth, air, fire, and water. Living bodies were thought to be made of four
«humors»—blood, yellow bile, black bile, and phlegm— and all disease
supposedly arose from an excess of one of the humors.
The greatest biologist of the Greeks was also their greatest philosopher,
Aristotle. Bom when Hippocrates was still alive, Aristotle realized(unlike almost everyone before him) that knowledge of nature requires
systematic observation. Through careful examination he recognized an
astounding amount of order within the living world, a crucial first step.
Aristotle grouped animals into two general categories—those with blood,and those without—that correspond closely to the modem classificationsof vertebrate and invertebrate. Within the vertebrates he recognized thecategories of mammals, birds, and fish. He put most amphibians andreptiles in a single group, and snakes in a separate class. Even though hisobservations were unaided by instruments, much of Aristotle's reasoning
remains sound despite the knowledge gained in the thousands of years
since he died.
Only a few significant biological investigators lived during themillennium following Aristotle. One of them was Galen, a second-century
A.D. physician in Rome. Galen's work shows that careful observation of theoutside and (with dissection) the inside of plants and animals, althoughnecessary, is not sufficient to comprehend biology. For example, Galen
tried to understand the function of animal organs. Although he knew thatthe heart pumped blood, he could not tell just from looking that the blood
circulated and returned to the heart.
Galen mistakenly thought that blood was pumped out to «irrigate» thetissues, and that new blood was made continuously to resupply the heart.

8 THE BOX IS OPENEDHis idea was taught for nearly fifteen hundred years.
It was not until the seventeenth century that an Englishman, William
Harvey, introduced the theory that blood flows continuously in one
direction, making a complete circuit and returning to the heart. Harvey
calculated that if the heart pumps out just two ounces of blood per beat,at 72 beats per minute, in one hour it would have pumped 540 pounds ofblood—triple the weight of a man! Since making that much blood in soshort a time is clearly impossible, the blood had to be reused. Harvey's
logical reasoning (aided by the still-new Arabic numerals, which madecalculating easy) in support of an unobservable activity was unprecedented;
it set the stage for modern biological thought.
In the Middle Ages the pace of scientific investigation quickened. The
example set by Aristotle had been followed by increasing numbers ofnaturalists. Many plants were described by the early botanists Brunfels,
Bock, Fuchs, and Valerius Cordus. Scientific illustration developed as
Rondelet drew animal life in detail. The encyclopedists, such as Conrad
Gesner, published large volumes summarizing all of biological knowledge.
Linnaeus greatly extended Aristotle's work of classification, inventing
the categories of class, order, genus, and species. Studies of comparative
biology showed many similarities between diverse branches of life, and theidea of common descent began to be discussed.
Biology advanced rapidly in the seventeenth and eighteenth centuries
as scientists combined Aristotle's and Harvey's examples of attentive
observation and clever reasoning. Yet even the strictest attention andcleverest reasoning will take you only so far if important parts of a systemaren't visible. Although the human eye can resolve objects as small as onetenth of a millimeter, a lot of the action in life occurs on a micro level, aLilliputian scale. So biology reached a plateau: One black box, the grossstructure of organisms, was opened only to reveal the black box of thefiner levels of life. In order to proceed further biology needed a series oftechnological breakthroughs. The first was the microscope.

BLACK BOXES WITHIN BLACK BOXES

Lenses were known in ancient times, and by the fifteenth century theiruse in spectacles was common. It was not until the seventeenth century,
however, that a convex and a concave lens were put together in a tube toform the first crude microscope. Galileo used one of the first instruments,and he was amazed to discover the compound eyes of insects. Stelluti

LILIPUTIAN BIOLOGY 9looked at the eyes, tongue, antennae, and other parts of bees and weevils.
Malpighi confirmed the circulation of the blood through capillaries and hedescribed the early development of the embryonic chick heart. Nehemiah
Grew inspected plants; Swammeniam dissected the mayfly; Leeuwenhoek
was the first person ever to see a bacterial cell; and Robert Hooke described
cells in cork and leaves (although their importance escaped him.)
The discovery of an unanticipated Lilliputian world had begun,
overturning settled notions of what living things are. Charles Singer, thehistorian of science, noted that «the infinite complexity of living things
thus revealed was as philosophically disturbing as the ordered majestyof the astronomical world which Galileo had unveiled to the previous
generation, though it took far longer for its implications to sink into men's
minds.» In other words, sometimes the new boxes demand that we revise
all of our theories. In such cases, great unwillingness can arise.
The cell theory of life was finally put forward in the early nineteenth
century by Matthias Schleiden and Theodor Schwann. Schleiden worked
primarily with plant tissue; he argued for the central importance of a dark
spot—the nucleus—within all cells. Schwann concentrated on animal
tissue, in which it was harder to see cells. Nonetheless he discernedthat animals were similar to plants in their cellular structure. Schwann
concluded that cells or the secretions of cells compose the entire bodies
of animals and plants, and that in some way the cells are individual units
with a life of their own. He wrote that «the question as to the fundamental
power of organized bodies resolves itself into that of individual cells.» As
Schleiden added, «Thus the primary question is, what is the origin of thispeculiar little organism, the cell?»Schleiden and Schwann worked in the early to middle 1800s—the timeof Darwin's travels and the writing of The Origin of Species. To Darwin,
then, as to every other scientist of the time, the cell was a black box.
Nonetheless he was able to make sense of much biology above the levelof the cell. The idea that life evolves was not original with Darwin, but heargued it by far the most systematically, and the theory of how evolution
works—by natural selection working on variation—was his own.

10 THE BOX IS OPENED
Meanwhile, the cellular black box was steadily explored. The
investigation of the cell pushed the microscope to its limits, which are
set by the wavelength of light. For physical reasons a microscope cannot
resolve two points that are closer together than approximately one-half of
the wavelength of the light that is illuminating them. Since the wavelengthof visible light is roughly one-tenth the diameter of a bacterial cell, manysmall, critical details of cell structure simply cannot be seen with a lightmicroscope. The black box of the cell could not be opened without further
technological improvements.
In the late nineteenth century, as physics progressed rapidly,
J. J. Thomson discovered the electron; the invention of the electron
microscope followed several decades later. Because the wavelength ofthe electron is shorter than the wavelength of visible light, much smaller
objects can be resolved if they are «illuminated» with electrons. Electron
microscopy has a number of practical difficulties, not least of which is thetendency of the electron beam to fry the sample. But ways were foundto get around the problems, and after World War II electron microscopy
came into its own. New subcellular structures were discovered: Holes wereseen in the nucleus, and double membranes detected around mitochondria(a cell's power plants). The same cell that looked so simple under a lightmicroscope now looked much different. The same wonder that the earlylight microscopists felt when they saw the detailed structure of insects wasagain felt by twentieth-century scientists when they saw the complexitiesof the cell.
This level of discovery began to allow biologists to approach thegreatest black box of all. The question of how life works was not one thatDarwin or his contemporaries could answer. They knew that eyes were
for seeing—but how, exactly, do they see? How does blood clot? How does
the body fight disease? The complex structures revealed by the electron
microscope were themselves made of smaller components. What were
those components? What did they look like? How did they work? The
answers to these questions take us out of the realm of biology and into
chemistry. They also take us back into the nineteenth century.

LILIPUTIAN BIOLOGY 11

THE CHEMISTRY OF LIFEAs anyone can readily see, living things look different from nonliving
things. They act different. They feel different, too: Hide and hair canbe distinguished easily from rocks and sand. Most people up until thenineteenth century quite naturally thought that life was made of a special
kind of material, one different from the material that composed inanimate
objects. But in 1828 Friedrich Wohler heated ammonium cyanate and wasamazed to find that urea, a biological waste product, was formed. The
synthesis of urea from nonliving material shattered the easy distinction
between life and nonlife, and the inorganic chemist Justus von Liebig thenbegan to study the chemistry of life (or biochemistry). Liebig showed thatthe body heat of animals is due to the combustion of food; it is not simply
an innate property of life. From his successes he formulated the idea of
metabolism, whereby the body builds up and breaks down substances
through chemical processes. Ernst Hoppe-Seyler crystallized the redmaterial from blood (hemoglobin) and showed that it attaches to oxygen inorder to carry the latter throughout the body. Emil Fischer demonstrated
that the large class of substances called proteins all were constituted fromonly twenty types of building blocks (called amino acids) joined into
chains.
What do proteins look like? Although Emil Fischer showed that they
were made of amino acids, the details of their structures were unknown.
Their size put them below the reach of even electron microscopy, yet it
was becoming clear that proteins were the fundamental machines of life,
catalyzing the chemistry and building the structures of the cell. A newtechnique therefore was needed to study protein structure.
During the first part of the twentieth century, X-ray crystallography
was used to determine the structures of small molecules. Crystallography
involves shining a beam of X-rays onto a crystal of a chemical; the rays
scatter by a process called diffraction. If photographic film is placed behindthe crystal, then the diffracted X-rays can be detected by examining theexposed film. The pattern of diffraction can, after the application ofstrenuous mathematics, indicate the position of each and every atom inthe molecule. Turning the guns of X-ray crystallography onto proteinswould show their structure, but there was a big

12 THE BOX IS OPENED
problem: the more atoms in a molecule, the harder the mathematics, andthe harder the task of crystallizing the chemical in the first place. Because
proteins have dozens of times more atoms than the molecules typicallyexamined by crystallography, that makes the problem dozens of times
more difficult. But some people have dozens of times more perseverance
than the rest of us.
In 1958, after decades of work, J. С. Kendrew determined the structureof the protein myoglobin using X-ray crystallography; finally, a technique
showed the detailed structure of one of the basic components of life. And
what was seen? Once again, more complexity. Before the determinationof myoglobin's structure, it was thought that proteins would turn out tobe simple and regular structures, like salt crystals. Upon observing theconvoluted, complicated, bowel-like structure of myoglobin, however, Max
Perutz groaned, «Could the search for ultimate truth really have revealed
so hideous and visceral-looking an object?» Biochemists have since grown
to like the intricacies of protein structure. Improvements in computersand other instruments make crystallography a lot easier today than it wasfor Kendrew, although it still requires substantial effort.
As the result of the X-ray work of Kendrew on proteins and (mostfamously) Watson and Crick on DNA, for the first time biochemists
actually knew the shapes of the molecules that they were working on. The
beginning of modem biochemistry, which has progressed at a breakneck
pace since, can be dated to that time. Advances in physics and chemistry,
too, have spilled over and created a strong synergism for research on life.
Although in theory X-ray crystallography can determine the structureof all the molecules of living things, practical problems limit its use toa relatively small number of proteins and nucleic acids. New techniques,though, have been introduced at a dizzying pace to complement andsupplement crystallography. One important technique for determining
structure is called nuclear magnetic resonance (NMR). With NMR amolecule can be studied while in solution—it doesn't have to be tediously
crystallized. Like X-ray crystallography, NMR can determine the exact
structure of proteins and nucleic acids. Also like crystallography, NMR
has limitations that make it usable only with a portion of known proteins.
But together NMR and X-ray crystallogra-

LILIPUTIAN BIOLOGY 13
phy have been able to solve the structures of enough proteins to givescientists a detailed understanding of what they look like.
When Leeuwenhoek used a microscope to see a tinier mite on a tiny
flea, it inspired Jonathan Swift to write a ditty anticipating an endlessprocession of smaller and smaller bugs:
So naturalists observe, a flea
Has smaller fleas that on him prey;
And these have smaller still to bite 'em;
And so proceed ad infinitum.
Swift was wrong; the procession does not go on forever. In the latetwentieth century we are in the flood tide of research on life, and the end
is in sight. The last remaining black box was the cell, which was opened toreveal molecules—the bedrock of nature. Lower we cannot go. Moreover,
the work that has already been done on enzymes, other proteins, andnucleic acids has illuminated the principles at work at the ground level oflife. Many details remain to be filled in, and some surprises undoubtedly
remain. But unlike earlier scientists, who looked at a fish or a heart or acell and wondered what it was and what made it work, modem scientists
are satisfied that the actions of proteins and other molecules are sufficient
explanations for the basis of life. From Aristotle to modern biochemistry,
one layer after another has been peeled away until the cell—Darwin's blackbox—stands open.

LITTLE JUMPS, BIG JUMPSSuppose a 4-foot-wide ditch in your backyard, running to the horizon
in both directions, separates your property from that of your neighbor's. If
one day you met him in your yard and asked how he got there, you would
have no reason to doubt the answer, «I jumped over the ditch.» If the ditch
were 8 feet wide and he gave the same answer, you would be impressedwith his athletic ability. If the ditch were 15 feet wide, you might become
suspicious and ask him to jump again while you watched; if he declined,
pleading a sprained knee, you would harbor your doubts but wouldn't becertain that he was just telling a tale. If the «ditch» were actually a canyon
100 feet wide, how-

14 THE BOX IS OPENED
ever, you would not entertain for a moment the bald assertion that hejumped across.
But suppose your neighbor—a clever man—qualifies his claim. He
did not come across in one jump. Rather, he says, in the canyon there
were a number of buttes, no more than 10 feet apart from one another;he jumped from one narrowly spaced butte to another to reach your side.
Glancing toward the canyon, you tell your neighbor that you see no buttes,
just a wide chasm separating your yard from his. He agrees, but explainsthat it took him years and years to come over. During that time buttes
occasionally arose in the chasm, and he progressed as they popped up.
After he left a butte it usually eroded pretty quickly and crumbled backinto the canyon. Very dubious, but with no easy way to prove him wrong,
you change the subject to baseball.
This little story teaches several lessons. First, the word jump can beoffered as an explanation of how someone crossed a barrier; but the
explanation can range from completely convincing to totally inadequate
depending on details (such as how wide the barrier is). Second, long
journeys can be made much more plausible if they are explained as а seriesof smaller jumps rather than one great leap. And third, in the absence ofevidence of such smaller jumps, it is very difficult to prove right or wrong
someone who asserts that stepping stones existed in the past but havedisappeared.
Of course, the allegory of jumps across narrow ditches versus canyons
can be applied to evolution. The word evolution has been invoked to explaintiny changes in organisms as well as huge changes. These are often given
separate names: Roughly speaking, microevolution describes changes
that can be made in one or a few small jumps, whereas macroevolution
describes changes that appear to require large jumps.
The proposal by Darwin that even relatively tiny changes could occur
in nature was a great conceptual advance; the observation of such changes
was a hugely gratifying confirmation of his intuition. Darwin saw similar
but not identical species of finches on the various Galapagos Islands andtheorized that they descended from a common ancestor. Recently somescientists from Princeton actually observed the average beak size of finch
populations changing over the course of a few years.3 Earlier it was shownthat the numbers of dark- versus light-colored moths in a population
changed as the environment went

LILIPUTIAN BIOLOGY 15
from sooty to clean. Similarly, birds introduced into North America by
European settlers have diversified into several distinct groups. In recent
decades it has been possible to gain evidence for microevolution on amolecular scale. For instance, viruses such as the one that causes AIDS
mutate their coats in order to evade the human immune system. Diseasecausing bacteria have made a comeback as strains evolved the ability to
defend against antibiotics. Many other examples could be cited.
On a small scale, Darwin's theory has triumphed; it is now about as
controversial as an athlete's assertion that he or she could jump over afour-foot ditch. But it is at the level of macroevolution—of large jumps—
that the theory evokes skepticism. Many people have followed Darwin inproposing that huge changes can be broken down into plausible, small steps
over great periods of time. Persuasive evidence to support that position,
however, has not been forthcoming. Nonetheless, like a neighbor's story
about vanishing buttes, it has been difficult to evaluate whether the elusive
and ill-defined small steps could exist... until now.
With the advent of modem biochemistry we are now able to look at therock-bottom level of life. We can now make an informed evaluation ofwhether the putative small steps required to produce large evolutionarychanges can ever get small enough. You will see in this book that thecanyons separating everyday life forms have their counterparts in thecanyons that separate biological systems on a microscopic scale. Likea fractal pattern in mathematics, where a motif is repeated even as you
look at smaller and smaller scales, unbridgeable chasms occur even at thetiniest level of life.

A SERIES OF EYES

Biochemistry has pushed Darwin's theory to the limit. It has done
so by opening the ultimate black box, the cell, thereby making possible
our understanding of how life works. It is the astonishing complexity ofsubcellular organic structures that has forced the question, How could all
this have evolved? To feel the brunt of the question—and to get a taste ofwhat's in store for us—let's look at an example of a biochemical system. An
explanation for the origin of a function must keep pace with contemporary
science. Let's see how science's explanation

16 THE BOX IS OPENED
for one function, vision, has progressed since the nineteenth century,then ask how that affects our task of explaining its origin.
In the nineteenth century, the anatomy of the eye was known in detail.
The pupil of the eye, scientists knew, acts as a shutter to let in enough light
to see in either brilliant sunlight or nighttime darkness. The lens of theeye gathers light and focuses it on the retina to form a sharp image. The
muscles of the eye allow it to move quickly. Different colors of light, withdifferent wavelengths, would cause a blurred image, except that the lens of
the eye changes density over its surface to correct for chromatic aberration.
These sophisticated methods astounded everyone who was familiar withthem. Scientists of the nineteenth century knew that if a person lacked anyof the eye's many integrated features, the result would be a severe loss ofvision or outright blindness. They concluded that the eye could function
only if it were nearly intact.
Charles Darwin knew about the eye, too. In The Origin of Species Darwin
dealt with many objections to his theory of evolution by natural selection.
He discussed the problem of the eye in a section of the book appropriately
entitled «Organs of Extreme Perfection and Complication.» In Darwin's
thinking, evolution could not build a complex organ in one step or a few
steps; radical innovations such as the eye would require generations oforganisms to slowly accumulate beneficial changes in a gradual process.
He realized that if in one generation an organ as complex as the eye
suddenly appeared, it would be tantamount to a miracle. Unfortunately,
gradual development of the human eye appeared to be impossible, since
its many sophisticated features seemed to be interdependent. Somehow,
for evolution to be believable, Darwin had to convince the public thatcomplex organs could be formed in a step-by-step process.
He succeeded brilliantly. Cleverly, Darwin didn't try to discover areal pathway that evolution might have used to make the eye. Rather, hepointed to modem animals with different kinds of eyes (ranging from thesimple to the complex) and suggested that the evolution of the human eye
might have involved similar organs as intermediates (Figure 1-1).
Here is a paraphrase of Darwin's argument: Although humans havecomplex camera-type eyes, many animals get by with less. Some tiny
creatures have just a simple group of pigmented cells—not much

LILIPUTIAN BIOLOGY 17
more than a light-sensitive spot. That simple arrangement can hardly
be said to confer vision, but it can sense light and dark, and so it meets thecreature's needs. The light-sensing organ of some starfishes is somewhat
more sophisticated. Their eye is located in a depressed region. Since thecurvature of the depression blocks off light from some directions, theanimal can sense which direction the light is coming from. The directional
sense of the eye improves if the curvature becomes more pronounced,
but more curvature also lessens the amount of light that enters the eye,decreasing its sensitivity. The sensitivity can be increased by placementof gelatinous material in the cavity to act as a lens; some modern animals
have eyes with such
FIGURE 1-1
A series of eyes. (Left) A simple patch of photoreceptors,
such as may be found in jellyfish. (Right) A cupped eye foundin marine limpets. (Bottom) An eye with a lens, from a marine
snail.

18 THE BOX IS OPENED
crude lenses. Gradual improvements in the lens could then provide
increasingly sharp images to meet the requirements of the animal's
environment.
Using reasoning like this, Darwin convinced many of his readersthat an evolutionary pathway leads from the simplest light-sensitive spot
to the sophisticated camera-eye of man. But the question of how vision
began remained unanswered. Darwin persuaded much of the world that amodern eye evolved gradually from a simpler structure, but he did not even
try to explain where his starting point—the relatively simple light-sensitive
spot—came from. On the contrary, Darwin dismissed the question of theeye's ultimate origin: «How a nerve comes to be sensitive to light hardly
concerns us more than how life itself originated.»4
He had an excellent reason for declining the question: it was completely
beyond nineteenth-century science. How the eye works—that is, what
happens when a photon of light first hits the retina—simply could not beanswered at that time. As a matter of fact, no question about the underlying
mechanisms of life could be answered. How did animal muscles cause
movement? How did photosynthesis work? How was energy extracted
from food? How did the body fight infection? No one knew.

THE VISION OF BIOCHEMISTRY

To Darwin, vision was a black box, but after the cumulative hard workof many biochemists, we are now approaching answers to the questionof sight.5 The following five paragraphs give a biochemical sketch of
the eye's operation. (Note: These technical paragraphs are set off by
 at the beginning and end.) Don't be put off by the strange names of
the components. They're just labels, no more esoteric than carburetor
or differential are to someone reading a car manual for the first time.
Readers with an appetite for detail can find more information in manybiochemistry textbooks; others may wish to tread lightly, and/or refer toFigures 1-2 and 1-3 for the gist.
 When light first strikes the retina a photon interacts with a molecule
called 11-cis-retinal, which rearranges within picoseconds to trans-retinal.
(A picosecond is about the time it takes light toLILIPUTIAN BIOLOGY 19
FIGURE 1-2
The first step in vision. A photon of light causes a change inthe shape of a small organic molecule, retinal. This forcesa change in the shape of the much larger protein, rhodopsin,to which it is attached. The cartoon drawing of the protein
is not to scale.

travel the breadth of a single human hair.) The change in the shape ofthe retinal molecule forces a change in the shape of the protein, rhodopsin,to which the retinal is tightly bound. The protein's metamorphosis alters
its behavior. Now called metarhodopsin II, the protein sticks to anotherprotein, called transducin. Before bumping into metarhodopsin II,transducin had tightly bound a small molecule called GDP. But whentransducin interacts with

20 THE BOX IS OPENED
Figure 1-3
The biochemistry of vision. Rh, rhodopsin; Rhk, rhodopsin
kinase; A, arrestin; GC, guanylate cyclase; T, transducin;
PDE, phosphodiesterase.

metarhodopsin II, the GDP falls off, and a molecule called GTP binds totransducin. (GTP is closely related to, but critically different from, GDP.)
GTP-transducin-metarhodopsin II now binds to a protein called
phosphodiesterase, located in the inner membrane of the cell. When
attached to metarhodopsin II and its entourage, the phosphodiesterase
acquires the chemical ability to «cut» a molecule called cGMP (a chemical
relative of both GDP and GTP). Initially there are a lot of cGMP moleculesin the cell, but the phosphodiesterase lowers its concentration, just as apulled plug lowers the water level in a bathtub.

LILIPUTIAN BIOLOGY 21
Another membrane protein that binds cGMP is called an ion channel.
It acts as a gateway that regulates the number of sodium ions in the cell.
Normally the ion channel allows sodium ions to flow into the cell, while
a separate protein actively pumps them out again. The dual action of theion channel and pump keeps the level of sodium ions in the cell within anarrow range. When the amount of cGMP is reduced because of cleavage
by the phosphodiesterase, the ion channel closes, causing the cellularconcentration of positively charged sodium ions to be reduced. This causes
an imbalance of charge across the cell membrane that, finally, causes acurrent to be transmitted down the optic nerve to the brain. The result,when interpreted by the brain, is vision.
If the reactions mentioned above were the only ones that operated in
the cell, the supply of 11-cis-retinal, cGMP and sodium ions would quickly
be depleted. Something has to turn off the proteins that were turned on
and restore the cell to its original state. Several mechanisms do this. First,
in the dark the ion channel (in addition to sodium ions) also lets calcium
ions into the cell. The calcium is pumped back out by a different protein sothat a constant calcium concentration is maintained. When cGMP levels
fall, shutting down the ion channel, calcium ion concentration decreases,
too. The phosphodiesterase enzyme, which destroys cGMP slows down atlower calcium concentration. Second, a protein called guanylate cyclase
begins to resynthesize cGMP when calcium levels start to fall. Third,
while all of this is going on, metarhodopsin II is chemically modified byan enzyme called rhodopsin kinase. The modified rhodopsin then binds toa protein known as arrestin, which prevents the rhodopsin from activating
more transducin. So the cell contains mechanisms to limit the amplified
signal started by a single photon.
Trans-retinal eventually falls off of rhodopsin and must be reconverted
to 11-cis-retinal and again bound by rhodopsin to get back to the starting
point for another visual cycle. To accomplish this, trans-retinal is firstchemically modified by an enzyme to trans-retinol—a form containing
two more hydrogen atoms. A second enzyme then converts the molecule
to 11-cis-retinol. Finally, a third enzyme removes the previously addedhydrogen atoms to form 11-cis-rennal, a cycle is complete. 22 THE BOX IS OPENEDThe above explanation is just a sketchy overview of the biochemistryof vision. Ultimately, though, this is the level of explanation for whichbiological science must aim. In order to truly understand a function, onemust understand in detail every relevant step in the process. The relevant
steps in biological processes occur ultimately at the molecular level, so
a satisfactory explanation of a biological phenomenon—such as sight,
digestion, or immunity—must include its molecular explanation.
Now that the black box of vision has been opened, it is no longer
enough for an evolutionary explanation of that power to consider only
the anatomical structures of whole eyes, as Darwin did in the nineteenth
century (and as popularizers of evolution continue to do today). Each of
the anatomical steps and structures that Darwin thought were so simple
actually involves staggeringly complicated biochemical processes thatcannot be papered over with rhetoric. Darwin's metaphorical hops frombutte to butte are now revealed in many cases to be huge leaps between
carefully tailored machines—distances that would require a helicopter tocross in one trip.
Thus biochemistry offers a Lilliputian challenge to Darwin. Anatomyis, quite simply, irrelevant to the question of whether evolution could takeplace on the molecular level. So is the fossil record. It no longer matterswhether there are huge gaps in the fossil record or whether the record
is as continuous as that of U.S. presidents. And if there are gaps, it does
not matter whether they can be explained plausibly.6 The fossil record
has nothing to tell us about whether the interactions of ll-ris-retinal withrhodopsin, transducin, and phosphodiesterase could have developed
step-by-step. Neither do the patterns of biogeography matter, nor thoseof population biology, nor the traditional explanations of evolutionary
theory for rudimentary organs or species abundance. This is not to say that
random mutation is a myth, or that Darwinism fails to explain anything(it explains microevolution very nicely), or that large-scale phenomena
like population genetics don't matter. They do. Until recently, however,
evolutionary biologists could be unconcerned with the molecular detailsof life because so little was known about them. Now the black box of thecell has been opened, and the infinitesmal world that stands revealed must
be explained.

LILIPUTIAN BIOLOGY 23

CALVINISM

It seems to be characteristic of the human mind that when it sees a
black box in action, it imagines that the contents of the box are simple.
A happy example is seen in the comic strip «Calvin and Hobbes» (Figure1-4). Calvin is always jumping in a box with his stuffed tiger, Hobbes, andtraveling back in time, or «transmogrifying» himself into animal shapes,
or using it as a «duplicator» and making clones of him-self. A little boy like
Calvin easily imagines that a box can fly like an airplane (or something),
because Calvin doesn't know how airplanes work.
In some ways, grown-up scientists are just as prone to wishful thinking
as little boys like Calvin. For example, centuries ago it was thought that
insects and other small animals arose directly from spoiled food. Thiswas easy to believe, because small animals were thought to be very simple(before the invention of the microscope, naturalists thought that insects
had no internal organs.) But as biology progressed and careful experiments
showed that protected food did not breed life, the theory of spontaneous
generation retreated to the limits beyond which science could not detect
what was really happening. In the nineteenth century that meant the cell.
When beer, milk, or urine were allowed to sit for several days in containers,
even closed ones, they always became cloudy from something growing inthem.
FIGURE 1-4
CALVIN AND HOBBES FLY IN THEIR BLACK BOX.

24 THE BOX IS OPENEDThe microscopes of the eighteenth and nineteenth centuries showedthat the growth was very small, apparently living cells. So it seemed
reasonable that simple living organisms could arise spontaneously fromliquids.
The key to persuading people was the portrayal of the cells as «simple.»
One of the chief advocates of the theory of spontaneous generation during
the middle of the nineteenth century was Ernst Haeckel, a great admirerof Darwin and an eager popularizer of Darwin's theory. From the limited
view of cells that microscopes provided, Haeckel believed that a cell wasa «simple little lump of albuminous combination of carbon,»7 not muchdifferent from a piece of microscopic Jell-O. So it seemed to Haeckel thatsuch simple life, with no internal organs, could be produced easily frominanimate material. Now, of course, we know better.
Here is a simple analogy: Darwin is to our understanding of the originof vision as Haeckel is to our understanding of the origin of life. In bothcases brilliant nineteenth-century scientists tried to explain Lilliputian
biology that was hidden from them, and both did so by assuming that theinside of the black box must be simple. Time has proven them wrong.
In the first half of the twentieth century, the many branches of
biology did not often communicate with each other.8 As a result genetics,
systematics, paleontology, comparative anatomy, embryology, and otherareas developed their own views of what evolution meant. Inevitably,
evolutionary theory began to mean different things to different disciplines;
a coherent view of Darwinian evolution was being lost. In the middle of the
century, however, leaders of the fields organized a series of interdisciplinary
meetings to combine their views into a coherent theory of evolution basedon Darwinian principles. The result has been called the «evolutionary
synthesis,» and the theory called neo-Darwinism. Neo-Darwinism is thebasis of modern evolutionary thought.
One branch of science was not invited to the meetings, and for goodreason: it did not yet exist. The beginnings of modem biochemistry came
only after neo-Darwinism had been officially launched. Thus, just as
biology had to be reinterpreted after the complexity of microscopic life
was discovered, neo-Darwinism must be reconsidered in

LILIPUTIAN BIOLOGY 25
light of advances in biochemistry. The scientific disciplines that were partof the evolutionary synthesis are all nonmolecular. Yet for the Darwinian
theory of evolution to be true, it has to account for the molecular structureof life. It is the purpose of this book to show that it does not.

CHAPTER 2

NUTS AND BOLTS

THE NATIVES ARE RESTLESS

Lynn Margulis is Distinguished University Professor of Biology at the
University of Massachusetts. Lynn Margulis is highly respected for her
widely accepted theory that mitochondria, the energy source of plant andanimal cells, were once independent bacterial cells. And Lynn Margulis
says that history will ultimately judge neo-Darwinism as «a minor
twentieth-century religious sect within the sprawling religious persuasionof Anglo-Saxon biology.»1 At one of her many public talks she asks themolecular biologists in the audience to name a single, unambiguous
example of the formation of a new species by the accumulation of
mutations. Her challenge goes unmet. Proponents of the standard theory,
she says, «wallow in their zoological, capitalistic, competitive, cost-benefit
interpretation of Darwin—having mistaken him. . . . Neo-Darwinism,
which insists on (the slow accrual of mutations), is in a complete funk.»
Juicy quotes, these. And she is not alone in her unhappiness. Over the
past 130 years Darwinism, although securely entrenched, has met a steadystream of dissent both from within the scientific community and fromwithout it. In the 1940s the geneticist Richard Goldschmidt

26

NUTS AND BOLTS 27
became so disenchanted with Darwinism's explanation for the origins
of new structures that he was driven to propose the «hopeful monster»theory. Goldschmidt thought that occasionally large changes might occur
just by chance—perhaps a reptile laid an egg once, say, and from it hatcheda bird.
The hopeful-monster theory didn't catch on, but dissatisfaction with aDarwinian interpretation of the fossil record bubbled up several decades
later. Paleontologist Niles Eldredge describes the problem:2
No wonder paleontologists shied away from evolution for so long. It neverseems to happen. Assiduous collecting up cliff faces yields zigzags, minor
oscillations, and the very occasional slight accumulation of change—overmillions of years, at a rate too slow to account for all the prodigious changethat has occurred in evolutionary history. When we do see the introductionof evolutionary novelty, it usually shows up with a bang, and often with nofirm evidence that the fossils did not evolve elsewhere! Evolution cannot
forever be going on somewhere else. Yet that's how the fossil record has
struck many a forlorn paleontologist looking to learn something about
evolution.2

To try to alleviate the dilemma, in the early 1970s Eldredge and Stephen
Jay Gould proposed a theory they called «punctuated equilibrium»3 The
theory postulates two things: that for long periods most species undergo
little observable change; and that, when it does occur, change is rapid andconcentrated in small, isolated populations. If this happened, then fossil
intermediates would be hard to find, squaring with the spotty fossil record.
Like Goldschmidt, Eldredge and Gould believe in common descent but
think that a mechanism other than natural selection is needed to explain
rapid, large-scale changes.
Gould has been at the forefront of the discussion of another fascinating
phenomenon: the «Cambrian explosion.» Careful searches show only asmattering of fossils of multicellular creatures in rocks older than about
600 million years. Yet in rocks just a little bit younger is seen a profusionof fossilized animals, with a host of widely differing body plans. Recently
the estimated time over which the explosion took place has been revised
downward from 50 million years to 10 million years—a blink of the eye
in geological terms. The shorter time estimate has forced headline writers
to grope for new superlatives, a favorite being the «biological Big Bang.»
Gould has argued that the rapid

28 THE BOX IS OPENED
rate of appearance of new life forms demands a mechanism other thannatural selection for its explanation.4
Ironically, we have come full circle from Darwin's day. When Darwin
first proposed his theory a big difficulty was the estimated age of the earth.
Nineteenth-century physicists thought the earth was only about a hundred
million years old, yet Darwin thought natural selection would require
much more time to produce life. At first he was proven right; the earth
is now known to be much older. With the discovery of the biological Big
Bang, however, the window of time for life to go from simple to complex
has shrunk to much less than nineteenth-century estimates of the earth'sage.
It is not just paleontologists looking for bones, though, who aredisgruntled. A raft of evolutionary biologists examining whole organisms
wonder just how Darwinism can account for their observations. The
English biologists Mae-Wan Ho and Peter Saunders complain as follows:
It is now approximately half a century since the neo-Darwinian synthesis
was formulated. A great deal of research has been carried on within theparadigm it defines. Yet the successes of the theory are limited to theminutiae of evolution, such as the adaptive change in coloration of moths;
while it has remarkably little to say on the questions which interest us
most, such as how there came to be moths in the first place.5

University of Georgia geneticist John McDonald notes a conundrum:
The results of the last 20 years of research on the genetic basis of adaptation
has led us to a great Darwinian paradox. Those [genes] that are obviously
variable within natural populations do not seem to lie at the basis of many
major adaptive changes, while those [genes] that seemingly do constitute thefoundation of many, if not most, major adaptive changes apparently are notvariable within natural populations.6 [Emphasis in original]

Australian evolutionary geneticist George Miklos puzzles over theusefulness of Darwinism:
What then does this all-encompassing theory of evolution predict? Given a
handful of postulates, such as random mutations, and selection coefficients,
it will predict changes in [gene] frequencies over time. Is this what a grandtheory of evolution ought to be about?7

NUTS AND BOLTS 29
Jerry Coyne, of the Department of Ecology and Evolution at the
University of Chicago, arrives at an unanticipated verdict:
We conclude—unexpectedly—that there is little evidence for the neoDarwinian view: its theoretical foundations and the experimental evidence
supporting it are weak.8

And University of California geneticist John Endler ponders how
beneficial mutations arise:
Although much is known about mutation, it is still largely a «black box»
relative to evolution. Novel biochemical functions seem to be rare inevolution, and the basis for their origin is virtually unknown.9

Mathematicians over the years have complained that Darwinism's
numbers just do not add up. Information theorist Hubert Yockey argues
that the information needed to begin life could not have developed bychance; he suggests that life be considered a given, like matter or energy.10
In 1966 leading mathematicians and evolutionary biologists held asymposium at the Wistar Institute in Philadelphia because the organizer,
Martin Kaplan, had overheard «a rather weird discussion between four
mathematicians ... on mathematical doubts concerning the Darwinian
theory of evolution.»11 At the symposium one side was unhappy, and theother was uncomprehending. A mathematician who claimed that there
was insufficient time for the number of mutations apparently needed tomake an eye was told by the biologists that his figures must be wrong. The
mathematicians, though, were not persuaded that the fault was theirs. As
one said:
There is a considerable gap in the neo-Darwinian theory of evolution, andwe believe this gap to be of such a nature that it cannot be bridged with thecurrent conception of biology.12

Stuart Kauffman of the Santa Fe Institute is a leading proponent of«complexity theory.» Simply put, it proposes that many features of living
systems are the result of self-organization—the tendency of complex
systems to arrange themselves in patterns—and not natural selection:
Darwin and evolution stand astride us, whatever the muttering of creation
scientists. But is the view right? Better, is it adequate? I believe it is not. It
is not that Darwin is wrong, but that he got hold of only part of the truth.13

30 THE BOX IS OPENED
Complexity theory has so far attracted few followers but much
criticism. John Maynard Smith, under whom Kauffman did graduate
work, complains that the theory is too mathematical and is unconnected
to real-life chemistry.14 Although the complaint has merit, Smith offers nosolution to the problem which Kauffman identified—the origin of complex
systems.
All told, Darwin's theory has generated dissent from the time it was
published, and not just for theological reasons. In 1871 one of Darwin's
critics, St. George Mivart, listed his objections to the theory, many ofwhich are surprisingly similar to those raised by modern critics.
What is to be brought forward (against Darwinism) may be summed up
as follows: That «Natural Selection» is incompetent to account for theincipient stages of useful structures. That it does not harmonize with theco-existence of closely similar structures of diverse origin. That there are
grounds for thinking that specific differences may be developed suddenly
instead of gradually. That the opinion that species have definite thoughvery different limits to their variability is still tenable. That certain fossil
transitional forms are absent, which might have been expected to bepresent. ... That there are many remarkable phenomena in organic forms
upon which «Natural Selection» throws no light whatever.15

It seems, then, that the same argument has gone on without resolution
for over a century. From Mivart to Margulis, there have always beenwell-informed, respected scientists who have found Darwinism to beinadequate. Apparently, either the questions first raised by Mivart havegone unanswered, or some people have not been satisfied by the answers
they received.
Before going further we should note the obvious: if a poll were taken of
all the scientists in the world, the great majority would say they believed
Darwinism to be true. But scientists, like everybody else, base most of theiropinions on the word of other people. Of the great majority who accept
Darwinism, most (though not all) do so based on authority. Also, andunfortunately, too often criticisms have been dismissed by the scientificcommunity for fear of giving ammunition to creationists. It is ironic thatin the name of protecting science, trenchant scientific criticism of natural
selection has been brushed aside.
It is time to put the debate squarely in the open, and to disregard public
relations problems. The time for the debate is now because at

NUTS AND BOLTS 31
last we have reached the bottom of biology, and a resolution is possible.
At the tiniest levels of biology—the chemical life of the cell—we havediscovered a complex world that radically changes the grounds on which
Darwinian debates must be contested. Consider, for example, what abiochemical view does to the creationist/Darwinist debate about thebombardier beetle.

BEETLE BOMBS

The bombardier beetle is an insect of unassuming appearance,measuring about one half-inch in length. When it is threatened by anotherbug, however, the beetle has a special method of defending itself, squirtinga boiling-hot solution at the enemy out of an aperture in its hind section.16
The heated liquid scalds its target, which then usually makes other plansfor dinner. How is this trick done?
It turns out that the bombardier beetle is using chemistry. Prior to battle,
specialized structures called secretory lobes make a very concentrated
mixture of two chemicals, hydrogen peroxide and hydroquinone (Figure2-1). The hydrogen peroxide is the same material as one can buy in a
drugstore; hydroquinone is used in photographic development. The
mixture is sent into a storage chamber called the collecting vesicle.
The collecting vesicle is connected to, but ordinarily sealed off from, asecond compartment called (evocatively) the explosion chamber. The
two compartments are kept separate from one another by a duct with asphincter muscle, much like the sphincter muscles upon which humans
depend for continence. Attached to the explosion chamber are a numberof small knobs called ectodermal glands; these secrete enzyme catalysts
into the explosion chamber. When the beetle feels threatened it squeezes
muscles surrounding the storage chamber while simultaneously relaxing
the sphincter muscle. This forces the solution of hydrogen peroxide andhydroquinone to enter the explosion chamber, where it mixes with the
enzyme catalysts.
Now, chemically, things get very interesting. The hydrogen peroxide
rapidly decomposes into ordinary water and oxygen, just as a store-boughtbottle of hydrogen peroxide will decompose over time if left open. The
oxygen reacts with the hydroquinone to yield more water, plus a highly
irritating chemical called quinone. These reactions release a large quantityof heat. The temperature of the solution rises to32 THE BOX IS OPENEDFIGURE 2-1
Defensive apparatus of a bombardier beetle: B, collecting
vesicle; E, explosion chamber; G, ectodermal glands secretingcatalase; L, secretory lobes; M, sphincter muscle; O, outlet
duct. B contains a mixture of hydroquinone and hydrogen
peroxide, exploded by catalase when it passes into E.

the boiling point; in fact, a portion vaporizes into steam. The steam
and oxygen gas exert a great deal of pressure on the walk of the explosion
chamber. With the sphincter muscle now closed, a channel leading outward
from the beetle's body provides the only exit for the boiling mixture.
Muscles surrounding the channel allow the steam jet to be directed at thesource of danger. The end result is that the beetle's enemy is scalded by asteaming solution of the toxic chemical quinone.
You may wonder why the mixture of hydrogen peroxide and quinone
did not react explosively when they were in the collecting vesicle. The
reason is that many chemical reactions occur quite slowly if there is noeasy way for the molecules to get together on the atomic level—otherwise,
this book would burst into flame as it reacted with oxygen in the air. Asan analogy, consider a locked door. There is no easy way for people (say,teenage boys and girls) on opposite sides of the door to get together, even
if they would be happy to do so. If someone has the key, however, then thedoor can be opened and proper introductions can be made. The enzyme
catalysts play the role of theNUTS AND BOLTS 33
key, allowing the hydrogen peroxide and hydroquinone to get together
on the atomic level so that a reaction can take place.
The bombardier beetle is a favorite of creationists. (A storybook forchildren, Bomby, the Bombardier Beetle by Hazel May Rue, has been
published by the Institute for Creation Research.) They twit evolutionists
with the beetle's remarkable defensive system, inviting them to explain
how it could have evolved gradually. Richard Dawkins, professor ofzoology at Oxford University, has taken up their challenge. Dawkins is thebest modern popularizer of Darwinism around. His books, including thecritically acclaimed The Blind Watchmaker, are accessible to the interested
layman and very entertaining to boot. Dawkins writes with passion
because he believes Darwinism is true. He also believes that atheism is alogical deduction from Darwinism and that the world would be better off
if more people shared that view.
In The Blind Watchmaker Dawkins turns his attention briefly to thebombardier beetle. First he cites a passage from The Neck of the Giraffe,a book by science writer Francis Hitching, that describes the bombardier
beetle's defensive system, as part of an argument against Darwinism:[The bombardier beetle] squirts a lethal mixture of hydroquinone andhydrogen peroxide into the face of its enemy. These two chemicals, whenmixed together; literally explode. So in order to store them inside its body,the bombardier beetle has evolved a chemical inhibitor to make themharmless. At the moment the beetle squirts the liquid out of its tail, an antiinhibitor is added to make the mixture explosive once again. The chain of
events that could have led to the evolution of such a complex, coordinatedand subtle process is beyond biological explanation on a simple step-bystep basis. The slightest alteration in the chemical balance would result
immediately in a race of exploded beetles.17

Replies Dawkins:
A biochemist colleague has kindly provided me with a bottle of hydrogen
peroxide, and enough hydroquinone for 50 bombardier beetles. I am about
to mix the two together. According to [Hitching], they will explode in myface. Here goes.... Well, I'm still here. I poured the hydrogen peroxide into
the hydroquinone, and absolutely nothing happened. It didn't even get
warm.... The statement that «these two chemicals, when mixed34 THE BOX IS OPENED
together; literally explode,» is, quite simply, false, although it is regularly
repeated throughout the creationist literature. If you are curious about
the bombardier beetle, by the way, what actually happens is as follows.
It is true that it squirts a scaldingly hot mixture of hydrogen peroxide andhydroquinone at enemies. But hydrogen peroxide and hydroquinone
don't react violently together unless a catalyst is added. This is what thebombardier beetle does. As for the evolutionary precursors of the system,
both hydrogen peroxide and various kinds of quinones are used for otherpurposes in body chemistry. The bombardier beetle's ancestors simply
pressed into different service chemicals that already happened to bearound. That's how evolution works.18

Although Dawkins gets the better of the exchange, neither he nor thecreationists make their case. Dawkins's explanation for the evolution of
the system rests on the fact that the system's elements «happened to bearound.» Thus evolution might be possible. But Dawkins has not explained
how hydrogen peroxide and quinones came to be secreted together atvery high concentration into one compartment that is connected througha sphinctered tube to a second compartment that contains enzymes
necessary for the rapid reaction of the chemicals.
The key question is this: How could complex biochemical systems be
gradually produced? The problem with the above «debate» is that bothsides are talking past each other. One side gets its facts wrong; the other side
merely corrects the facts. But the burden of the Darwinians is to answer
two questions: First, what exactly are the stages of beetle evolution, in all
their complex glory? Second, given these stages, how does Darwinism get
us from one to the next?
Dawkins didn't give us any details of how the bombardier beetle's
defensive system might have evolved. To point out the problem with hisargument, however, let's use what we know of the beetle's anatomy to build
the best possible case for the evolution of the bombardier bee-tle. First, weshould note that the function of the bombardier beetle's defensive apparatus
is to repel attackers. The components of the system are (1) hydrogen
peroxide and hydroquinone, which are produced by the secretory lobes;(2) the enzyme catalysts, which are made by the ectodermal glands; (3) thecollecting vesicle; (4) the sphincter

NUTS AND BOLTS 35
muscle; (5) the explosion chamber; and (6) the outlet duct. Not all ofthese components, though, are necessary for the function of the system.
Hydroquinone itself is noxious to predators. A large number of beetle
species synthesize quinones that are not even secreted, but which «taste
bad.» Initially a number of individual beetles are chewed up and spit out,
but a predator learns to avoid their noxious counterparts in the future, andthus the species as a whole benefits from this defense.
Hydroquinone alone, then, has the defensive function that we ascribed to
the whole system. Can the other components be added to the bombardier's
system in such a way that the function continuously improves? It would
seem that they can. We can imagine that the beetle would benefit fromconcentrating the hydroquinone in a holding space such as the collecting
vesicle. This would allow the beetle to make a large amount of the noxious
chemical, and in so doing become very untasty, without causing internal
problems. If the collecting vesicle somehow developed a channel to theoutside, the hydroquinone could leak and perhaps repel attackers before
they actually ate the bug. Many beetles have defensive apparatuses called
pygidial glands that have this basic structure: a simple holding spacewith a duct leading to the outside, often surrounded by a muscle to help
expel the contents of the space. This might be improved by developing asphincter muscle that would prevent the contents from leaking until theproper time.
Indeed, hydrogen peroxide is also an irritant, and so a beetle might
be safer if it could secrete, even at low temperature, both hydroquinone
and hydrogen peroxide in order to increase the irritant effect. Almost
all cells carry an enzyme called catalase, which breaks down hydrogen
peroxide into water and oxygen with the release of heat. If cells lining thetract to the outside secreted a little bit of catalase, then during ejectionsome of the hydrogen peroxide would be decomposed, warming thesolution and thereby making it more irritating. Bombardier beetle species
from Australia19 and Papua New Guinea20 spray solutions that range intemperature from warm to hot, but not boiling. If the cells released morecatalase the solution would become hotter; eventually an optimum would
be reached between the hotness of the solution and the durability of theexit channel. Over time the exit channel could be toughened and expanded
to allow increased temperature36 THE BOX IS OPENED
right up to the boiling point of the solution. Subsequent secretion ofperoxidases into the catalytic mixture would give an apparatus essentially
identical to that pictured in Figure 2-1.
Now we have a scenario fit for the evolutionary literature. But has
the development of the defensive apparatus of the bombardier beetle
truly been explained? Unfortunately, the explanation here is no moredetailed than Darwin's nineteenth-century story about the eye. Although
we seem to have a continuously changing system, the components that
control its operation are not known. For example, the collection vesicle
is a complex, multicelled structure. What does it contain? Why does it
have its particular shape? Saying that «the beetle would benefit fromconcentrating the hydroquinone in a holding space» is like saying «society
benefits from concentrating power in a centralized government»: In bothcases the manner of concentrating and the holding vessel are unexplained,
and the benefits of either would depend sharply on the details. The
collecting vesicle, the sphincter muscle, the explosion chamber, andthe exit port are all complex structures in their own right, with many
unidentified components. Furthermore, the actual processes responsible
for the development of the explosive capability are unknown: What causes
a collection vesicle to develop, hydrogen peroxide to be excreted, or asphincter muscle to wrap around?
All we can conclude at this point is that Darwinian evolution might
have occured. If we could analyze the structural details of the beetle down
to the last protein and enzyme, and if we could account for all these details
with a Darwinian explanation, then we could agree with Dawkins. For
now, though, we cannot tell whether the step-by-step accretions of ourhypothetical evolutionary stream are single-mutation «hops» or helicopter
rides between distant buttes.

SEEING IS BELIEVING

Let's go back to the human eye. Dawkins and Hitching also clash overthis classic complex organ. Hitching had stated in The Neck of the Giraffethat
it is quite evident that if the slightest thing goes wrong en route—if thecornea is fuzzy, or the pupil fails to dilate, or the lens becomes opaque, or

NUTS AND BOLTS 37
the focusing goes wrong—then a recognizable image is not formed. Theeye either functions as a whole or not at all. So how did it come to evolveby slow, steady, infinitesimally small Darwinian improvements? Is it reallyplausible that thousands upon thousands of lucky chance mutations
happened coincidentally so that the lens and the retina, which cannot
work without each other, evolved in synchrony? What survival value canthere be in an eye that doesn't see?21

Dawkins, grateful that Hitching again leads with his chin, doesn't missthe opportunity:
Consider the statement that «if the slightest thing goes wrong ... [if] thefocusing goes wrong ... a recognizable image is not formed.» The odds
cannot be far from 50/50 that you are reading these words throughglass lenses. Take them off and look around. Would you agree that «arecognizable image is not formed»? . .. (Hitching) also states, as though it
were obvious, that the lens and the retina cannot work without each other.
On what authority? Someone close to me has had a cataract operation inboth eyes. She has no lenses in her eyes at all. Without glasses she couldn't
even begin to play lawn tennis or aim a rifle. But she assures me that you
are far better off with a lensless eye than with no eye at all. You can tell
if you are about to walk into a wall or another person. If you were a wild
creature, you could certainly use your lensless eye to detect the looming
shape of a predator, and the direction from which it was approaching.22

After attacking Hitching—as well as scientists Richard Goldschmidt
and Stephen Jay Gould—for worrying about the eye's complexity, Dawkins
goes on to paraphrase Charles Darwin's argument for the plausibility ofeye evolution:
Some single-celled animals have a light-sensitive spot with a little pigment
behind it. The screen shields it from light coming from one direction, which
gives it some «idea» of where the light is coming from. Among many-celled
animals ... the pigment-backed light-sensitive cells are set in a little cup.
This gives slightly better direction-finding capability. ... Now, if you makea cup very deep and turn the sides over, you eventually make a lenslesspinhole camera.. . . When you have a cup for an eye, almost any vaguely
convex, vaguely transparent or even translucent material over its opening
will constitute an improvement, because of its slight lens-like38 THE BOX IS OPENED
properties. Once such a crude proto-lens is there, there is a continuously
graded series of improvements, thickening it and making it moretransparent and less distorting, the trend culminating in what we would allrecognize as a true lens.23

We are invited by Dawkins and Darwin to believe that the evolution of
the eye proceeded step-by-step through a series of plausible intermediates
in infinitesimal increments. But are they infinitesimal? Remember thatthe «light-sensitive spot» that Dawkins takes as his starting point requires
a cascade of factors, including 11-cis-retinal and rhodopsin, to function.
Dawkins doesn't mention them. And where did the «little cup» comefrom? A ball of cells—from which the cup must be made—will tend to
be rounded unless held in the correct shape by molecular supports. In
fact, there are dozens of complex proteins involved in maintaining cell
shape, and dozens more that control extracellular structure; in theirabsence, cells take on the shape of so many soap bubbles. Do thesestructures represent single-step mutations? Dawkins did not tell us how
the apparently simple «cup» shape came to be. And although he reassures
us that any «translucent material» would be an improvement (recall that
Haeckel mistakenly thought it would be easy to produce cells since they
were certainly just «simple lumps»), we are not told how difficult it is to
produce a «simple lens.» In short, Dawkins's explanation is only addressedto the level of what is called gross anatomy.
Both Hitching and Dawkins have misdirected their focus. The eye,or indeed almost any large biological structure, consists of a number of
discrete systems. The function of the retina alone is the perception of light.
The function of the lens is to gather light and focus it. If a lens is used witha retina, the working of the retina is improved, but both the retina and lens
can work by themselves. Similarly, the muscles that focus the lens or turnthe eye function as a contraction apparatus, which can be applied to manydifferent systems. The perception of light by the retina is not dependent on
them. Tear ducts and eyelids are also complex systems, but separable fromthe function of the retina.
Hitching's argument is vulnerable because he mistakes an integrated
system of systems for a single system, and Dawkins rightly points out the
separability of the components. Dawkins, however, merely adds complex
systems to complex systems and calls that an explanation.

NUTS AND BOLTS 39
This can be compared to answering the question «How is a stereo system
made?» with the words «By plugging a set of speakers into an amplifier,and adding a CD player, radio receiver, and tape deck.» Either Darwinian
theory can account for the assembly of the speakers and amplifier, or it
can't.

IRREDUCIBLE COMPLEXITY AND THE NATURE OF
MUTATION

Darwin knew that his theory of gradual evolution by natural selection
carried a heavy burden:
If it could be demonstrated that any complex organ existed which could not
possibly have been formed by numerous, successive, slight modifications,my theory would absolutely break down.24

It is safe to say that most of the scientific skepticism about Darwinism
in the past century has centered on this requirement. From Mivart's
concern over the incipient stages of new structures to Margulis's dismissalof gradual evolution, critics of Darwin have suspected that his criterionof failure had been met. But how can we be confident? What type of
biological system could not be formed by «numerous, successive, slight
modifications»?
Well, for starters, a system that is irreducibly complex. By irreduciblycomplex I mean a single system composed of several well-matched,interacting parts that contribute to the basic function, wherein the removalof any one of the parts causes the system to effectively cease functioning.
An irreducibly complex system cannot be produced directly (that is, bycontinuously improving the initial function, which continues to work by
the same mechanism) by slight, successive modifications of a precursor
system, because any precursor to an irreducibly complex system that is
missing a part is by definition nonfunctional. An irreducibly complex
biological system, if there is such a thing, would be a powerful challenge
to Darwinian evolution. Since natural selection can only choose systems
that are already working, then if a biological system cannot be produced
gradually it would have to arise as an integrated unit, in one fell swoop, fornatural selection to have anything to act on.

40 THE BOX IS OPENEDEven if a system is irreducibly complex (and thus cannot have been
produced directly), however, one can not definitively rule out the possibilityof an indirect, circuitous route. As the complexity of an interacting
system increases, though, the likelihood of such an indirect route drops
precipitously. And as the number of unexplained, irreducibly complex
biological systems increases, our confidence that Darwin's criterion of
failure has been met skyrockets toward the maximum that science allows.
In the abstract, it might be tempting to imagine that irreducible
complexity simply requires multiple simultaneous mutations—that
evolution might be far chancier than we thought, but still possible. Suchan appeal to brute luck can never be refuted. Yet it is an empty argument.
One may as well say that the world luckily popped into existence yesterdaywith all the features it now has. Luck is metaphysical speculation; scientificexplanations invoke causes. It is almost universally conceded that suchsudden events would be irreconcilable with the gradualism Darwin
envisioned. Richard Dawkins explains the problem well:
Evolution is very possibly not, in actual fact, always gradual. But it must
be gradual when it is being used to explain the coming into existence ofcomplicated, apparently designed objects, like eyes. For if it is not gradualin these cases, it ceases to have any explanatory power at all. Without
gradualness in these cases, we are back to miracle, which is simply asynonym for the total absence of explanation.25

The reason why this is so rests in the nature of mutation.
In biochemistry, a mutation is a change in DNA. To be inherited,the change must occur in the DNA of a reproductive cell. The simplest
mutation occurs when a single nucleotide (nucleotides are the «building
blocks» of DNA) in a creature's DNA is switched to a different nucleotide.
Alternatively, a single nucleotide can be added or left out when the DNA
is copied during cell division. Sometimes, though, a whole region of
DNA—thousands or millions of nucleotides—is accidentally deleted or
duplicated. That counts as a single mutation, too, because it happens at
one time, as a single event. Generally a single mutation can, at best, makeonly a small change in a creature—even if the change impresses us as a big
one. For example, there is a well-NUTS AND BOLTS 41
known mutation called antennapedia that scientists can produce ina laboratory fruit fly: the poor mutant creature has legs growing out of
its head instead of antennas. Although that strikes us as a big change, it
really isn't. The legs on the head are typical fruit-fly legs, only in a different
location.
An analogy may be useful here: Consider a step-by-step list of
instructions. A mutation is a change in one of the lines of instructions. So
instead of saying, «Take a 1/4-inch nut,» a mutation might say, «Take a 3/8inch nut.» Or instead of «Place the round peg in the round hole,» we might
get «Place the round peg in the square hole.» Or instead of «Attach the seatto the top of the engine,» we might get «Attach the seat to the handlebars»(but we could only get this if the nuts and bolts could be attached to thehandlebars). What a mutation cannot do is change all the instructions in
one step—say, to build a fax machine instead of a radio.
Thus, to go back to the bombardier beetle and the human eye, thequestion is whether the numerous anatomical changes can be accounted
for by many small mutations. The frustrating answer is that we can't tell.
Both the bombardier beetle's defensive apparatus and the vertebrate eye
contain so many molecular components (on the order of tens of thousandsof different types of molecules) that listing them— and speculating on themutations that might have produced them—is currently impossible. Toomany of the nuts and bolts (and screws, motor parts, handlebars, and soon) are unaccounted for. For us to debate whether Darwinian evolution
could produce such large structures is like nineteenth century scientists
debating whether cells could arise spontaneously. Such debates are fruitless
because not all the components are known.
We should not, however, lose our perspective over this; other ages havebeen unable to answer many questions that interested them. Furthermore,because we can't yet evaluate the question of eye evolution or beetle
evolution does not mean we can't evaluate Darwinism's claims for any
biological structure. When we descend from the level of a whole animal(such as a beetle) or whole organ (such as an eye) to the molecular level,
then in many cases we can make a judgment on evolution because allof the parts of many discrete molecular systems are known. In the next
five chapters we will meet a number of such systems—and render our
judgment.

42 THE BOX IS OPENED
Now, let's return to the notion of irreducible complexity. At this pointin our discussion irreducible complexity is just a term whose power resides
mostly in its definition. We must ask how we can recognize an irreduciblycomplex system. Given the nature of mutation, when can we be sure that abiological system is irreducibly complex?
The first step in determining irreducible complexity is to specify boththe function of the system and all system components. An irreduciblycomplex object will be composed of several parts, all of which contribute to
the function. To avoid the problems encountered with extremely complex
objects (such as eyes, beetles, or other multicellular biological systems) I
will begin with a simple mechanical example: the humble mousetrap.
The function of a mousetrap is to immobilize a mouse so that it can't
perform such unfriendly acts as chewing through sacks of flour or electrical
cords, or leaving little reminders of its presence in unswept comers. The
mousetraps that my family uses consist of a number of parts (Figure 2-2):(1) a flat wooden platform to act as a base; (2) a metal hammer, which does
the actual job of crushing the litle mouse; (3) a spring with extended ends
to press against the platform and the hammer when the trap is charged;(4) a sensitive catch that releases when slight pressure is applied, and (5)a metal bar that connects to the catch and holds the hammer back when
the trap is charged. (There are also assorted staples to hold the system
together.)
The second step in determining if a system is irreducibly complex is to
ask if all the components are required for the function. In this example,
the answer is clearly yes. Suppose that while reading one evening, you hear
the patter of little feet in the pantry, and you go to the utility drawer to geta mousetrap. Unfortunately, due to faulty manufacture, the trap is missing
one of the parts listed above. Which part could be missing and still allow
you to catch a mouse? If the wooden base were gone, there would be noplatform for attaching the other components. If the hammer were gone, themouse could dance all night on the platform without becoming pinned to
the wooden base. If there were no spring, the hammer and platform would
jangle loosely, and again the rodent would be unimpeded. If there were nocatch or metal holding bar, then the spring would snap the hammer shut
as soon as you let go of it; in order to use a trap like that you would have tochase the mouse around while holding the trap open.

NUTS AND BOLTS 43
FIGURE 2-2
A household mousetrap.

To feel the full force of the conclusion that a system is irreduciblycomplex and therefore has no functional precursors, we need to
distinguish between a physical precursor and a conceptual precursor. The
trap described above is not the only system that can immobilize a mouse.
On other occasions my family has used a glue trap. In theory, at least, one
can use a box propped open with a stick that could be tripped. Or one cansimply shoot the mouse with a BB gun. These are not physical precursors
to the standard mousetrap, however, since they cannot be transformed,
step by Darwinian step, into a trap with a base, hammer, spring, catch,and holding bar.
To clarify the point, consider this sequence: skateboard, toy wagon,
bicycle, motorcycle, automobile, airplane, jet plane, space shuttle. It seems
like a natural progression, both because it is a list of objects that all canbe used for transportation and also because they are lined up in orderof complexity. They can be conceptually connected and blended together
into a single continuum. But is, say, a bicycle a physical (and potentially
Darwinian) precursor of a motorcycle? No. It is only a conceptual
precursor. No motorcycle in history, not even the first, was made simply
by modifying a bicycle in a stepwise fashion. It might easily be the casethat a teenager on a Saturday afternoon could take an old bicycle, an oldlawnmower engine, and some spare parts and (with44 THE BOX IS OPENEDa couple of hours of effort) build himself a functioning motorcycle.
But this only shows that humans can design irreducibly complex systems,
which we knew already. To be a precursor in Darwin's sense we mustshow that a motorcycle can be built from «numerous, successive, slight
modifications» to a bicycle.
So let us attempt to evolve a bicycle into a motorcycle by the gradualaccumulation of mutations. Suppose that a factory produced bicycles,
but that occasionally there was a mistake in manufacture. Let us further
suppose that if the mistake led to an improvement in the bicycle, thenthe friends and neighbors of the lucky buyer would demand similar bikes,
and the factory would retool to make the mutation a permanent feature.
So, like biological mutations, successful mechanical mutations would
reproduce and spread. If we are to keep our analogy relevant to biology,
however, each change can only be a slight modification, duplication, or
rearrangement of a preexisting component, and the change must improve
the function of the bicycle. So if the factory mistakenly increased the sizeof a nut or decreased the diameter of a bolt, or added an extra wheel onto
the front axle or left off the rear tire, or put a pedal on the handlebars oradded extra spokes, and if any of these slight changes improved the bikeride, then the improvement would immediately be noticed by the buying
public and the mutated bikes would, in true Darwinian fashion, dominate
the market.
Given these conditions, can we evolve a bicycle into a motorcycle? We
can move in the right direction by making the seat more comfortable insmall steps, the wheels bigger, and even (assuming our customers prefer the«biker» look) imitating the overall shape in various ways. But a motorcycle
depends on a source of fuel, and a bicycle has nothing that can be slightly
modified to become a gasoline tank. And what part of the bicycle could be
duplicated to begin building a motor? Even if a lucky accident brought a
lawnmower engine from a neighboring factory into the bicycle factory, themotor would have to be mounted on the bike and be connected in the right
way to the drive chain. How could this be done step-by-step from bicycle
parts? A factory that made bicycles simply could not produce a motorcycle
by natural selection acting on variation—by «numerous, successive, slight
modifications»—and in fact there is no example in history of a complex
change in a product occurring in this manner.

NUTS AND BOLTS 45
A bicycle thus may be a conceptual precursor to a motorcycle, but it is
not a physical one. Darwinian evolution requires physical precursors.

MINIMAL FUNCTION

So far we have examined the question of irreducible complexity asa challenge to step-by-step evolution. But there is another difficulty for
Darwin. My previous list of factors that render a mousetrap irreduciblycomplex was actually much too generous, because almost any device
with the five components of a standard mousetrap will nonetheless fail tofunction. If the base were made out of paper, for example, the trap would
fall apart. If the hammer were too heavy, it would break the spring. If
the spring were too loose, it would not move the hammer. If the holding
bar were too short, it would not reach the catch. If the catch were toolarge, it would not release at the proper time. A simple list of components
of a mousetrap is necessary, but not sufficient, to make a functioning
mousetrap.
In order to be a candidate for natural selection a system must haveminimal function: the ability to accomplish a task in physically realistic
circumstances. A mousetrap made of unsuitable materials would notmeet the criterion of minimal function, but even complex machines that
do what they are supposed to do may not be of much use. To illustrate,
suppose that the world's first outboard motor had been designed and was
being marketed. The motor functioned smoothly— burning gasoline ata controlled rate, transmitting the force along an axle, and turning thepropeller—but the propeller rotated at only one revolution per hour. Thisis an impressive technological feat; after all, burning gasoline in a cannext to a propeller doesn't turn it at all. Nonetheless, few people wouldpurchase such a machine, because it fails to perform at a level suitable forits purpose.
Performance can be unsuitable for either of two reasons. The firstreason is that the machine does not get the job done. A couple fishing in
the middle of a lake in a boat with a slow-tuming propeller would not getto the dock: random currents of the water and wind would knock theirboat off course. The second reason that performance might be unsuitable
is if it is less efficient than can be achieved with

46 THE BOX IS OPENED
simpler means. No one would use an inefficient, outboard motor if they
could do just as well or better with a sail.
Unlike irreducible complexity (where we can enumerate discreteparts), minimal function is sometimes hard to define. If one revolution
per hour is insufficient for an outboard motor; how about a hundred? Ora thousand? Nonetheless, minimal function is critical in the evolutionof biological structures. For example, what is the minimum amountof hydroquinone that a predator can taste? How much of a rise in thetemperature of the solution will it notice? If the predator didn't notice a tiny
bit of hydroquinone or a small change in temperature, then our Dawkinsesque tale of the bombardier beetle's evolution can be filed alongside thestory of the cow jumping over the moon. Irreducibly complex systems are
nasty roadblocks for Darwinian evolution; the need for minimal function
greatly exacerbates the dilemma.

NUTS AND BOLTS

Biochemistry has demonstrated that any biological apparatus involving
more than one cell (such as an organ or a tissue) is necessarily an intricate
web of many different, identifiable systems of horrendous complexity.
The «simplest» self-sufficient, replicating cell has the capacity to produce
thousands of different proteins and other molecules, at different times
and under variable conditions. Synthesis, degradation, energy generation,
replication, maintenance of cell architecture, mobility, regulation, repair,communication—all of these functions take place in virtually every
cell, and each function itself requires the interaction of numerous parts.
Because each cell is such an interwoven meshwork of systems, we would
be repeating the mistake of Francis Hitching by asking if multicellular
structures could have evolved in step-by-step Darwinian fashion. Thatwould be like asking not whether a bicycle could evolve into a motorcycle,
but whether a bicycle factory could evolve into a motorcycle factory!
Evolution does not take place on the factory level; it takes place on the
nut-and-bolt level.
The arguments of Dawkins and Hitching fail because they never discuss
what is contained in the systems over which they are arguing. Not onlyis the eye exceedingly complex, but the «light-sensitive spot» with which
Dawkins begins his case is itself a multicelled organ, each of whose cells
makes the complexity of a motorcycle or television set

NUTS AND BOLTS 47
look paltry in comparison. Not only does the defensive apparatus of thebombardier beetle depend on a number of interacting components, but
the cells that produce hydroquinone and hydrogen peroxide depend on avery large number of components to do so; the cells that secrete catalaseare very complex; and the sphincter muscle separating the collection
vesicle from the explosion chamber is a system of systems. Because of this,Hitching's arguments about the splendid complexity of the bombardier
beetle are easily blurred into irrelevance, and Dawkins's reply satisfies us
only until we ask for more details.
In contrast to biological organs, the analysis of simple mechanicalobjects is relatively straightforward. We showed in short order that amousetrap is irreducibly complex, and so we can conclude what we alreadyknew—that a mousetrap is made as an intact system. We already knewthat a motorcycle was not unconsciously produced by small, successive
improvements to a bicycle, and a quick analysis shows us that it is
impossible to do so. Mechanical objects can't reproduce and mutate likebiological systems, but hypothesizing comparable events at an imaginary
factory shows that mutation and reproduction are not the main barriers
to evolution of mechanical objects. It is the requirements of the structurefunction relationship itself that block Darwinian-style evolution.
Machines are relatively easy to analyze because both their function
and all of their parts, each nut and bolt, are known and can be listed. It
is then simple to see if any given part is required for the function of thesystem. If a system requires several closely matched parts to function thenit is irreducibly complex, and we can conclude that it was produced as anintegrated unit. In principle, biological systems can also be analyzed inthis manner, but only if all the parts of the system can be enumerated anda function recognized.
In the past several decades, modem biochemistry has elucidated all ormost of the components of a number of biochemical systems. In the next
five chapters I will discuss a few of them. In Chapter 3 I will look at afascinating structure called a «cilium,» which some cells use to swim. In
the next chapter I will discuss what happens when you cut your finger—
and show that the apparent simplicity of blood clotting is deceptively
complicated. After that I will consider how cells transport materials fromone subcellular compartment to another, encountering many of the sameproblems that Federal Express meets in delivering

48 THE BOX IS OPENED
packages. In Chapter 6 I will discuss the art of self-defense—on thecellular level, of course. My final biochemical example will be in Chapter 7,
where I will look at the intricate system the cell requires just to make oneof its «building blocks.» In each chapter I will consider whether the system
discussed could have developed gradually in a Darwinian fashion, as wellas what the scientific community has said about the possible evolution of
the systems.
I have endeavored to keep these five «example chapters» as readable
and enjoyable as possible. I don't discuss any esoteric concepts peculiar tobiochemistry—nothing that is more difficult than the idea of «stick to» or«cut.» Nonetheless, as I mentioned in the Preface, to appreciate complexity
you have to experience it. The systems I discuss are complex because they
contain many components. There is, however, no examination at the endof the book. The detailed descriptions are intended only to give you anappreciation of the complexity of the system, not to test your memory.
Some readers may wish to plough right through; others might want toskim and refer back when they are ready for more detail.
I apologize in advance for the complexity of the material, but it isinherent in the point I wish to make. Richard Dawkins can simplify to hisheart's content, because he wants to convince his readers that Darwinianevolution is «a breeze.» In order to understand the barriers to evolution,
however, we have to bite the bullet of complexity.

PART IIEXAMINING THE CONTENTS OF THE BOX

CHAPTER 3

ROW, ROW, ROW YOUR BOATPROTEINSAs strange as it may seem, modern biochemistry has shown that thecell is operated by machines—literally, molecular machines. Like their
man-made counterparts (such as mousetraps, bicycles, and space shuttles),molecular machines range from the simple to the enormously complex:
mechanical, force-generating machines, like those in muscles; electronic
machines, like those in nerves; and solar-powered machines, like thoseof photosynthesis. Of course, molecular machines are made primarily ofproteins, not metal and plastic. In this chapter I will discuss molecularmachines that allow cells to swim, and you will see what is required forthem to do so.
But first, some necessary details. In order to understand the molecularbasis of life one has to have an idea of how proteins work. Those who wantto know all the details—how proteins are made, how their structures
allow them to work so effectively, and so on—are encouraged to borrow
an introductory biochemistry textbook from the library. For those whowant to know a few details—such as what amino acids look like, and what
are the levels of protein structure—I have included an Appendix that
discusses proteins and nucleic acids.
51

52 EXAMINING THE CONTENTS OF THE BOX
For present purposes, however, an overview of these remarkablebiochemicals will suffice.
Most people think of proteins as something you eat. In the body ofa living animal or plant, however, they play very active roles. Proteins
are the machines within living tissue that build the structures and carryout the chemical reactions necessary for life. For example, the first stepin capturing the energy in sugar and changing it into a form the bodycan use is carried out by a catalyzing protein (also known as an enzyme)
called hexokinase; skin is made up mostly of a protein called collagen;and when light strikes your retina, the protein called rhodopsin initiates
vision. You can see even by this limited number of examples that proteinsare amazingly versatile. Nonetheless, a given protein has only one or a few
uses: rhodopsin cannot form skin, and collagen cannot interact usefully
with light. Therefore a typical cell contains thousands and thousands ofdifferent kinds of proteins to perform the many tasks of life.
Proteins are made by chemically hooking together amino acids into a
chain. A protein chain typically has anywhere from about fifty to about
one thousand amino acid links. Each position in the chain is occupied
by one of twenty different amino acids. In this they are like words, which
can come in various lengths but are made up from a set of just 26 letters.
As a matter of fact, biochemists often refer to each amino acid by a singleletter abbreviation—G for glycine, S for serine, H for histidine, and soforth. Each different kind of amino acid has a different shape and different
chemical properties. For example, W is large but A is small, R carries apositive charge but E carries a negative charge, S prefers to be dissolved inwater but I prefers oil, and so on.
When you think of a chain, you probably think of something that isvery flexible, without much overall shape. But chains of amino acids— inother words, proteins—aren't like that. Proteins that work in a cell foldup into very precise structures, and the structure can be quite different
for different types of proteins. The folding is done automatically when,say, a positively charged amino acid attracts a negatively charged one,oil-preferring amino acids huddle together to exclude water, large aminoacids are pushed out of small spaces, and so on. Two different amino acidsequences (that is two different proteins) can fold into structures as specificand different from each other as an adjustable wrench and a jigsaw.

ROW, ROW, ROW YOUR BOAT 53
It is the shape of a folded protein and the precise positioning of thedifferent kinds of amino acid groups that allow a protein to work (Fig-ure
3-1). For example, if it is the job of one protein to bind specifically to asecond protein, then their two shapes must fit each other like a hand in a
glove. If there is a positively charged amino acid on the first protein, thenthe second protein better have a negatively charged amino acid; otherwise,
the two will not stick together. If it is the job of a protein to catalyze achemical reaction, then the shape of the enzyme generally matches theshape of the chemical that is its target. When it binds, the enzyme hasamino acids precisely positioned to cause a chemical reaction. If the shapeof a wrench or a jigsaw is significantly warped, then the tool doesn't work.
Likewise, if the shape of a protein is warped then it fails to do its job.
Modern biochemistry was launched forty years ago when science began
to learn what proteins look like. Since then, great strides have been madein understanding exactly how particular proteins carry out particulartasks. In general, the cell's work requires teams of proteins; each memberof the team carries out just one part of a larger task. To keep things as
simple as possible, in this book I will concentrate on protein teams. Now,
let's go swimming.

SWIMMING

Suppose, on a summer day, you find yourself taking a trip to theneighborhood pool for a bit of exercise. After slathering on the sunblock,you lie on a towel reading the latest issue of Nucleic Acids Research and wait
for the adult swim period to begin. When at long last the whistle blows
and the overly energetic younger crowd clears the water; you gingerly dip
your toes in. Slowly, painfully, you lower the rest of your body into thesurprisingly cold water. Because it would not be dignified, you will not
do any cannonballs or fancy dives from the diving board, nor play watervolleyball with the younger adults. Rather, you will swim laps.
Pushing off from the side, you bring your right arm up over your headand plunge it into the water, completing one stroke. During the stroke,nerve impulses travel from your brain to your arm muscles, stimulatingthem to contract in a specific order. The contracting muscles tug against
your bones, causing the humerus to rise and rotate.

54 EXAMINING THE CONTENTS OF THE BOX
FIGURE 3-1(Top) When two proteins bind specifically, their shapes
match each other closely. (Bottom) To catalyze a chemical
reaction an enzyme positions groups close to the chemicalthat it binds. The scissors represents groups on the proteinthat will chemically cut a specific molecule, represented
by the light-colored shape.

At the same time other muscles squeeze the bones of your fingers
together, so that your hand forms a closed cup. Successive nerve impulses
provoke other muscles to relax and contract, pulling in various ways on
the radius and ulna, and directing the hand downward into the water. The
force of the arm and hand on the water propel you forward.
After completion of about half of the actions listed above a similar

ROW, ROW, ROW YOUR BOAT 55
cycle begins, this time with the bones and muscles of the left arm.
Simultaneously, nerve impulses travel to the muscles of your legs, causing
them to contract and relax rhythmically, pulling the leg bones up anddown. Slicing through the water at a stunning two miles per hour, though,you notice that it's getting hard to think; there's a burning sensation in yourlungs; and, even though your eyes are open, things start to go black. Ah,
yes—you forgot to breathe. It was said of President Ford that he couldn't
walk and chew gum at the same time; you find it difficult to coordinate
the turning of your head to the water's surface and back again with theother motions required for swimming. Without oxygen to metabolize fuelyour brain starts to shut down, preventing conscious nerve impulses fromtraveling to the distant regions of your body.
Before you pass out and suffer the humiliation of being rescued by aGeneration X lifeguard you stop, stand up in the four feet of water, andnotice that you're only about twenty feet from the side. To get aroundthe breathing problem, you decide to do the backstroke. The backstroke
involves most of the same muscles as freestyle swimming, and allows you
to breathe without coordinating neck muscles with everything else. But
now you can't see where you're going. Inevitably you drift off course, cometoo close to the volleyball game, and are smacked in the head by an errant
overhand smash.
In order to get far away from the apologetic volleyballers, you decide
simply to tread water in the deep end of the pool. Treading water uses
your leg muscles, giving you the exercise you want. It also allows both easy
breathing and clear vision. After a few minutes, however, your legs begin
to cramp. Deep inside your flabby limbs, unknown to you, your seldomused muscles keep on hand enough fuel for only short bursts of activity,
followed by long periods of rest. During the unusually prolonged exercise
they quickly run out of sustenance and cease to function effectively. Nerve
impulses frantically try to provoke the motions necessary for swimming,
but with the muscles malfunctioning, your legs are as useless as amousetrap with a broken spring.
You relax and remain still. Fortunately, the large region of your bodyaround the waist has a density less than that of water, and so it keeps you
afloat. After a minute or two of bobbing in the water, your cramped muscles
relax. You spend the rest of the adult swim period floating serenely aroundthe deep end. This doesn't provide much

56 EXAMINING THE CONTENTS OF THE BOX
exercise, but at least it is enjoyable—until the whistle blows again, andyou are pummeled by the cannonballs of undignified kids.

WHAT IT TAKESThe neighborhood pool scenario illustrates the requirements for
swimming. It also shows that efficiency can be improved by adding
auxiliary systems to the basic swimming equipment. To take the last scene
first, floating requires only that an object be less dense than water; it does
not require activity. The ability to float—to be able to keep a portion of the
body out of the water with no active effort—can certainly be useful. Yet
because the floater simply drifts along with the current, the ability to float
is not the same thing as the ability to swim.
A direction-finding system (such as eyesight) is also useful for
swimming; however, it is not the same thing as the ability to swim. In thestory you could do the backstroke for a while and still advance throughthe water. Eventually, an inability to sense the surroundings can lead to
accidents. Nonetheless, one can swim sighted or one can swim blind.
Swimming clearly requires energy; cramped, useless muscles
immediately cause the system to fail. But you traveled twenty feet before
running out of oxygen, and then treaded water for a short while before
cramping set in. Although they certainly affect the distance a swimmer
can go, the size and efficiency of the fuel reserve system thus are not partsof the swimming system itself.
Now let's consider the mechanical requirements of swimming. You
used your hands and feet to contact the water and push it, thus moving
your body in the opposite direction. Without the limbs, or some substitute,active swimming would be quite impossible. So we can conclude that one
requirement for swimming is a paddle. Another requirement is a motoror power source that has at least enough fuel to last several cycles. At theorgan level in humans, the motor is the leg or arm muscle that alternately
contracts and relaxes. If the muscle is paralyzed, there is no effective motor,
and swimming is impossible. The final requirement is for a connection
between the motor and the paddling surface: in humans, these are theareas of bones to which the muscles adhere. If a muscle is detached from abone it can still con-

ROW, ROW, ROW YOUR BOAT 57
tract; because it does not move the bone, however, swimming does nottake place.
Mechanical examples of swimming systems are easy to find. My
youngest daughter has a toy wind-up fish that wiggles its tail, propellingitself somewhat awkwardly through the bathtub. The tail of the toy
fish is the paddle surface, the wound spring is the energy source, and aconnecting rod transmits the energy. If one of the components—thepaddle, motor, or connector—is missing, then the fish goes nowhere.
Like a mousetrap without a spring, a swimming system without a paddle,
motor, or connector is fatally incomplete. Because the swimming systems
need several parts to work, they are irreducibly complex.
Keep in mind that we are discussing only the parts common to all
swimming systems—even the most primitive. Additional complexity
is frequently seen. For example, my daughter's toy fish has, besides its
tail, spring, and connecting rod, several gears that transmit force fromthe rod to the tail. A propeller-driven ship has all manner of gears androds redirecting the energy of the motor until it is finally transmitted tothe propeller. Unlike the eye of a swimmer, which is separate from theswimming system itself, such extra gears are indeed part of the system—
removing them causes the whole setup to grind to a halt. When a real-lifesystem has more than the theoretically minimum number of parts, thenyou have to check each of the other parts to see if they're required for thesystem to work.

WHAT ELSE IT TAKES

A simple list of pieces shows the very minimum of requirements. In
the last chapter I discussed how a mousetrap that had all the necessary
pieces—a hammer, base, spring, catch, and holding bar—still might notwork. If the holding bar were too short or the spring too lightweight, forexample, the trap would be a failure. Similarly, the pieces of a swimming
system must be matched to each other to have at least minimal function.
The paddle is necessary, but if its surface is too small a boat might not
make enough progress in a required amount of time. Conversely, if thepaddle surface is too large, the connector or motor might strain and breakwhen moving. The motor must

58 EXAMINING THE CONTENTS OF THE BOX
be strong enough to move the paddle. It must also be regulated to go at
an appropriate speed: too slow, and the swimmer does not make physicallynecessary progress; too fast, and the connector or paddle may break.
But even if we have the right parts of a swimming system, and even if theparts are the right size and strength and are matched to each other; moreis needed. The additional requirement—the need to control the timing
and direction of the paddle strokes—is easier to see in the example of ahuman swimmer than in the case of a paddleboat. When a non-swimmer
falls into the water he helplessly flails his arms and legs, making no moreprogress than if he simply floated. Even a beginning swimmer like myoldest daughter, who is just learning the strokes, quickly sinks unless Dad
supports her. Her individual strokes are adequate, but their timing is notcoordinated, she doesn't hold herself parallel to the water's surface, and she
keeps her head out of the water.
Mechanical systems seem not to have those problems. A ship doesn't
flail its propeller, and the timing and direction of a paddle-boat's strokes
are smooth and regular from the beginning. But the argument is deceptive.
The apparently effortless abilities are actually built into the shape andconnectivity of the paddlewheel, rotor, and motor of the boat. Imagine a
steamboat in which the paddle boards were not arranged nicely around acircular frame. Suppose the boards went off at various angles and the rotor
turned first forward, then backward, then side to side. Instead of taking
a scenic tour of the Mississippi the boat would drift helplessly, spasticallyfloating with the current toward the Gulf of Mexico. A propeller with blades
set at haphazard angles would churn water, but it wouldn't move a boat
in any particular direction. The apparent ease with which a mechanicalsystem paddles—compared to the difficulties of a human non-swimmer—
is an illusion. The engineer who designed the system «trained» it to swim,
pushing the water in the correct direction with the correct timing.
In the unforgiving world of nature, an organism spending energy to
flail helplessly in the water would have no advantage over the organism
floating serenely beside it. Do any cells swim? If so, what swimming
systems do they use? Are they, like a Mississippi steamboat, irreduciblycomplex? Could they have evolved gradually?

ROW, ROW, ROW YOUR BOAT 59

THE CILIUM

Some cells swim using a cilium. A cilium is a structure that, crudely
put, looks like a hair and beats like a whip. If a cell with a cilium is free tomove about in a liquid, the cilium moves the cell much as an oar moves aboat. If the cell is stuck in the middle of a sheet of other cells, the beating
cilium moves liquid over the surface of the stationary cell. Nature uses
cilia for both jobs. For example, sperm use cilia to swim. In contrast, thestationary cells that line the respiratory tract each have several hundredcilia. The large number of cilia beat in synchrony, much like the oars
handled by slaves on a Roman galley ship, to push mucus up to the throat
for expulsion. The action removes small foreign particles—like soot—that
are accidentally inhaled and stick in the mucus.
Light microscopes showed thin hairs on some cells, but discovery of
the Lilliputian details of cilia had to wait for the invention of the electron
microscope, which revealed that the cilium is quite a complicated structure.
I will be discussing the structure of the cilium for the next few pages.
Most readers will probably find the discussion easier to follow by referring
frequently to Figure 3-2.
 The cilium consists of a membrane-coated bundle of fibers.1 The
ciliary membrane (think of it as a sort of plastic cover) is an outgrowthof the cell membrane, so the interior of the cilium is connected to theinterior of the cell. When a cilium is sliced crossways and the cut end is
examined by electron microscopy, you see nine rod-like structures aroundthe periphery. The rods are called microtubules. When high-quality
photographs are closely inspected, each of the nine microtubules is seen toactually consist of two fused rings. Further examination shows that one of
the rings is made from thirteen individual strands. The other ring, joined
to the first, is made from ten strands. Summarizing briefly, each of thenine outer microtubules of a cilium is made of a ring of ten strands fused
to a ring of thirteen strands.
Biochemical experiments show that microtubules are made from aprotein called tubulin. In a cell, tubulin molecules come together likebricks that form a cylindrical smokestack. Each of the nine outer rods isa microtubule that resembles a fused, double-smokestack with bricks oftubulin. Pictures produced by electron microscopy

60 EXAMINING THE CONTENTS OF THE BOX
FIGURE 3-2(Top) Cross-section of a cilium showing the fused doublering structure of the outer microtubules, the single-ring
structure of the central microtubules, connecting proteinsand dynein motor. (Bottom) The sliding motion induced bydynein «walking» up a neighboring microtubule is converted
to a bending motion by the flexible linker protein nexin.

ROW, ROW, ROW YOUR BOAT 61
also show two rods in the middle of the cilium. They, too, aremicrotubules. Instead of being double smokestacks, however, they are
individual smokestacks, each made of thirteen strands of tubulin.
When conditions are right within the cell (for example, when thetemperature is within certain limits and when the concentration of calcium
is just right), tubulin—the «brick» that makes up the smokestacks—
automatically comes together to form microtubules. The forces that bringtubulins together are much like those that fold an individual protein into
a compact shape: positive charges attract negative charges, oily aminoacids squeeze together to exclude water, and so forth. One end of a tubulin
molecule has a surface that is complementary to the opposite end of asecond tubulin molecule, so the two stick together. A third tubulin canthen stick onto the end of the second molecule, a fourth onto the end of
the third, and so on. As an analogy, think of the stacking of tuna cans.
In the grocery store where my family shops the tuna cans, because thebottom is beveled and is the same diameter as the straight-edged top, stacksnugly one on top of the other. If the stack is gently bumped, the cansremain in place.
If two tuna cans are stacked top-to-top instead of top-to-bottom,
though, they do not stack securely and can be moved by a casual bump.
Furthermore, if Brand X tuna does not have a beveled bottom, it does
not stack securely on itself because its cans do not have complementarysurfaces. The association of tubulin molecules is much more specific than
the stacking of tuna cans. After all, in the cell there are thousands ofdifferent proteins, and tubulin has to be sure to associate only with othertubulins—-not with just any protein that comes along. Perhaps, then, we
should think of tubulin as a tuna can with ten short needle-like projections
distributed over the top surface, and ten indentations in the bottom thatexactly match the positions of the projections on the top. Now no tuna canwill accidentally stack with any other type of can.
Extending our tuna analogy, suppose we also had several projections
sticking out one side of the can that were complementary to indentations
located almost, but not quite, on the exact opposite side. Then we could
stick the cans together side by side and, because the holes were not quite
opposite the projections, when we62 EXAMINING THE CONTENTS OF THE BOX
put more cans together they would eventually circle around and forma closed loop. Stacking loops upon loops we eventually (after thoroughly
mixing our metaphors) make a structure like a smokestack from our tuna
cans.
Although tubulin has the power to self-associate into microtubules,
microtubules do not aggregate with one another without help from otherproteins. There is a good reason for this: microtubules have a number ofjobs to do in the cell. For most jobs, single, unassociated microtubules
are needed. For other jobs (including ciliary motion), however, bundles of
microtubules are needed. So microtubules lie around individually, like therods from the game of pick-up sticks, unless purposely bundled together
for a particular job.
In photographs of cilia taken by an electron microscope, several
different types of connectors can be seen tying together the individual
microtubules (see Figure 3-2). There is a protein that bridges the twocentral single microtubules in the middle of the cilium. Also, from eachof the double microtubules, a radial spoke projects toward the center ofthe cilium. The structure ends in a knobby mass called the spoke head.
Finally, a protein called nexin connects each outer; double microtubule tothe one beside it.
Two other projections adorn each peripheral microtubule; they arecalled the outer arm and the inner arm. Biochemical analysis has shownthat these projections contain a protein called dynein. Dynein is a memberof a class of proteins called motor proteins, which function as tiny motors
in the cell, powering mechanical motion. 

HOW A CILIUM WORKS

Knowing the structure of a complex machine and knowing how it
works are two different matters. One could open the hood of a car andtake pictures of the motor until the cows come home, but the snapshots bythemselves would not give a clear idea of how the different parts produced
the function. Ultimately, in order to find out how a thing works, you haveto take it apart and reassemble it, stopping at many points to see if function
has yet been restored. Even this may notROW, ROW, ROW YOUR BOAT 63
yield a clear idea of how the machine operates, but it does give aworking knowledge of which components are critical. The basic strategy ofbiochemistry in this century has been to take apart molecular systems andtry to put them back together. The strategy has yielded enormous insights
into the operations of the cell.
 Experiments of this sort have given biochemists clues to how thecilium works. The first clue comes from isolated cilia. Nature has kindly
arranged it so that cilia can be separated from cells by vigorous shaking.
The shaking breaks off the projections cleanly and, by spinning thesolution at high speed (which causes big, heavy particles to sediment
more quickly than small, light particles), one can obtain a solution ofpure cilia in a test tube. If the cilia are stripped of their membrane andthen supplied with a chemical form of energy called ATP, they will beatin characteristic whip-like fashion. This result shows that the motor to
power ciliary motion resides in the cilium itself—not in the interior of the
now-missing cell. The next clue is that if (through biochemical tricks) thedynein arms are removed but the rest of the cilium is left intact, then thecilium is paralyzed, as if in rigor mortis. Adding back fresh dynein to thestiffened cilia allows motion to resume. So it appears that the motor of thecilium is contained in the dynein arms.
Further experiments gave more clues. There are enzymes (called
proteases) that have the ability to chew up other proteins, decomposing
them into amino acids. When a small amount of a protease is added for ashort time to a solution containing cilia, the protease quickly slices up thenexin linkers at the edge of the structure. The rest of the cilium remains
intact. The reason that the protease rapidly attacks the linkers is that,
unlike the other proteins of the cilium, the nexin linkers are not folded
up tightly; instead, they are loose, flexible chains. Because they are loose,the protease can cut them as rapidly as a pair of scissors can cut a paper
ribbon. (The protease cuts tightly folded proteins as rapidly as scissors cut
a closed paperback book.)
Proteases allowed biochemists to see how a cilium would work without
nexin linkers. What would removal of the linkers do? Perhaps the cilium
would work just fine without them, or perhaps it would go into rigor mortis
as it did when the dynein arms were removed.

64 EXAMINING THE CONTENTS OF THE BOX
In fact, neither of these possibilities occurred. Instead, the linkerlesscilium did something quite unexpected. When biochemical energy was
supplied to the cilium, instead of bending, it rapidly unraveled. The
individual microtubules began to slide past one another like the segmentsof a radio antenna slide past one another when it is opened. They continued
to slide until the length of the cilium had increased by almost tenfold.
From this result biochemists concluded that the motor was working, since
something had to move the individual microtubules. They also concluded
that the nexin linkers are needed to keep the cilium together when it istrying to bend.
These clues have led to a model for how the cilium works (see Figure3-2). Imagine several smokestacks made of tuna cans that are tightly held
together. The tuna can smokestacks are connected by slack wires. Attached
to one smokestack is a little motor with an arm that reaches out and holds
on to a tuna can in a neighboring smokestack. The motor arm pushes thesecond smokestack down, sliding it past the first one. As the smokestacks
slide past each other, the slack wires begin to stretch and become taut. As the
motor arm pushes more, the strain from the wire makes the smokestacks
bend. Thus the sliding motion has been converted into a bending motion.
Now, let's translate the analogy into biochemical terms. The dynein arms
on one microtubule attach to a second, neighboring microtubule, andthe dynein uses the biological energy of ATP to «walk up» its neighbor.
When this happens the two microtubules begin to slide past each other.
In the absence of nexin, they would continue to slide until they separated;
however, the protein cross-links prevent neighboring microtubules fromsliding by more than a short distance. When the flexible nexin linkers
have been elongated to their limit, further walking by dynein makes thenexin linkers tug on the microtubules. As dynein continues its walk,strain increases. Fortunately the microtubules are somewhat flexible, so
the dynein-in-duced sliding motion is converted to a bending motion. Now, let us sit back, review the workings of the cilium, and consider
what they imply. What components are needed for a cilium to work?
Ciliary motion certainly requires microtubules; otherwise, there would be
no strands to slide. Additionally it requires a motor, or else the mi-

ROW, ROW, ROW YOUR BOAT 65
crotubules of the cilium would lie stiff and motionless. Furthermore,
it requires linkers to tug on neighboring strands, converting the sliding
motion into a bending motion, and preventing the structure from fallingapart. All of these parts are required to perform one function: ciliary
motion. Just as a mousetrap does not work unless all of its constituent
parts are present, ciliary motion simply does not exist in the absence of
microtubules, connectors, and motors. Therefore we can conclude that thecilium is irreducibly complex—an enormous monkey wrench thrown into
its presumed gradual, Darwinian evolution.
The fact that the cilium is irreducibly complex should surprise no one.
Earlier in this chapter we saw that a swimming system requires a paddle
to contact the water, a motor or source of energy, and a connector to link
the two. All systems that move by paddling—ranging from my daughter's
toy fish to the propeller of a ship—fail if any one of the components isabsent. The cilium is a member of this class of swimming systems. The
microtubules are the paddles, whose surface contacts the water and pushes
against it. The dynein arms are the motors, supplying the force to movethe system. The nexin arms are the connectors, transmitting the force ofthe motor from one microtubule to its neighbor.2
The complexity of the cilium and other swimming systems is inherent
in the task itself. It does not depend on how large or small the system is,whether it has to move a cell or move a ship: in order to paddle, several
components are required. The question is, how did the cilium arise?

AN INDIRECT ROUTE

Some evolutionary biologists—like Richard Dawkins—have fertile
imaginations. Given a starting point, they almost always can spin a story
to get to any biological structure you wish. The talent can be valuable,
but it is a two-edged sword. Although they might think of possible
evolutionary routes other people overlook, they also tend to ignore details
and roadblocks that would trip up their scenarios. Science, however,cannot ultimately ignore relevant details, and at the molecular level all the«details» become critical. If a molecular nut or bolt is missing, then thewhole system can crash. Because the cilium is

66 EXAMINING THE CONTENTS OF THE BOX
irreducibly complex, no direct, gradual route leads to its production.
So an evolutionary story for the cilium must envision a circuitous route,perhaps adapting parts that were originally used for other purposes.
Let's try, then, to imagine a plausible indirect route to a cilium using preexisting parts of the cell.
To begin, microtubules occur in many cells and are usually used asmere structural supports, like girders, to prop up cell shape. Furthermore, motor proteins also are involved in other cell functions, such astransporting cargo from one end of the cell to another. The motor proteins
are known to travel along microtubules, using them as little highways to
get from one point to another. An indirect evolutionary argument mightsuggest that at some point several microtubules stuck together, maybe
to reinforce some particular cell shape. After that, a motor protein that
normally traveled on microtubules might have accidentally acquired theability to push two neighboring microtubules, causing a slight bending
motion that somehow helped the organism survive. Further small
improvements gradually produced the cilium we find in modern cells.
Intriguing as this scenario may sound, though, critical details areoverlooked. The question we must ask of this indirect scenario is one forwhich many evolutionary biologists have little patience: but how exactly?
For example, suppose you wanted to make a mousetrap. In yourgarage you might have a piece of wood from an old Popsicle stick (forthe platform), a spring from an old wind-up clock, a piece of metal (forthe hammer) in the form of a crowbar, a darning needle for the holding
bar, and a bottle cap that you fancy to use as a catch. But these pieces
couldn't form a functioning mousetrap without extensive modification,
and while the modification was going on, they would be unable to work as
a mousetrap. Their previous functions make them ill-suited for virtually
any new role as part of a complex system.
In the case of the cilium, there are analogous problems. The mutatedprotein that accidentally stuck to microtubules would block their function
as «highways» for transport. A protein that indiscriminately boundmicrotubules together would disrupt the cell's shape—just as a building's
shape would be disrupted by an erroneously placed cable that accidentallypulled together girders supporting the building. A linker that strengthened
microtubule bundles for structural supports

ROW, ROW, ROW YOUR BOAT 67
would tend to make them inflexible, unlike the flexible linker nexin.
An unregulated motor protein, freshly binding to microtubules, would
push apart microtubules that should be close together. The incipientcilium would not be at the cell surface. If it were not at the cell surface,then internal beating could disrupt the cell; but even if it were at the cellsurface, the number of motor proteins would probably not be enough tomove the cilium. And even if the cilium moved, an awkward stroke would
not necessarily move the cell. And if the cell did move, it would be an
unregulated motion using energy and not corresponding to any need of
the cell. A hundred other difficulties would have to be overcome before an
incipient cilium would be an improvement for the cell.

SOMEBODY MUST KNOW

The cilium is a fascinating structure that has intrigued scientists
from many disciplines. The regulation of its size and structure interests
biochemists; the dynamics of its power stroke fascinate biophysicists;
the expression of the many separate genes coding for its components
engrosses the minds of molecular biologists. Even physicians study them,because cilia are medically important: they occur in some infectious
microorganisms, and cilia in the lungs get clogged in the genetic diseasecystic fibrosis. A quick electronic search of the professional literatureshows more than a thousand papers in the past several years that havecilia or a similar word in the title. Papers have appeared on related topics
in almost all the major biochemistry journals, including Science, Nature,
Proceedings of the National Academy of Sciences, Biochemistry, Journal of
Biological Chemistry, Journal of Molecular Biology, Cell, and numerous
others. In the past several decades, probably ten thousand papers havebeen published concerning cilia.
Since there is such a large literature on the cilium, since it is of interest to
such diverse fields, and since it is widely stated that the theory of evolution
is the basis of all modern biology, then one would expect that the evolutionof the cilium would be the subject of a significant number of papers in
the professional literature. One might also expect that, although perhaps
some details would be harder to explain than others, on the whole scienceshould have a good grasp of how the cilium evolved. The intermediatestages it probably went

68 EXAMINING THE CONTENTS OF THE BOX
through, the problems that it would encounter at early stages, thepossible routes around such problems, the efficiency of a putative incipientcilium as a swimming system—all of these would certainly have beenthoroughly worked over. In the past two decades, however, only two
articles even attempted to suggest a model for the evolution of the cilium
that takes into account real mechanical considerations. Worse, the two
papers disagree with each other even about the general route such an
evolution might take. Neither paper discusses crucial quantitative details,
or possible problems that would quickly cause a mechanical device such asa cilium or a mousetrap to be useless.
The first paper, authored by T. Cavalier-Smith, appeared in 1978 in ajournal called BioSystems.3 The paper does not try to present a realistic,
quantitative model for even one step in the development of a cilium ina cell line originally lacking that structure. Instead it paints a picture ofwhat the author imagines must have been significant events along theway to a cilium. These imaginary steps are described in phrases such as«flagella [long cilia are frequently called «flagella»] are so complex that
their evolution must have involved many stages»; «l suggest that flagellainitially need not have been motile, but were slender cell extensions»;«organisms would evolve with a great variety of axonemal structures»; and«it is likely that mechanisms of phototaxis [motion toward light] evolved
simultaneously with flagella.»
The quotations give the flavor of the fuzzy word-pictures typical ofevolutionary biology. The lack of quantitative details—a calculation
or informed estimation based on a proposed intermediate structureof how much any particular change would have improved the active
swimming ability of the organism—makes such a story utterly useless forunderstanding how a cilium truly might have evolved.
Let me hasten to add that the author (a well-known scientist who hasmade a number of important contributions to cell biology) didn't intend
that the paper should be taken as presenting a realistic model; he was justtrying to be provocative. He was hoping to entice other workers with thepromise of his model, however vaguely constructed—to goad them into
doing some work to flesh out the emaciated skeleton. Such provocation
can be an important service in science. Unfortunately, in the intervening
years no one has built upon the model.
The second paper, authored nine years later by a Hungarian scien-ROW, ROW, ROW YOUR BOAT 69
tist named Eörs Szathmary and also appearing in BioSystems, issimilar in many ways to the first paper.4 Szathmary is an advocate of theidea, championed by Lynn Margulis, that cilia resulted when a type ofswimming bacterium called a «spirochete» accidentally attached itself to a
eukaryotic cell.5 The idea faces the considerable difficulty that spirochetes
move by a mechanism (described later) that is totally different from thatfor cilia. The proposal that one evolved into the other is like a proposal thatmy daughter's toy fish could be changed, step by Darwinian step, into a
Mississippi steamboat. Margulis herself is not concerned with mechanicaldetails; she is content to look for general similarities in some components
of cilia and bacterial swimming systems. Szathmary attempted to go a little
further and actually discuss mechanical difficulties that would have to be
overcome in such a scenario. Inevitably, however, his paper (like CavalierSmith's) is a simple word-picture that presents an underdeveloped modelto the scientific community for further work. It also has failed at provoking
such experimental or theoretical work, either by the author or by others.
Margulis and Cavalier-Smith have clashed in print in recent years.6
Each points out the enormous problems with the other's model, and eachis correct. What is fatal, however, is that neither side has filled in any
mechanistic details for its model. Without details, discussion is doomed to
be unscientific and fruitless. The scientific community at large has ignored
both contributions; neither paper has been cited by other scientists morethan a handful of times in the years since publication.7
The amount of scientific research that has been and is being doneon the cilium—and the great increase over the past few decades in our
understanding of how the cilium works—lead many people to assume
that even if they themselves don't know how the cilium evolved, somebody
must know. But a search of the professional literature proves them wrong.
Nobody knows.

THE BACTERIAL FLAGELLUM

We humans tend to have a rather exalted opinion of ourselves, and that
attitude can color our perception of the biological world. In particular, ourattitude about what is higher and lower in biology, what is an advanced
organism and what is a primitive organism, naturally

70 EXAMINING THE CONTENTS OF THE BOX
starts with the presumption that the pinnacle of nature is ourselves.
The presumption can be defended by citing human dominance, and alsowith philosophical arguments. Nonetheless, other organisms, if they could
talk, could argue strongly for their own superiority. This includes bacteria,
which we often think of as the rudest forms of life.
Some bacteria boast a marvelous swimming device, the flagellum, which
has no counterpart in more complex cells.8 In 1973 it was discovered thatsome bacteria swim by rotating their flagella. So the bacterial flagellum
acts as a rotary propeller—in contrast to the cilium, which acts more likean oar.
 The structure of a flagellum (Figure 5-3) is quite different from thatof a cilium. The flagellum is a long, hairlike filament embedded in thecell membrane. The external filament consists of a single type of protein,called «flagellin.» The flagellin filament is the paddle surface that contacts
the liquid during swimming. At the end of the flagellin filament near thesurface of the cell, there is a bulge in the thickness of the flagellum. It is herethat the filament attaches to the rotor drive. The attachment material iscomprised of something called «hook protein.» The filament of a bacterial
flagellum, unlike a cilium, contains no motor protein; if it is broken off,
the filament just floats stiffly in the water. Therefore the motor that rotates
the filament-propeller must be located somewhere else. Experiments havedemonstrated that it is located at the base of the flagellum, where electron
microscopy shows several ring structures occur. The rotary nature of
the flagellum has clear, unavoidable consequences, as noted in a popularbiochemistry textbook:[The bacterial rotary motor] must have the same mechanical elements
as other rotary devices: a rotor (the rotating element) and a stator (thestationary element.)9

The rotor has been identified as the M ring in Figure 3-3, and the stator
as the S ring. The rotary nature of the bacterial flagellar motor was a startling,
unexpected discovery. Unlike other systems that generate mechanicalmotion (muscles, for example) the bacterial motor does not directly use
energy that is stored in a «carrier» molecule such as ATP. Rather, toROW, ROW, ROW YOUR BOAT 71
FIGURE 3-3(Top) Drawing of a bacterial flagellum showing the filament,
hook and the motor imbedded in the inner and outer cell
membranes and the cell wall. (Bottom) One proposed modelfor the functioning of the acid-driven, rotary motor. The
drawing shows the internal complexity of the motor, which
is not discussed in the text.

72 EXAMINING THE CONTENTS OF THE BOX
move the flagellum it uses the energy generated by a flow of acidthrough the bacterial membrane. The requirements for a motor based onsuch a principle are quite complex and are the focus of active research. A
number of models for the motor have been suggested; none of them are
simple. (One such model is shown in Figure 3-3 just to give the reader ataste of the motor's expected complexity.)
The bacterial flagellum uses a paddling mechanism. Therefore it mustmeet the same requirements as other such swimming systems. Because
the bacterial flagellum is necessarily composed of at least three parts—a
paddle, a rotor, and a motor—it is irreducibly complex. Gradual evolutionof the flagellum, like the cilium, therefore faces mammoth hurdles.
The general professional literature on the bacterial flagellum is about asrich as the literature on the cilium, with thousands of papers published on
the subject over the years. That isn't surprising; the flagellum is a fascinating
biophysical system, and flagellated bacteria are medically important. Yet
here again, the evolutionary literature is totally missing. Even though weare told that all biology must be seen through the lens of evolution, no
scientist has ever published a model to account for the gradual evolutionof this extraordinary molecular machine.

IT ONLY GETS WORSE

Above I noted that the cilium contains tubulin, dynein, nexin, andseveral other connector proteins. If you take these and inject theminto a cell that lacks a cilium, however, they do not assemble to give afunctioning cilium. Much more is required to obtain a cilium in a cell.
A thorough biochemical analysis shows that a cilium contains over two
hundred different kinds of proteins; the actual complexity of the cilium
is enormously greater than what we have considered. All of the reasonsfor such complexity are not yet clear and await further experimental
investigation. Other tasks for which the proteins might be required,however, include attachment of the cilium to a base structure inside thecell; modification of the elasticity of the cilium; control of the timing of thebeating; and strengthening of the ciliary membrane.
The bacterial flagellum, in addition to the proteins already discussed,
requires about forty other proteins for function. Again, theROW, ROW, ROW YOUR BOAT 73
exact roles of most of the proteins are not known, but they include signals
to turn the motor on and off; «bushing» proteins to allow the flagellum topenetrate through the cell membrane and cell wall; proteins to assist in theassembly of the structure; and proteins to regulate the production of theproteins that make up the flagellum.
In summary, as biochemists have begun to examine apparently simple
structures like cilia and flagella, they have discovered staggering complexity,with dozens or even hundreds of precisely tailored parts. It is very likelythat many of the parts we have not considered here are required for any
cilium to function in a cell. As the number of required parts increases,
the difficulty of gradually putting the system together skyrockets, andthe likelihood of indirect scenarios plummets. Darwin looks more andmore forlorn. New research on the roles of the auxiliary proteins cannot
simplify the irreducibly complex system. The intransigence of the problem
cannot be alleviated; it will only get worse. Darwinian theory has given no
explanation for the cilium or flagellum. The overwhelming complexity ofthe swimming systems push us to think it may never give an explanation.
As the number of systems that are resistant to gradualist explanation
mounts, the need for a new kind of explanation grows more apparent. Cilia
and flagella are far from the only problems for Darwinism. In the next
chapter I will look at the biochemical complexity underlying the apparent
simplicity of blood clotting.

CHAPTER 4

RUBE GOLDBERG IN THE BLOOD

SATURDAY MORNING CARTOONSThe name of Rube Goldberg—the great cartoonist who entertained
America with his silly machines (Figure 4-1)—lives on in our culture,
although the man himself has pretty much faded from view. I was
introduced to the notion of Rube Goldberg machine as a kid watching
Saturday morning cartoons. My favorite cartoon was the Bugs Bunnyshow, and I always enjoyed the loud-mouthed rooster Foghorn Leghorn.
I remember a number of episodes in which Foghorn Leghorn would be
stuck baby-sitting some smart young chicken with thick glasses while hiswidowed mother (usually rich) went shopping. At some point Foghorn
would annoy the youngster, who would then plot his revenge. A brief scene
would show the perturbed chick scribbling some equations on a piece of
paper. This got across just how smart he was (after all, you have to be pretty
smart to scribble equations) and was an omen that the revenge would be
exacted in a precise, scientific way.
A scene or two later Foghorn would be walking along, notice a dollar
bill or some other bait on the ground, and pick it up. The dollar was tied
by a string to a stick that was propped against a ball. When

74

RUBE GOLDBERG IN THE BLOOD 75

FIGURE 4-1 A Rube Goldberg Machine

76 EXAMINING THE CONTENTS OF THE BOX
the dollar bill was moved, the attached string pulled down the stickand the ball would start to roll away as Foghorn stared slack-jawed at thedeveloping action. The ball then would fall off a cliff onto the raised endof a seesaw, smacking it down and sending a rock with an attached pieceof sandpaper hurtling into the air. On its upward journey the sandpaper
would strike a match sticking out of the cliff, which lit the fuse to a cannon.
The cannon would fire; on its downward track the cannonball would hit
the rim of a funnel (the only allowance for error in the whole scenario),
roll around the edge a few times, and fall through. As it came out of thefunnel, the cannonball would hit against a lever that started a circularsaw. The saw would cut through a rope, which was holding up a telephonepole. Slowly the telephone pole would begin to fall, and too late Foghorn
Leghorn would realize that the fascinating show was at his expense. As heturns to run, the very tip of the telephone pole smacks him on the headand drives him like a peg into the ground.
When you think about it for a moment, you realize that the Rube
Goldberg machine is irreducibly complex. It is a single system composedof several interacting parts that contribute to the basic function, andwhere the removal of any one of the parts causes the system to cease
functioning. Unlike the examples of irreducible complexity discussed inprevious chapters—the mousetrap, the eukaryotic cilium, and the bacterial
flagellum—the cartoon system is not a single piece where the components
simultaneously exert force against each other. Rather, it is composed of
separate pieces each acting in turn, one after the other, to accomplish its
function.
Because the components of the cartoon system are separated from eachother in time and space, just one of them (the telephone pole) accomplishes
the ultimate purpose of the system (bopping the victim on the head).
Nonetheless, the complexity of the system is not thereby reduced, because
all system components are required to deliver the blow at the correct time
and the correct place. If the mechanism to trigger its fall were not in place,
Foghorn could walk back and forth in front of the telephone pole all day
and no harm would come to him.
Just as one can catch a mouse with a glue trap instead of a mechanicaltrap, there are other systems that can deliver a crushing blow to Foghorn
Leghorn. You could use a baseball bat, or chop the pole down with an ax
while Foghorn was standing in the right place. You could

RUBE GOLDBERG IN THE BLOOD 77
use a nuclear bomb instead of a pole, or attach the string on the bait
directly to a shotgun. But none of these other systems are Darwinianprecursors to the system used in the cartoon. For example, suppose thestring were attached to a dollar bill and directly to the cannon, which
would then blast the rooster when he picked up the bait. A Darwiniantransformation of that simpler system into the more complex system inthe cartoon would require gradually repositioning the cannon, pointing it
in a different direction, removing the string from the cannon, reattaching
it to the stick, and adding the other paraphernalia. Clearly, however, thesystem therefore would be out of commission much of the time, so a stepby-step Darwinian transformation is not possible.
Rube Goldberg systems always get a good laugh; the audience enjoys
watching the contraption work and appreciates the humor in applying
great gobs of ingenuity to a silly purpose. But sometimes a complicatedsystem is used for a serious purpose. In this case the humor fades, butadmiration for the delicate interactions of the components remains.
Modern biochemists have discovered a number of Rube Goldberg-likesystems as they probe the workings of life on the molecular scale. In thebiochemical systems the string, stick, ball, seesaw, rock, sandpaper, match,fuse, cannon, cannonball, funnel, saw, rope, and telephone pole of the
cartoon are replaced by proteins with eye-glazing names such as «plasma
thromboplastin antecedent» or «high-molecular-weight kininogen.» The
inner balance and crisp functioning, however, are the same.

OF MILK CARTONS AND CUT FINGERS

When Charles Darwin was climbing the rocks of the Galapagos
Islands—pursuing the finches that would eventually bear his name—hemust have cut his finger occasionally or scraped a knee. Young adventurer
that he was, he probably paid no attention to the little stream of blood
trickling out. Pain was a fact of life to the intrepid island explorer, and it
had to be borne patiently if any work were to get done.
Eventually the blood would have stopped flowing, and the cut would
have healed. If Darwin noticed, it would not have done him much good to
speculate about what was going on. He didn't have

78 EXAMINING THE CONTENTS OF THE BOX
enough information to even guess at the underlying mechanism of clot
formation; the discovery of the structure of the molecules of life lay morethen a century in the future. Darwin was an intellectual giant and a great
innovator, but no one can guess the future, especially in critical details.
Blood behaves in a peculiar way. When a container of liquid—like acarton of milk, or a tank truck filled with gasoline—springs a leak, thefluid drains out. The rate of flow can depend on the thickness of theliquid (for example, maple syrup will leak more slowly than alcohol), but
eventually it all comes out. No active process resists it. In contrast, whena person suffers a cut it ordinarily bleeds for only a short time before aclot stops the flow; the clot eventually hardens, and the cut heals over.
Blood clot formation seems so familiar to us that most people don't give itmuch thought. Biochemical investigation, however, has shown that bloodclotting is a very complex, intricately woven system consisting of a score ofinterdependent protein parts. The absence of, or significant defects in, any
one of a number of the components causes the system to fail: blood does
not clot at the proper time or at the proper place.
Some tasks leave little room for error. For example, the most frightening
part of an airplane ride for me is the landing. Much of the fear comesfrom knowing that the plane has to skip over the houses or trees that often
are near an airport, and also from realizing that the plane has to stop
before it goes off the end of the runway. A few years ago a plane skidded
off a runway at LaGuardia Airport into Long Island Sound, killing several
people; and it seems that headlines frequently tell of planes crashing justshort of the runway. If runways were twenty miles long instead of one
mile, I for one would feel more secure.
The landing of an airplane is just one example of a system that has
to work within very tight restrictions to avoid disaster. Even the Wright
brothers had to worry about landing properly. A little too short or a little
too long on the landing, or aiming a little too low or a little too high,and the plane and passengers are in big trouble. But imagine the greaterdifficulty of landing a plane on autopilot—with no conscious agent toguide it! Blood clotting is on autopilot, and blood clotting requires extreme
precision. When a pressurized blood circulation system is punctured, aclot must form quickly or the animal will bleed to death. If blood congeals
at the wrong time or place, though, then the

RUBE GOLDBERG IN THE BLOOD 79
clot may block circulation as it does in heart attacks and strokes.
Furthermore, a clot has to stop bleeding all along the length of the cut,sealing it completely. Yet blood clotting must be confined to the cut or theentire blood system of the animal might solidify, killing it. Consequently,
the clotting of blood must be tightly controlled so that the clot forms only
when and where it is required.

PATCHWORKOver the next few pages you will meet the score of protein players in thegame of blood clotting and learn a bit about their roles. Like members ofa sports team, some of the players have strange names. Don't worry if thenames or the roles of the protein quickly slip your mind—the purpose of
the discussion is not for you to memorize trivia. (Besides, the names andrelationships will all be shown in Figure 4-3.) Rather, my purpose is to help
you get a feel for the complexity of blood clotting and to determine if it
could have arisen step by step.
 About 2 to 3 percent of the protein in blood plasma (the part that's left
after the red blood cells are removed) consists of a protein complex calledfibrinogen.1 The name fibrinogen is easy to remember because the protein
makes «fibers» that form the clot. Yet fibrinogen is only the potential
clot material. Like the telephone pole before it is felled in the story about
Foghorn Leghorn, fibrinogen is a weapon waiting to be unleashed. Almost
all of the other proteins involved in blood clotting control the timing
and placement of the clot. This too is similar to our cartoon example: allcomponents except the telephone pole were required to control the pole's
fall.
Fibrinogen is a composite of six protein chains, containing twin pairsof three different proteins. Electron microscopy has shown that fibrinogenis a rod-shaped molecule, with two round bumps on each end of the rod
and a single round bump in the middle. So fibrinogen resembles a set ofbarbells with an extra set of weights in the middle of the bar.
Normally fibrinogen is dissolved in plasma, like salt is dissolved inocean water. It floats around, peacefully minding its own business, until
a cut or injury causes bleeding. Then another protein, called thrombin,slices off several small pieces from two of the three80 EXAMINING THE CONTENTS OF THE BOX
pairs of protein chains in fibrinogen. The trimmed protein—now
called fibrin2—has sticky patches exposed on its surface that had been
covered by the pieces that were cut off. The sticky patches are precisely
complementary to portions of other fibrin molecules. The complementary
shapes allow large numbers of fibrins to aggregate with each other, like thetubulin-tuna cans from Chapter 3. Just as tubulin does not aggregate toform a random glob but forms a smokestack, however, neither do fibrins
stick randomly. Because of the shape of the fibrin molecule, long threads
form, cross over each other, and (much as a fisherman's net traps fish)
make a pretty protein meshwork that entraps blood cells. This is the initialclot (Figure 4-2). The meshwork covers a large area with a minimum ofprotein; if it simply formed a lump, much more protein would be required
to clog up an area.
FIGURE 4-2
A blood cell caught in the fibrin protein meshwork of a clot.

RUBE GOLDBERG IN THE BLOOD 81
Thrombin, which cuts off the pieces from fibrinogen, is like the circularsaw from the Foghorn Leghorn cartoon. Like the saw, thrombin sets inmotion the final step of a controlled process. But what if the circular saw
ran continuously, without needing the other steps to turn it on? In thatcase the saw would immediately cut the rope holding up the telephonepole, well before Foghorn moseyed into the vicinity. Similarly, if the only
proteins involved in blood coagulation were thrombin and fibrinogen,the process would be uncontrolled. Thrombin would quickly clip all of
the fibrinogen to make fibrin; a massive clot would form throughout the
animal's circulatory system, solidifying it. Unlike cartoon characters,
real animals would rapidly perish. To avoid such an unhappy ending anorganism must control the activity of thrombin.

THE CASCADE The body commonly stores enzymes (proteins that catalyze a chemical
reaction, like the cleavage of fibrinogen) in an inactive form for later use.
The inactive forms are called proenzymes. When a signal is received thata certain enzyme is needed, the corresponding proenzyme is activated togive the mature enzyme. As with the conversion of fibrinogen to fibrin,proenzymes are often activated by cutting off a piece of the proenzymethat is blocking a critical area. The strategy is commonly used withdigestive enzymes. Large quantities can be stored as inactive proenzymes,
then quickly activated when the next good meal comes along.
Thrombin initially exists as the inactive form, prothrombin. Because it
is inactive, prothrombin can't cleave fibrinogen, and the animal is saved
from death by massive, inappropriate clotting. Still, the dilemma of control
remains. If the cartoon saw were inactivated, the telephone pole would not
fall at the wrong time. If nothing switches on the saw, however, then it
would never cut the rope; the pole wouldn't fall even at the right time. If
fibrinogen and prothrombin were the only proteins in the blood-clotting
pathway, again our animal would be in bad shape. When the animal
was cut, prothrombin would just float helplessly by the fibrinogen as theanimal bled to death. Because prothrombin cannot cleave fibrinogen to
fibrin, something is needed to activate prothrombin.

82 EXAMINING THE CONTENTS OF THE BOX
Perhaps the reader can see why the blood-clotting system is called acascade—a system where one component activates another component,
which activates a third component, and so on. Since things are beginningto get complicated, it will help a lot to keep track of the discussion with
Figure 4-3.
A protein called Stuart factor cleaves prothrombin, turning it into activethrombin that can then cleave fibrinogen to fibrin to form the blood clot.3
Unfortunately, as you may have guessed, if Stuart factor, prothrombin,and fibrinogen were the only blood-clotting proteins, then Stuart factor
would rapidly trigger the cascade, congealing all
FIGURE 4-3
The blood coagulation cascade. Proteins whose names areshown in normal type face are involved in promoting clot
formation; proteins whose names are italicized are involvedin the prevention, localization, or removal of blood clots.
Arrows ending in a bar indicate proteins acting to prevent,localize, or remove blood clots.

RUBE GOLDBERG IN THE BLOOD 83
the blood of the organism. So Stuart factor also exists in an inactive
form that must first be activated.
At this point there's a little twist to our developing chicken-and-egg
scenario. Even activated Stuart factor can't turn on prothrombin. Stuart
factor and prothrombin can be mixed in a test tube for longer than it would
take a large animal to bleed to death without any noticeable productionof thrombin. It turns out that another protein, called accelerin, is needed
to increase the activity of Stuart factor. The dynamic duo—accelerin
and activated Stuart factor— cleave prothrombin fast enough to do thebleeding animal some good. So in this step we need two separate proteinsto activate one proenzyme.
Yes, accelerin also initially exists in an inactive form, called proaccelerin(sigh). And what activates it? Thrombin! But thrombin, as we have seen,
is further down the regulatory cascade than proaccelerin. So thrombin
regulating the production of accelerin is like having the granddaughter
regulate production of the grandmother. Nonetheless, due to a very low
rate of cleavage of prothrombin by Stuart factor, it seems there is always
a trace of thrombin in the bloodstream. Blood clotting is therefore autocatalytic, because proteins in the cascade accelerate the production of
more of the same proteins.
We need to back up a little at this point because, as it turns out,
prothrombin as it is initially made by the cell can't be transformed into
thrombin, even in the presence of activated Stuart factor and accelerin.
Prothrombin must first be modified (not shown in Figure 4-2) by having
ten specific amino acid residues, called glutamate (Glu) residues, changedto «γ-carboxyglutamate (Gla) residues. The modification can be comparedto placing a lower jaw onto the upper jaw of a skull. The completed
structure can bite and hang on to the bitten object; without the lower jaw,
the skull couldn't hang on. In the case of prothrombin, Gla residues «bite»(or bind) calcium, allowing prothrombin to stick to the surfaces of cells.
Only the intact, modified calcium-prothrombin complex, bound to a cell
membrane, can be cleaved by activated Stuart factor and accelerin to givethrombin.
The modification of prothrombin does not happen by accident. Like
virtually all biochemical reactions, it requires catalysis by a specific84 EXAMINING THE CONTENTS OF THE BOX
enzyme. In addition to the enzyme, however, the conversion of Glu
to Gla needs another component: vitamin K. Vitamin К is not a protein;rather, it is a small molecule, like the 11-cis-retinal (described in Chapter 1)that is necessary for vision. Like a gun that needs bullets, the enzyme thatchanges Glu to Gla needs vitamin К to work. One type of rat poison isbased on the role that vitamin К plays in blood coagulation. The synthetic
poison, called «warfarin» (for the Wisconsin Alumni Research Fund,which receives a cut of the profits from its sale), was made to look likevitamin К to the enzyme that uses it. In the presence of warfarin the
enzyme is unable to modify prothrombin. When rats eat food poisoned
with warfarin, prothrombin is neither modified nor cleaved, and the
poisoned animals bleed to death.
But it still seems we haven't made much progress—now we have togo back and ask what activates Stuart factor. It turns out that it can be
activated by two different routes, called the intrinsic and the extrinsic
pathways. In the intrinsic pathway, all the proteins required for clotting
are contained in the blood plasma; in the extrinsic pathway, some clotting
proteins occur on cells. Let's first examine the intrinsic pathway. (Please
follow along using Figure 4-3.)
When an animal is cut, a protein called Hageman factor sticks to thesurface of cells near the wound. Bound Hageman factor is then cleaved bya protein called HMK to yield activated Hageman factor. Immediately theactivated Hageman factor converts another protein, called prekallikrein, to
its active form, kallikrein. Kallikrein helps HMK speed up the conversionof more Hageman factor to its active form. Activated Hageman factorand HMK then together transform another protein, called РТА, to its
active form. Activated РТА in turn, together with the activated form of
another protein (discussed below) called convertin, switch a protein called
Christmas factor to its active form. Finally, activated Christmas factor,
together with antihemophilic factor (which is itself activated by thrombin
in a manner similar to that of proaccelerin) changes Stuart factor to its
active form.
Like the intrinsic pathway, the extrinsic pathway is also a cascade. The
extrinsic pathway begins when a protein called proconvertin is turned
into convertin by activated Hageman factor and thrombin. In the presenceof another protein, tissue factor, convertin

RUBE GOLDBERG IN THE BLOOD 85changes Stuart factor to its active form. Tissue factor, however, only
appears on the outside of cells that are usually not in contact with blood.
Therefore, only when an injury brings tissue into contact with blood
will the extrinsic pathway be initiated. (A cut plays a role similar to thatof Foghorn Leghorn picking up the dollar. It is the initiating event—something outside of the cascade mechanism itself.)
The intrinsic and extrinsic pathways cross over at several points.
Hageman factor, activated by the intrinsic pathway, can switch on
proconvertin of the extrinsic pathway. Convertin can then feed backinto the intrinsic pathway to help activated РТА activate Christmas
factor. Thrombin itself can trigger both branches of the clotting cascadeby activating antihemophilic factor, which is required to help activatedChristmas factor in the conversion of Stuart factor to its active form, andalso by activating proconvertin. 
Slogging through a description of the blood-clotting system makes afellow yearn for the simplicity of a cartoon Rube Goldberg machine.

SIMILARITIES AND DIFFERENCES

There are some conceptual differences between Foghorn Leghorn's
cartoon contraption and the real-life blood clotting system; the differencesemphasize the greater complexity of the biochemical system. The mostimportant contrast is that the clotting cascade has to be turned off at somepoint before the organism completely solidifies (this will be discussed
shortly). A second difference is that the control pathway for blood clotting
splits in two. Potentially, then, there are two possible ways to trigger
clotting. The relative importance of the two pathways in living organisms
is still rather murky. Many experiments on blood clotting are hard to do;some of the proteins—especially the ones involved at the early stages ofthe pathway—are found in only minute amounts in blood. For example,
one hundred gallons of blood contain only about 1 one-thousandth of anounce of antihemophilic factor. Furthermore, because the initial stages ofclotting feed back to generate more of the initial activating proteins, it's
often quite difficult to sort out just who is activating whom.
There is also an important conceptual similarity between the

86 EXAMINING THE CONTENTS OF THE BOX
Foghorn attack system and the blood-clotting pathway: both are
irreducibly complex. Leaving aside the system before the fork in thepathway, where some details are less well known, the blood-clotting
system fits the definition of irreducible complexity. That is, it is a single
system composed of several interacting parts that contribute to the basic
function, and where the removal of any one of the parts causes the systemeffectively to cease functioning. The function of the blood clotting system
is to form a solid barrier at the right time and place that is able to stop
blood flow out of an injured vessel. The components of the system (beyond
the fork in the pathway) are fibrinogen, prothrombin, Stuart factor, andproaccelerin. Just as none of the parts of the Foghorn system is used foranything except controlling the fall of the telephone pole, so none of thecascade proteins are used for anything except controlling the formation ofa blood clot. Yet in the absence of any one of the components, blood does
not clot, and the system fails.
There are other ways to stop blood flow from wounds, but those ways
are not step-by-step precursors to the clotting cascade. For example, thebody can constrict blood vessels near a cut to help stanch blood flow. Also,
blood cells called platelets stick to the area around a cut, helping to plugsmall wounds. But those systems cannot be transformed gradually into
the blood-clotting system any more than a glue trap can be transformed
into a mechanical mousetrap.
The simplest blood-clotting system imaginable might be just a single
protein that randomly aggregated when the organism was cut. We can liken
this to a telephone pole that has been sawed completely through, balancing
precariously, depending on the slight vibrations of the ground as Foghorn
Leghorn walks by to set it off. The wind or other factors, however, might
easily topple the pole when the rooster was not around. Furthermore, thepole is not aimed in any particular direction (such as toward the bait)
where Foghorn is likely to be. Similarly, the simplistic clotting system
would be triggered inappropriately, causing random damage and wasting
resources. Neither the simplified cartoon or clotting «systems» would
meet the criterion of minimal function. In Rube Goldberg systems, it is
not the final activity (telephone pole falling, clot formation) that is the
problem—rather, it is the control system.
One could imagine a blood-clotting system that was somewhat simpler
than the real one—where, say, Stuart factor, after activation by

RUBE GOLDBERG IN THE BLOOD 87
the rest of the cascade, directly cuts fibrinogen to form fibrin, bypassing
thrombin. Leaving aside for the moment issues of control and timing ofclot formation, upon reflection we can quickly see that even such a slightly
simplified system cannot change gradually into the more complex, intact
system. If a new protein were inserted into the thrombin-less system it
would either turn the system on immediately—resulting in rapid death—or it would do nothing, and so have no reason to be selected. Because of thenature of a cascade, a new protein would immediately have to be regulated.
From the beginning, a new step in the cascade would require both aproenzyme and also an activating enzyme to switch on the proenzyme
at the correct time and place. Since each step necessarily requires several
parts, not only is the entire blood-clotting system irreducibly complex, but
so is each step in the pathway.
I think a ship canal is a good analogy for this aspect of the bloodclotting system. The Panama Canal allows ships to cross the Isthmus
from the Pacific Ocean to the Caribbean Sea. Because the land is higher
than sea level, water in a lock lifts a ship up to a level where it can travel
along for a while. Then another lock lifts the ship to the next level, andlocks on the other side lower the ship back down to sea level. At each lockthere is a gate that holds back the water as the ship is raised or lowered;
there is also a sluice or water pump that drains or fills the lock. From the
beginning each lock must have both features— a gate and a sluice—or
it does not function. Consequently, each of the locks along the canal isirreducibly complex. Analogously, each of the control points of the bloodclotting cascade needs both an inactive proenzyme and a separate enzyme
to activate it.

IT'S NOT OVER YET

 Once clotting has begun, what stops it from continuing until all the
blood in the animal has solidified? Clotting is confined to the site of injury
in several ways. (Please refer to Figure 4-3.) First, a plasma protein called
antithrombin binds to the active (but not the inactive) forms of mostclotting proteins and inactivates them. Antithrombin is itself relatively
inactive, however, unless it binds to a substance called heparin. Heparinoccurs inside cells and undamaged blood vessels. A second way in whichclots are localized is

88 EXAMINING THE CONTENTS OF THE BOX
through the action of protein C. After activation by thrombin, protein
С destroys accelerin and activated antihemophilic factor. Finally, a protein
called thrombomodulin lines the surfaces of the cells on the inside ofblood vessels. Thrombomodulin binds thrombin, making it less able to cut
fibrinogen and simultaneously increasing its ability to activate protein C.
When a clot initially forms, it is quite fragile: if the injured area isbumped the clot can easily be disrupted, and bleeding starts again. To
prevent this, the body has a method to strengthen a clot once it has formed.
Aggregated fibrin is «tied together» by an activated protein called FSF (for«fibrin stabilizing factor»), which forms chemical cross-links between
different fibrin molecules. Eventually, however the blood clot must be
removed after wound healing has progressed. A protein called plasmin
acts as a scissors specifically to cut up fibrin clots. Fortunately, plasmin
does not work on fibrinogen. Plasmin cannot act too quickly, however, or
the wound wouldn't have sufficient time to heal completely. It therefore
occurs initially in an inactive form called plasminogen. Conversion ofplasminogen to plasmin is catalyzed by a protein called t-PA. There arealso other proteins that control clot dissolution, including α2-antiplasmin,
which binds to plasmin, preventing it from destoying fibrin clots. The cartoon machine that conked Foghorn Leghorn depended criticallyon the precise alignment, timing, and structure of many components. If thestring attached to the dollar bill were too long, or the cannon misaligned,then the whole system would fail. In the same way, the clotting cascade
depends critically on the timing and speed at which the different reactions
occur. An animal could solidify if thrombin activated proconvertin at
the wrong time; it could bleed to death if proaccelerin or antihemophilic
factor were activated too slowly. An organism would fade into history if
thrombin activated protein С much faster than it activated proaccelerin,
or if antithrombin inactivated Stuart factor as fast as it was formed. If
plasminogen was activated immediately upon clot formation, then it
would quickly dissolve the clot, frustrating the pathway.
The formation, limitation, strengthening, and removal of a blood clot is
an integrated biological system, and problems with single components cancause the system to fail. The lack of some blood clotting

RUBE GOLDBERG IN THE BLOOD 89
factors, or the production of defective factors, often results in serious
health problems or death. The most common form of hemophilia
arises from a deficiency of antihemophilic factor, which helps activatedChristmas factor in the conversion of Stuart factor to its active form. Lackof Christmas factor is the second most common form of hemophilia.
Severe health problems can also result if other proteins of the clotting
pathway are defective, although these are less common. Bleeding disorders
also accompany deficiencies in FSF, vitamin K, or α2-antiplasmin, which
are not involved directly in clotting. Additionally, lack of protein С causes
death in infancy due to the occurrence of numerous, inappropriate clots.

SHUFFLIN' AROUND

Is it possible that this ultra-complex system could have evolved
according to Darwinian theory? Several scientists have devoted much
effort to wondering how blood coagulation might have evolved. In thenext section you will see what the state-of-the-art explanation is for bloodclotting in the professional science literature. But first, there are a few
details to attend to.
In the early 1960s it was noticed that some proteins had aminoacid sequences that were similar to other proteins' sequences. For
example, suppose the first ten amino acids in one protein sequence were
ANVLEGKIIS, and in a second protein ANLLDGKIVS. Those twosequences are alike at seven positions and different at three positions. In
some proteins, sequences can be similar over hundreds of amino acidpositions. To explain the similarity of two proteins it was theorized thatin the past a gene was somehow duplicated, and over time the two copiesof the gene independently accumulated changes (mutations) in theirsequences.4 After a while there would be two proteins whose sequenceswere similar, but not identical.
The king of Siam once asked his wise men for a proverb that would
be appropriate for any occasion. They suggested «This, too, shall pass.»
Well, in biochemistry an equally appropriate saying for all occasions is«Things are more complicated than they seem.» In the middle 1970s it was
shown that genes could occur in pieces. That is, the portion of DNA thatcoded for the left-hand portion of a protein could be separated along thesequence from portions that coded for the middle,

90 EXAMINING THE CONTENTS OF THE BOX
and these could be separated from the DNA that coded for the righthand portion. It was as if you looked up the word carnival in the dictionary
and found it listed as «hkcasafjrnivckjealksy.» One type of gene might bein one piece; another type might be in dozens of pieces.
The observation of split genes led to the hypothesis that perhaps new
proteins could be made by shuffling the DNA fragments of genes that codefor parts of old proteins—much as cards can be picked from several piles
to give a new arrangement. To support the hypothesis, advocates point tosimilarities in the amino acid sequences and shapes of discrete portions(called domains) of different proteins.
The proteins of the blood coagulation cascade are often used as evidence
for shuffling. Some regions of cascade proteins coded by separate genepieces have similarities in their amino acid sequences with other regions of
the same protein—that is, they are self-similar. Also, there are similarities
between regions of different proteins of the cascade. For example,
proconvertin, Christmas factor, Stuart factor, and prothrombin all have aroughly similar region of their amino acid sequences. Additionally, in all
those proteins the sequence is modified by vitamin K. Furthermore, theregions are similar in sequence to other proteins (not involved with blood
coagulation at all) that are also modified by vitamin K.
The sequence similarities are there for all to see and cannot be disputed.
By itself however, the hypothesis of gene duplication and shuffling says
nothing about how any particular protein or protein system was first
produced—whether slowly or suddenly, or whether by natural selection
or some other mechanism. Remember, a mousetrap spring might in some
way resemble a clock spring, and a crowbar might resemble a mousetrap
hammer, but the similarities say nothing about how a mousetrap is
produced. In order to claim that a system developed gradually by aDarwinian mechanism a person must show that the function of the system
could «have been formed by numerous successive, slight modifications.»

THE STATE OF THE ART

Now we're ready to move forward. In this section I'll reproduce anattempt at an evolutionary explanation of blood clotting offered by Rusell
Doolittle. What he has done is to hypothesize a series of steps in whichclotting proteins appear one after another. Yet, as I will show in the next
section, the explanation is seriously inadequate because no reasons are

RUBE GOLDBERG IN THE BLOOD 91
given for the appearance of the proteins, no attempt is made to calculate
the probability of the proteins' appearance, and no attempt is made toestimate the new proteins' properties.
Russell Doolittle, a professor of biochemistry at the Center for
Molecular Genetics, University of California, San Diego, is the mostprominent person interested in the evolution of the clotting cascade. From
the time of his Harvard Ph.D thesis, «The Comparative Biochemistry of
Blood Coagulation» (1961), Professor Doolittle has examined the clotting
systems of different, «simpler» organisms in the hope that that would
lead to an understanding of how the mammalian system arose. Doolittle
recently reviewed the state of current knowledge in an article in the journal
Thrombosis and Haemostasis.5 The journal is intended for professional
scientists and doctors of medicine who work on aspects of blood clotting.
Essentially, the audience for the journal is those people who know more
about blood clotting than anyone else on earth.
Doolittle begins his article by asking the big question: «How in theworld did this complex and delicately balanced process evolve? ... The
paradox was, if each protein depended on activation by another, how could
the system ever have arisen? Of what use would any part of the scheme bewithout the whole ensemble?»
These questions go to the heart of this book's inquiry. It is worth
quoting Doolittle's article at length. (The reader will find it helpful to refer
to Figure 4-3.) I have changed some technical terms in the quote to makeit more readable for a general audience.
Blood clotting is a delicately balanced phenomenon involving proteases,
antiproteases, and protease substrates. Generally speaking, each forward
action engenders some backward-inclined response. Various metaphors
can be applied to its step-by-step evolution: action-reaction, point andcounterpoint, or good news and bad news. My favorite, however; is yin
and yang.
In ancient Chinese cosmology, all that comes to be is the result of combining
the opposite principles yin and yang. Yang is the masculine principle
and embodies activity, height, heat, light and dryness. Yin, the feminine
counterpoint, personifies passivity, depth, cold, darkness and wetness.
Their marriage yields the true essence of all things. Keeping in mind thatit's only a metaphor, consider thefollowing yin and yang scenario for theevolution of vertebrate clotting.

92 EXAMINING THE CONTENTS OF THE BOX
I have arbitrarily designated the enzymes or proenzymes as the yang, andthe nonenzymes as the yin.
 Yin: Tissue Factor (TF) appears as the result of the duplication of a genefor [another protein] that binds EGF domains. The new gene product only
comes into contact with the blood or hemolymph after tissue damage.
Yang: Prothrombin appears in an ancient guise with EGF domain(s)attached, the result of a ... protease gene duplication and ... shuffling.
The EGF domain serves as a site for attachment to and activation by the
exposed TF.
Yin: A thrombin-receptor is fashioned by virtue of the duplication of a gene
for a [protein region that will stick in a cell membrane]. Cleavage by the TFactivated prothrombin effects cell contractility or clumping.
Yin again: Fibrinogen is bom, a bastard protein derived from a thrombinsensitive [elongated] father and a [protein with a compact structure for a]mother.
Yin again: Antithrombin III appears, the product of a duplication of a[protein with a similar overall structure].
Yang: Plasminogen is generated from the vast inventory of... proteases
already on hand. It comes with ... domains that can bind to fibrin. Its
activation by binding to bacterial proteins ... reflects a previous role as an
antibacterial agent.
Yin: Antiplasmin arises from the duplication and modification of [a proteinwith a similar overall structure], probably antithrombin.
Yin and Yang: A thrombin-activatable [cross-linking protein] is unleashed.
Yang: Tissue Plasminogen Activator (TPA) springs forth. Variously shuffleddomains allow it to bind to several substances, including fibrin.
Marriage: The modification of prothrombin by the acquisition of a «gla»domain. The ability to bind calcium and bind to specific [negativelycharged] surfaces is conferred.
Yin: The appearance of proaccelerin6 as the result of duplicating the [genefor a protein with a similar overall structure] and the acquisition of someother [gene pieces].
Yang: Stuart factor appears, a duplic[ate] of the recently gla-anointed
prothrombin; its ability to bind to proaccelerin can bring about... activation

RUBE GOLDBERG IN THE BLOOD 93
of prothrombin, independent of the . . . activation by TF.
Yang again: Proconvertin is duplicated from Stuart factor, liberatingprothrombin for better binding to fibrin. When combined with tissue factor,
proconvertin is able to activate Stuart factor by [cutting it).
Yang again: Christmas factor from Stuart factor. For a period, both bind toproaccelerin.
Yin: Antihemophilic factor from proaccelerin. Quickly adapts to interact
with Christmas factor.
Yang: Protein C is genetically derived from prothrombin. Inactivates
proaccelerin and antihemophilic factor by limited [cutting].
Divorce: Prothrombin engages in an exchange [of gene piecesl that leaves
it with [domains] for binding to fibrin in place of its EGF domains, which
are no longer needed for interaction with TF. 

HOW'S THAT AGAIN?

Now let's take a little time to give Professor Doolittle's scenario a
critical look. The first thing to notice is that no causative factors are cited.
Thus tissue factor «appears,» fibrinogen «is born,» antiplasmin «arises,»
TPA «springs forth,» a cross-linking protein «is unleashed,» and so forth.
What exactly, we might ask, is causing all this springing and unleashing?
Doolittle appears to have in mind a step-by-step Darwinian scenario
involving the undirected, random duplication and recombination of genepieces. But consider the enormous amount of luck needed to get the rightgene pieces in the right places. Eukaryotic organisms have quite a few
gene pieces, and apparently the process that switches them is random.
So making a new blood-coagulation protein by shuffling is like picking adozen sentences randomly from an encyclopedia in the hope of making
a coherent paragraph. Professor Doolittle does not go to the trouble ofcalculating how many incorrect, inactive, useless «variously shuffleddomains» would have to be discarded before obtaining a protein with, say,
TPA-like activity.
To illustrate the problem, let's do our own quick calculation. Consider
that animals with blood-clotting cascades have roughly 10,000 genes, eachof which is divided into an average of three pieces. This gives a total of
about 30,000 gene pieces. TPA has four different types of domains.7 By«variously shuffling,» the odds of getting those four domains together8

94 EXAMINING THE CONTENTS OF THE BOX
is 30,000 to the fourth power, which is approximately one-tenth to theeighteenth power.9 Now, if the Irish Sweepstakes had odds of winningof one-tenth to the eighteenth power, and if a million people played thelottery each year, it would take an average of about a thousand billion
years before anyone (not just a particular person) won the lottery. A
thousand billion years is roughly a hundred times the current estimateof the age of the universe. Doolittle's casual language («spring forth,»etc.) conceals enormous difficulties. The same problem of ultra-slim odds
would trouble the appearance of prothrombin («the result of a ... proteasegene duplication and ... shuffling»), fibrinogen («a bastard protein derived
from .. .»), plasminogen, proaccelerin, and each of the several proposed
rearrangements of prothrombin. Doolittle apparently needs to shuffle
and deal himself a number of perfect bridge hands to win the game.
Unfortunately, the universe doesn't have time to wait.
The second question to consider is the implicit assumption that a protein
made from a duplicated gene would immediately have the new, necessary
properties. Thus we are told that «tissue factor appears as the result of
the duplication of a gene for [another protein].» But tissue factor would
certainly not appear as the result of the duplication— the other protein
would. If a factory for making bicycles were duplicated, it would makebicycles, not motorcycles; that's what is meant by the word duplication.
A gene for a protein might be duplicated by a random mutation, but it
does not just «happen» to also have sophisticated new properties. Since
a duplicated gene is simply a copy of the old gene, an explanation for
the appearance of tissue factor must include the putative route it took toacquire a new function. This problem is discreetly avoided. Doolittle's
scheme runs into the same problem in the production of prothrombin, athrombin receptor, antithrombin, plasminogen, antiplasmin, proaccelerin,
Stuart factor, proconvertin, Christmas factor, antihemophilic factor, andprotein С— virtually every protein of the system!
The third problem in the blood-coagulation scenario is that it avoids
the crucial issues of how much, how fast, when, and where. Nothing issaid about the amount of clotting material initially available, the strengthof the clot that would be formed by a primitive system, the length of time
the clot would take to form once a cut ocurred, what fluid pressure the clot
would resist, how detrimental theRUBE GOLDBERG IN THE BLOOD 95
formation of inappropriate clots would be, or a hundred other suchquestions. The absolute and relative values of these factors and others could
make any particular hypothetical system either possible or (much more
likely) wildly wrong. For example, if only a small amount of fibrinogen
were available it would not cover a wound; if a primitive fibrin formed arandom blob instead of a meshwork, it would be unlikely to stop blood
flow. If the initial action of antithrombin were too fast, the initial actionof thrombin too slow, or the original Stuart factor or Christmas factor or
antihemophilic factor bound too loosely or too tightly (or if they boundto the inactive forms of their targets as well as the active forms), then thewhole system would crash. At no step—not even one—does Doolittle givea model that includes numbers or quantities; without numbers, there isno science. When a merely verbal picture is painted of the developmentof such a complex system, there is absolutely no way to know if it would
actually work. When such crucial questions are ignored we leave scienceand enter the world of Calvin and Hobbes.
Yet the objections raised so far are not the most serious. The mostserious, and perhaps the most obvious, concerns irreducible complexity.
I emphasize that natural selection, the engine of Darwinian evolution,
only works if there is something to select—something that is useful rightnow, not in the future. Even if we accept his scenario for purposes of
discussion, however, by Doolittle's own account no blood clotting appears
until at least the third step. The formation of tissue factor at the first stepis unexplained, since it would then be sitting around with nothing to
do. In the next step (prothrombin popping up already endowed with theability to bind tissue factor, which somehow activates it) the poor protoprothrombin would also be twiddling its thumbs with nothing to do until,
at last, a hypothetical thrombin receptor appears at the third step andfibrinogen falls from heaven at step four. Plasminogen appears in one step,
but its activator (TPA) doesn't appear until two steps later. Stuart factor
is introduced in one step, but whiles away its time doing nothing until
its activator (proconvertin) appears in the next step and somehow tissue
factor decides that this is the complex it wants to bind. Virtually every stepof the suggested pathway faces similar problems.
Simple words like «the activator doesn't appear until two steps later»
may not seem impressive until you ponder the implications.

96 EXAMINING THE CONTENTS OF THE BOX
Since two proteins—the proenzyme and its activator—are both
required for one step in the pathway, then the odds of getting boththe proteins together are roughly the square of the odds of getting one
protein. We calculated the odds of getting TPA alone to be one-tenth tothe eighteenth power; the odds of getting TPA and its activator together
would be about one-tenth to the thirty-sixth power! That is a horrendously
large number. Such an event would not be expected to happen even if theuniverse's ten-billion year life were compressed into a single second andrelived every second for ten billion years. But the situation is actuallymuch worse: if a protein appeared in one step10 with nothing to do, thenmutation and natural selection would tend to eliminate it. Since it is doing
nothing critical, its loss would not be detrimental, and production of thegene and protein would cost energy that other animals aren't spending.
So producing the useless protein would, at least to some marginal degree,
be detrimental. Darwin's mechanism of natural selection would actuallyhinder the formation of irreducibly complex systems such as the clotting
cascade.
Doolittle's scenario implicitly acknowledges that the clotting cascade isirreducibly complex, but it tries to paper over the dilemma with a hail of
metaphorical references to yin and yang. The bottom line is that clusters
of proteins have to be inserted all at once into the cascade. This can bedone only by postulating a «hopeful monster» who luckily gets all of theproteins at once, or by the guidance of an intelligent agent.
Following Professor Doolittle's example, we could propose a route bywhich the first mousetrap was produced: The hammer appears as the resultof the duplication of a crowbar in our garage. The hammer comes into
contact with the platform, the result of shuffling several Popsicle sticks.
The spring springs forth from a grandfather clock that had been used asa timekeeping device. The holding bar is fashioned from a straw sticking
out of a discarded Coke can, and the catch is unleashed from the cap on
a bottle of beer. But things just don't happen that way unless someone orsomething else is guiding the process.
Recall that Doolittle's audience for the article in Thrombosis andHaemostasis are the leaders in clotting research—they know the state of
the art. Yet the article does not explain to them how clotting might
				
		
		

RUBE GOLDBERG IN THE BLOOD 97
have originated and subsequently evolved; instead, it just tells a story.
The fact is, no one on earth has the vaguest idea how the coagulation cascadecame to be.

APPLAUSE, APPLAUSE

The preceding discussion was not meant to disparage Russell Doolittle,
who has done a lot of fine work over the years in the field of protein
structure. In fact he deserves a lot of credit for being one of the very
few—possibly the only person—who is actually trying to explain how thiscomplex biochemical system arose. No one else has given this much effort
to pondering the origins of blood clotting. The discussion is meant simply
to illustrate the enormous difficulty (indeed, the apparent impossibility) of
a problem that has resisted the determined efforts of a top-notch scientist
for four decades. Blood coagulation is a paradigm of the staggering
complexity that underlies even apparently simple bodily processes. Facedwith such complexity beneath even simple phenomena, Darwinian theory
falls silent.
Like some ultimate Rube Goldberg machine, the clotting cascade isa breathtaking balancing act in which a menagerie of biochemicals—
sporting various decorations and rearrangements conferred by modifying
enzymes—bounce off one another at precise angles in a meticulously
ordered sequence until, at the denouement, Foghorn Leghorn pushes off
the telephone pole and gets up from the ground, the bleeding from his
wounds stopped. The audience rises to its feet in sustained applause.

CHAPTER 5FROM HERE TO THERE

THE MEASLESAt the clinic the doctor examines a third young patient who has missed
school because of fever, aches, and bloodshot eyes. Like the first two, theboy has the measles. Not rubella. Rubeola. Like the first two, the boy wasnever immunized. Few kids in the crowded, innercity neighborhood havebeen immunized. Measles is rare these days. People forget how dangerous
it can be. Parents think of it as a simple matter of temporary freckles and
bed rest. They're wrong. Measles makes the patient much more susceptible
to other infections. Like encephalitis. The doctor learns that the first
patient has just died.
Three cases within a week in the same neighborhood means that thedisease is spreading. The doctor fears an epidemic is under way. She
immediately calls city health officials and tells them the problem. The
health commissioner faxes a request to the Centers for Disease Control(CDC) in Atlanta for ten thousand doses of measles vaccine. The plan is toinitiate a crash program of vaccinations in the immediate neighborhood
so that spread of the disease will be damped. Infected children will bequarantined; after the outbreak is contained, an educational program will
be initiated to alert parents to the abiding
98

FROM HERE TO THERE 99
dangers of childhood viruses. But first things first: the vaccine is needed
immediately.
At the CDC the fax is received, and the request approved. A
technician goes down into a storage area where there are a number oflarge refrigerated rooms stocked with vaccines for measles, smallpox,
chicken pox, diphtheria, meningitis, and more. The technician checks thelabeling on the packages, sees that the cases in the back comer containmeasles vaccine, and loads them onto a cart. He pushes the cart out to aloading dock where a refrigerated truck is waiting to take the packages
to the airport. At the airport, the truck glides over to the terminal of acommercial package-delivery service. A number of planes are parked at
the terminal, but the truck driver finds a sign marking the plane headed
for the right city.
The cases of vaccine are loaded onto the plane, which takes off. At theaffected city's airport, another refrigerated truck is there to meet the plane.
The packages of vaccine are recognized by their labels, separated from theother packages on the plane, and loaded onto the truck. The driver reads
the clinic address from a slip of paper attached to the packages and roars
off. At the clinic, a phalanx of medical workers unloads the truck andopens the boxes. Soon a stream of children is entering the clinic to be
immunized. As each child passes by, a nurse takes a vial of vaccine, tears
off the soft metal cap, inserts the needle of a syringe into the vial, extracts
the liquid, and injects it into the arm of the grimacing youngster.
The strategy works. A few more children contract the measles, but nomore die. The epidemic is contained, and city officials move on to theeducational campaign.

UH-OH

The director leans back in his chair and tosses the script on the table.
«Epidemic!»—his first made-for-TV movie—is shaping up pretty well.
It has drama, action, cute kids, attractive doctors and nurses, and noble
government officials. A killer disease is defeated by human ingenuity,
planning, and technical expertise.
Bah! The director does not like happy endings. A cynic down to his
toes, he has run across too many stupid, incompetent people to swallow
this. His sister's gall bladder was removed by a skilled surgeon;

100 EXAMINING THE CONTENTS OF THE BOX
unfortunately, she had gone into the hospital for an appendectomy. The
zoning commission, chaired by a neighbor's uncle, allowed the neighborto open a video arcade in his quiet neighborhood. And hooligans from thelocal school let the air out of his tires. The director does not like doctors,
hates politicians, and despises kids.
Besides, the director wants to be a great artist. Great artists aresupposed to point out human foibles and the tragedies brought on byhuman limitations. Isn't that what Shakespeare did? They don't pander tothe sensibilities of the unwashed masses. So the director closes his eyesand sets to work imagining some different scenarios.
The epidemic begins, officials huddle, and the call goes out to the
CDC. The technician goes down to the refrigerated rooms and grabs theboxes labeled «measles vaccine.» Onto the truck, into the plane, off to thecity, and finally to the clinic. The children noisily file past the nurses andreceive their shots. Days pass; three more children die. A week passes, andtwo dozen children are dead. Some of the dead children had received thevaccine. Two months later, two hundred children are dead, and thousands
are sick. Almost all had received the vaccine. Puzzled officials order aninvestigation, which shows that the packages were mislabeled; the vaccine
is for diphtheria, not measles. Almost all of the children in the city are now
sick. Nothing can be done. The disease will run its course.
The director smiles. He'll be sure to cast some of the local hooligans as
doomed children.
Perhaps, though, the film needs more suspense as the epidemic takes
its course. So when the call goes out to the CDC, perhaps the technician
goes down to the storage area and sees that all the labels have fallen off
the boxes. The refrigerator fan has blown them all around, hopelessly
mixing them up. Sweat trickles down the technician's face; he knows that
it will take weeks to analyze the boxes to see which vaccine is the rightone. During those weeks the disease will spread, politicians will scream,children will die. He may be fired.
Variations on the theme could easily be done. The truck puts the boxesof vaccine on the wrong plane. The plane unloads its cargo into the wrong
receiving truck. The truck is hijacked on its way to the clinic. The truck
takes the vaccine to the wrong building. The caps on the vaccine bottles
are accidentally made from hard metal, not soft, and can't be removed
without breaking the bottle and contaminating

FROM HERE TO THERE 101
the vaccine. In all of these cases, the director notes approvingly, humanincompetence is highlighted. Great achievements of science— vaccines
to conquer disease, airplanes and automobiles to speed supplies on theirway—are frustrated by pure, simple stupidity.
The director slaps his knee. Yes, the movie's theme will be a battle, anepic struggle: Albert Einstein versus the Three Stooges. Einstein doesn't
have a prayer.

DELIVERY SERVICE

All the problems that cropped up in the director's scenarios concerndelivering a package to its final destination. Although the movie showcased
death and disease, the same problems are common to all attempts to get a
specific package to a specific destination. Suppose you went to a terminalin Philadelphia to catch a bus for New York. A hundred buses were all lined
up neatly in a row, motors running, ready to set out to their destinations.
But there were no signs on the buses, and the driver and passengers refused
to tell you where the bus was headed. So you hopped on board the closest
bus and ended up in Pittsburgh.
The bus system has to contend with the same problem that the CDC
had: delivering the correct packages (passengers) to the correct destination.
The pony express had the same problem. As a rider swooped down to pickup a sack of mail, somebody had to make sure that the mail in the sack was
supposed to go to the place where the horse was headed. And the rider had
to recognize his destination when he got there.
All cargo delivery systems face common problems: the cargo must belabeled with the correct delivery address; the transporter must recognize
the address and put the cargo in the correct delivery vehicle; the vehicle
must recognize when it has arrived at the right destination; and the cargomust be unloaded. If any of these steps is missing, then the whole systemfails. As we saw in the made-for-TV movie, if the package is mislabeled orno label is present, it doesn't get taken out of the storeroom. If the package
is delivered to the wrong address or the container can't be opened once it
arrives, then it may as well have never been sent. The entire system must
be in place before it works.
Ernst Haeckel thought that a cell was a «homogeneous globule of102 EXAMINING THE CONTENTS OF THE BOX
protoplasm.» He was wrong; scientists have shown that cells are complex
structures. In particular, eukaryotic cells (which include the cells of allorganisms except bacteria) have many different compartments in which
different tasks are performed. Just like a house has a kitchen, laundryroom, bedroom, and bathroom, a cell has specialized areas partitioned
off for discrete tasks (Figure 5-1). These areas include the nucleus (where
the DNA resides), the mitochondria (which produce the cell's energy), theendoplasmic reticulum (which processes proteins), the Golgi apparatus (away station for proteins being transported elsewhere), the lysosome (thecell's garbage disposal unit), secretory vesicles (which store cargo before it
must be sent out of the cell), and the peroxisome (which helps metabolizefats). Each compartment is sealed off from the rest of the cell by its own
membrane, just as a room is separated from the rest of the house by its
walls and door. The membranes themselves can also be considered separate
compartments, because the cell places material into membranes that is notfound elsewhere.
Some compartments have several discrete sections. For example,
mitochondria are surrounded by two different membranes. So a
FIGURE 5-1
The parts of an animal cell.

FROM HERE TO THERE 103
mitochondrion can be thought of as containing four separate sections:the space inside of the inner membrane, the inner membrane itself,
the space between the inner and the outer membranes, and the outermembrane itself. Counting membranes and interior spaces, there are morethan twenty different sections in a cell.
The cell is a dynamic system; it continually manufactures new structuresand gets rid of old material. Since the compartments of a cell are closed off,
each area faces the problem of obtaining new materials. There are two waysthat it could solve the problem. First, each compartment might make all of
its own supplies, like so many self-sufficient villages. Second, new materials
could be centrally made and then shipped to other compartments, like alarge city making blue jeans and radios to be sent to small towns. Or there
might be a mixture of these two possibilities.
In cells, although some compartments make some materials forthemselves, the great majority of proteins are centrally made and shipped
to other compartments. The shipping of proteins between compartments
is a fascinating and intricate process. The details can differ depending on
the destination of the protein, just as shipping details can differ dependingon whether a package is headed across town or across the ocean. In thischapter I will concentrate on the mechanisms a cell uses to get a protein to
the cell's garbage disposal, the lysosome. You will see that the cell must deal
with the same problems that the Centers for Disease Control encountersin shipping a vital package.

LOST IN SPACE

A new protein, freshly made in the cell, encounters many molecularmachines. Some of the machines grab hold of the protein and send it along
to the location it is destined to reach. In a little while I will follow a protein
along one pathway from start to finish. Protein machines all have rather
exotic names, however, and it is difficult for many people to picture thesethings in their minds if they are not used to thinking about them. So I will
first use an analogy, which will take the next several pages.
The time is far in the future. Humanity has tried to explore space
firsthand, but between comets, magnetic storms, and marauding

104 EXAMINING THE CONTENTS OF THE BOX
aliens, the dangers were too great. So the job has been given to mechanicalspace probes that have been shot out into the cosmos to explore the outeredges of our galaxy and beyond. Of course, it takes awhile to get to theedge of the galaxy, and even longer to get beyond, so the space probes havebeen built to be self-sufficient. They can set down on barren planets andmine for raw materials; they can manufacture brand new machines from
ore; and they can capture the energy in starlight and use it to charge theirbatteries.
The space probe is a machine, so it has to accomplish all of its tasks
by painfully detailed mechanisms, not magic. One task is to recycle oldbatteries; batteries go bad after awhile, so the probe makes new ones. The
new batteries are made by grinding up old batteries, recovering the oldcomponents, melting them down, recasting the casing, and adding freshchemicals. One of the machines that is used in this process is called the«battery crusher.»
The space probe is shaped like a huge sphere. Inside the sphere are anumber of smaller, self-contained spheres, each of which holds machinery
for specialized tasks. In the biggest of the interior spheres—let's call it the«library»—are the blueprints for making all the machines in the spaceprobe. These are not ordinary blueprints, however. They can be thoughtof as blueprints in braille—or perhaps as sheet music for a player piano—
where physical indentations in the blueprint cause a master machine to
make the machine for which the blueprint codes.
One fine day the space probe senses (by some mechanism we'll ignore)
that it needs to make another battery crusher and to send the newly
made machine to work in the garbage treatment room, where it will help
in recycling old batteries. So the process to do that is set in motion: The
blueprint for the battery crusher is photocopied in the library, and theblueprint copy floats over to a window in the library (remember; there's
no gravity). On the edge of the blueprint are punch holes arranged in a
special pattern, which exactly matches pegs on a scanner mechanism at
the window. When the blueprint hooks onto the scanner; the window
door opens like the shutter of a camera. The blueprint jiggles loose of thescanner and floats out of the library into the main area of the probe.
In the main area are many machines and machine parts; nuts, bolts,
and wires float freely about. In this section reside many copies of what

FROM HERE TO THERE 105
are called master machines, whose job it is to make other machines.
They do this by reading the punch holes in a blueprint, grabbing nuts,
bolts, and other parts that are floating by, and mechanically assembling
the machine piece by piece.
The blueprint for the battery crusher, floating in the main area, quickly
comes in contact with a master machine. Whirring, turning appendages
on the master machine grab some nuts and bolts and start assembling thecrusher. Before it assembles the body of the crusher, however, the mastermachine first makes a temporary «ornament» that marks the crusher as amachine that has to leave the main area.
In the main area is another machine, called a guide. The shape of theguide is exactly complementary to the shape of the ornament, and little
magnets on the guide allow it to attach securely. As the guide snuggles up
to the ornament it pushes down on the master machine's switch, causing
the master machine to halt its construction of the crusher.
On the outside of one of the interior spheres (we'll call the sphere«processing room #1») is a receiving site that has a shape complementary
to part of the guide and part of the ornament. When the guide, ornament,
and attached parts bump into that shaped section, the master machine's
switch is flipped back on, causing construction of the crusher to resume.
Right next to that shaped section is a window. When the ornament tapson the window (there's a lot of jostling going on), it activates a conveyor
belt inside the processing room and the conveyor belt pulls the new battery
crusher inside the processing room, leaving the master machine, blueprint,
and guide on the outside.
As the crusher was being pulled through the window another machine
removed the now-unnecessary ornament. Now, amazingly, constriction
machines embedded in the flexible walls of processing room #1 cause a
section of the wall to close in on and surround some of the machines,
forming a new, free-floating subroom. The remainder of the wall that wasleft behind smoothly seals itself.
The subroom now floats a short distance through the main area before
bumping into a second processing room. The subroom merges with thewall, and spills its contents into processing room #2. The battery crusher
then passes through processing rooms #3 and #4 by mechanisms similar
to those that took it from room #1 to room #2.

106 EXAMINING THE CONTENTS OF THE BOX
It is in the processing rooms that machines receive the tags that direct
them to their final destinations. An antenna is placed on the battery
crusher and quickly trimmed down to make a very special configuration;
the special shape of the trimmed antenna will tell other mechanisms todirect the crusher to the garbage treatment room.
In the wall of the last processing room are machines («haulers») witha shape complementary to that of the trimmed antenna of the battery
crusher. The crusher sticks to the haulers, and that area of the wall begins
to pinch off to form a subroom. Outside the subroom is another machine(the «delivery coder») with a shape that exactly complements the shapeof a machine (the «port marker») sticking out of the garbage treatment
room. The sub-room hooks up to the garbage treatment room throughthe two complementary machines. Another machine (the «gateway») thendrifts by. The gateway has a shape that is complementary to a portionof the delivery coder and the port marker. When it sticks to them thegateway punches a small hole in the garbage treatment room, and thetransit sphere merges with it, dumping its contents into the disposal. The
battery crusher is able to begin its work.
Perhaps by this point in the book, the reader can easily see how
the transport system that sent the battery crusher to its destination isirreducibly complex. If any of its numerous components is missing, thenthe crusher is not delivered to the garbage treatment room. Furthermore,
the delicate balance of the system must be maintained; each of the many
components that interlock must do so precisely and then disengage, andeach must arrive and depart at the proper times. Any single error willcause the system to fail.

REALITY CHECKThis is science fiction, isn't it? Things this complex don't exist in nature,
do they? The cell is a «homogeneous globule of protoplasm,» isn't it? Well,no, yes, and no.
All of the fantastic machines in our space probe have direct counterpartsin the cell. The space probe itself is the cell, the library is the nucleus, theblueprint is the DNA, the copy of the blueprint is RNA, the window of thelibrary is the nuclear pore, the master machines are ribosomes, the mainarea is the cytoplasm, the ornament is the signal

FROM HERE TO THERE 107
sequence, the battery crusher is a lysosomal hydrolase, the guide is thesignal recognition particle (SRP), the receiving site is the SRP receptor,
processing room 1 is the endoplasmic reticulum (ER), processing rooms 2
through 4 are the Golgi apparatus, the antenna is a complex carbohydrate,
the sub-rooms are coatomer or clathrin-coated vesicles, and various
proteins play the roles of the trimmer, hauler, delivery coder, port marker,
and gateway. The garbage treatment room is the lysosome.
Let's quickly run through a description of how a protein that is
synthesized in the cytoplasm eventually finds its way to the lysosome. This
will take just one paragraph. Don't worry if you rapidly forget the names
and procedures of cellular transport; the purpose is simply to give you aglimpse of the cell's complexity.
 An RNA copy (called messenger RNA, or just mRNA) is madeof the DNA gene coding for a protein that works in the cell's garbage
disposal—the lysosome. We'll call the protein «garbagease.» The
mRNA is made in the nucleus, then floats over to a nuclear pore.
Proteins in the pore recognize a signal on the mRNA, the pore opens,
and the mRNA floats into the cytoplasm. In the cytoplasm the cell's«master machines»—ribosomes—begin making garbagease using
the information in the mRNA. The first part of the growing protein
chain contains a signal sequence made of amino acids. As soon as thesignal sequence forms, a signal recognition particle (SRP) grabs onto
the signal and causes the ribosome to pause. The SRP and associatedmolecules then float over to an SRP receptor in the membrane of theendoplasmic reticulum (ER) and stick there. This simultaneously causes
the ribosome to resume synthesis and a protein channel to open in themembrane. As the protein passes through the channel and into the ER,
an enzyme clips off the signal sequence. Once in the ER, garbagease hasa large, complex carbohydrate placed on it. Coatomer proteins causea drop of the ER, containing some garbagease plus other proteins, topinch off, cross over to the Golgi apparatus, and fuse with it. Some of theproteins are returned to the ER if they contain the proper signal. This
happens two more times as the protein progresses through the several
compartments of the Golgi. Within the Golgi an enzyme recognizes thesignal patch on garbagease and108 EXAMINING THE CONTENTS OF THE BOX
places another carbohydrate group on it. A second enzyme trims the
freshly attached carbohydrate, leaving behind mannose-6-phosphate(M6P). In the final compartment of the Golgi, clathrin proteins gather
in a patch and begin to bud. Within the clathrin vesicle is a receptor
protein that binds to M6E. The M6P receptor grabs onto the M6P of
garbagease and pulls it on board before the vesicle buds off. On theoutside of the vesicle is a v-SNARE protein that specifically recognizes at-SNARE on the lysosome. Once docked, NSF and SNAP proteins fuse
the vesicle to the lysosome. Garbagease has now arrived at its destinationand can begin the job for which it was made. 
The fictional space probe is so complicated it hasn't been invented yet,even in a crude way. The authentic cellular system is already in place, andevery second of every day, this process happens uncounted billions of timein your body. Science is stranger than fiction.

THE DEMANDS OF THE JOB

Garbagease travels a distance of about one ten-thousandth of an inch onits journey from the cytoplasm to the lysosome, yet it requires the servicesof dozens of different proteins to ensure its safe arrival. In our imaginary
TV movie, the vaccine traveled perhaps a thousand miles from theCenters for Disease Control to the big city where it was needed—a trillion
times farther than garbagease traveled. But many of the requirements fortransporting the vaccine were the same as those for getting the enzyme
from the cytoplasm to the lysosome. The demands are imposed by thetype of task to be done; they don't depend on the distance traveled, thetype of vehicle used, or the materials out of which the signs are made.
A current textbook distinguishes three methods that the cell uses to get
proteins into compartments.1 The first, where a large gate opens or closes
to regulate the passage of proteins through the membrane, is known asgated transport. This is the mechanism that regulates the flow of material
such as newly-made mRNA between the nucleus and the cytoplasm (or inspace-probe language, the flow of the blueprint out of the library into themain area). The second method is transmembrane transport. This occurs
when a single protein is threaded throughFROM HERE TO THERE 109
a protein channel, as when garbagease passed from the cytoplasm into
the ER. The third way is vesicular transport, where protein cargo is loaded
into containers for shipment, as happened for the trip from the Golgi (thefinal processing room) to the lysosome (the garbage treatment room).
For our purposes the first two methods can be considered to be thesame: they both use portals in a membrane that selectively allow proteinsthrough. In the case of gated transport the portal is quite large, and proteinscan pass through in their folded form. In the case of transmembranetransport the portal is smaller, and proteins must be threaded through.
But in principle there is no roadblock to expanding or contracting the sizeof a portal, so these are equivalent. Therefore I will call both of these gatedtransport.
What are the bare, essential requirements for gated transport? Imagine
a parking garage that is reserved for persons with diplomatic license
plates. In place of a human attendant the garage has a scanner that reads
a barcode on the license plate, and if the barcode is correct the garage
door opens. A car with diplomatic plates drives up, the scanner scans thebarcode, the door opens, and the car drives in. It doesn't matter if the
car drove ten feet to the garage or ten thousand miles, or whether thevehicle is a truck, jeep, or motorcycle; if the barcode is there, it can passthrough. Thus three basic components are required for gated transport at
the garage: an identification tag; a scanner; and a gate that is activated by
the scanner. If any of these things are missing, then either the vehicle does
not get in or the garage is no longer a reserved area.
Because gated transport requires a minimum of three separate
components to function, it is irreducibly complex. And for this reason
the putative gradual, Darwinian evolution of gated transport in the cell
faces massive problems. If proteins contained no signal for transport, theywould not be recognized. If there were no receptor to recognize a signal
or no channel to pass through, again transport would not take place. And
if the channel were open for all proteins, then the enclosed compartment
would not be any different from the rest of the cell.
Vesicular transport is even more complicated than gated transport.
Suppose now that, instead of the diplomats' cars entering the garage one ata time, all diplomats had to drive their cars into the back of a large tractortrailer truck, the truck would drive into the special garage,

110 EXAMINING THE CONTENTS OF THE BOX
and the cars would drive off the truck and park. Now we need a way forthe truck to recognize the proper cars, a way for the garage to recognize
the truck, and a way for the cars to get out of the truck inside the garage.
Such a scenario requires six separate components: (1) an identification
tag on the cars; (2) a truck that can carry the cars; (3) a scanner on thetruck; (4) an identification tag on the truck; (5) a scanner on the garage;(6) an activatable garage gate. In the cell's vesicular transport system thesecomponents correspond to mannose-6-phosphate, the clathrin vesicle, theM6P receptor in the clathrin vesicle, v-SNARE, t-SNARE, and SNAP/NSF
proteins. In the absence of any of these functions, either vesicular transportcannot take place or the integrity of the destination compartment iscompromised.
Because vesicular transport requires several more componens thangated transport, it cannot develop gradually from gated transport. For
example, if we had barcode stickers on the diplomats' cars, placing cars
inside a truck (a vesicle to transport them) would hide the stickers, andthey would fail to enter the garage. Or suppose instead that the truck
had the same label that the cars had, so it could enter the garage. But
we would still be missing a mechanism to get the cars on the truck, so
the truck would be of no use. If some cars randomly entered the truck
then, again, nondiplomats' cars would enter the garage. Returning to theworld of the cell, if a vesicle just «happened» to form there would be no
mechanism for identifying the proteins that should enter it, and no way
to specify its destination. Placing proteins containing address labels into
an unlabeled vesicle would make the labels unavailable, and therefore
would be detrimental to the organism that had a happily functioning
gated transport system. Gated transport and vesicular transport are two
separate mechanisms; neither helps in understanding the other.
The brief sketch of the requirements for gated and vesicular transport
in this chapter did not take into account many complexities of thesystems. But since these only make the system more intricate, they cannot
ameliorate the irreducible complexity of targeted transport.

SECOND-HAND ROSE

Irreducibly complex systems like mousetraps, Rube Goldberg machines,
and the intracellular transport system cannot evolve in a Dar-

FROM HERE TO THERE 111
winian fashion. You can't start with a platform, catch a few mice, add
a spring, catch a few more mice, add a hammer, catch a few more mice,and so on: The whole system has to be put together at once or the mice getaway. Similarly, you can't start with a signal sequence and have a protein
go a little way towards the lysosome, add a signal receptor protein, go alittle further, and so forth. It's all or nothing.
Perhaps, though, we're overlooking something. Perhaps one of the partsof a mousetrap was used for some purpose other than trapping mice, andso were the other parts. At some point several parts that were being used
for other purposes suddenly came together to produce a functioning trap.
And perhaps the components of the intracellular transport system wereoriginally performing other tasks in the cell, then switched to their presentrole. Could that happen?
An exhaustive consideration of all possible roles for a particularcomponent can't be done. We can, however, consider a few likely roles
for some of the components of the transport system. Doing so shows
it is extremely implausible that components used for other purposes
fortuitously adapted to new roles in a complex system.
Suppose we start with a protein that because it had an oily region,
resided in the cell's membrane. Suppose further that it was beneficial
for the protein to be there because it toughened the membrane, making
it resistant to tears and holes. Could that protein somehow turn into agated channel? This is like asking if wooden beams in a wall could betransformed, step by Darwinian step, small mutation by small mutation,
into a door with a scanner. Suppose wooden beams were brought together,and the area between them was weakened so much that plaster cracked
and a hole formed in the wall. Would that be an improvement? The holein the wall would let insects, mice, snakes, and other things into the room;
it would let heat or air-conditioning out. Similarly, a mutation that caused
proteins to aggregate in the membrane, leaving a small hole, would let
stored foodstuffs, salt, ATP, and other needed materials float away. That is
no improvement. A house with a hole in the wall would never sell, and acell with a hole in it would be at a great disadvantage compared to othercells.
 Suppose instead that a protein could bind to the beginnings of
new proteins as they were being put together by the ribosome. Supposethat was an improvement because new, unfolded proteins are112 EXAMINING THE CONTENTS OF THE BOX
more vulnerable, so placing a folded protein on them would protect
them until they were fully made and folded. Could such a protein
develop into, say, the signal recognition particle (SRP)? No. Such a
protein would help a new protein fold rapidly, not keep it unfolded—
the opposite of what modern SRP does. Folded proteins, however, can't
get through the gated channel where the modern SRP takes them.
Further, if a proto-SRP caused the ribosome to halt its synthesizing, as
the modern SRP does, but the machinery to turn the ribosome back on
was not yet in place, then that would kill a cell (some deadly poisonskill by turning off the cell's ribosomes). So we have a dilemma: in the
beginning an uncontrolled inhibitor of protein synthesis would kill thecell, but a temporary halt in protein synthesis is crucial in modern cells.
If the ribosome does not pause, the new protein gets so big that it can't
fit through a gated channel. So it appears that the modern SRP could
not have developed from a protein whose job it was to bind new proteinsand protect them from degradation.
Suppose that an enzyme placed a large carbohydrate group (the«bauble») on proteins as they were made. Suppose that helped stabilize
the protein somehow, making it last longer in the cell. Could that step
eventually become part of the intracellular transport chain? No. The
bauble, because it would make the protein larger, would prevent it frompassing through any future gate that looked like a modern gate in the
ER. The bauble would actually be a hindrance to developing a transportsystem.
In the same way, other isolated parts of the system would actually
be damaging to the cell, not helpful. An enzyme that clipped off thesignal sequence (the «ornament») would be detrimental if the signal
sequence was playing a positive role in a primitive cell. Trimming of thebauble would be a step backward if the bauble had a job to do. Trappingof proteins like «garbagease» inside a vesicle would be harmful if
garbagease originally had to work in the open. 
In Chapter 2 I noted that one couldn't take specialized parts of othercomplex systems (such as the spring from a grandfather clock) and use
them directly as specialized parts of a second irreducible system (like amousetrap) unless the parts were first extensively modified. Analogous
parts playing other roles in other systems cannot relieve theFROM HERE TO THERE 113
irreducible complexity of a new system; the focus simply shifts from«making» the components to «modifying» them. In either case, there no
new function unless an intelligent agent guides the setup. In this chapter
we see that construction of a transport system faces the same problem: thesystem can't be put together piecemeal from either new or secondhand
parts.

DEATH AT AN EARLY AGE

In one version of our made-for-TV movie, a wrong label was placedon a carton of vaccine, and children died. Fortunately, it was only makebelieve: a story about a story. But in real life, mixed-up or missing labels
can cause real deaths.
A crying two-year-old girl stands in front of a height chart, with the aidof an adult's helping hand. She is only two feet tall. Her face and eyes are
puffed up, and her legs are bent. She moves stiffly. She is severely retarded.
A medical examination shows an enlarged heart, liver, and spleen. A coughand runny nose bespeak another of the many upper respiratory infections
she has endured in her young life. The doctor takes a tissue sample fromthe girl and sends it to a lab for analysis; a lab worker grows cells from thesample in a Petri dish and examines them under a microscope. Each of
the cells contains thousands of little, dense grains that aren't present innormal cells. The grains are called «inclusion bodies»; the little girl has
I-cell disease.2 Because the disease is progressive, the skeletal and neuraldifficulties will increase with time. The girl will die before the age of five.
I-cell disease is caused by a defect in the protein transport pathway.
The cells of patients with the disease lack one of the machines in the long
chain that takes proteins from the cytoplasm to the lysosome. Becauseof the defect, enzymes intended for the lysosome never make it there.
Instead they are shunted off in the wrong vesicle to the cell membraneand dumped into the extracellular space. The cell is a dynamic system,and just as it must build new structures, it must continually degrade oldones. Old material is brought to lysosome for degradation. In children
with I-cell disease, the garbage is dumped into the disposal as it should be,
but the disposal is broken: neither «garbagease» nor any other degradative
enzyme that normally decomposes old structures is present. As a result
garbage piles up, and lysosomes get filled.

114 EXAMINING THE CONTENTS OF THE BOX
The cell makes new lysosomes to accomodate the increasing waste, but
the new compartments eventually fill up with the detritus of cellular life.
Over time the entire cell becomes bloated, tissues become enlarged, andthe patient dies.
A child can die because of this single defect in one of the many machinesneeded for taking proteins to the lysosome. A single flaw in the cell'slabyrinthine protein-transport pathway is fatal. Unless the entire systemwere immediately in place, our ancestors would have suffered a similarfate. Attempts at a gradual evolution of the protein transport system are arecipe for extinction.
Because of the medical problems associated with the failure of thetransport system, and because the system is so intricate and fascinating, wemight expect the evolutionary development of vesicular protein transport
to be a busy area of research. How could such a system develop step-bystep? What hurdles would the cell have to overcome as it moved fromsome other method of dealing with garbage to a coated vesicle specificallytargeted to, and equipped for merger with, the lysosome? Once again, if
we looked in the literature for an explanation of the evolution of vesiculartransport, we would be crushingly disappointed. Nothing is there.
Annual Review of Biochemistry (or ARB)is a book series, very рopularwith biochemists, that reviews the current state of knowledge in selected
research areas. In 1992 an article was published in ARB concerning«Vesicle-Mediated Protein Sorting.»3 The authors begin their review
by stating the obvious: «The transport of proteins between membranebounded organelles is an immensely complex process.» They proceed inprofessional fashion to describe the systems and current research in thearea. But we can read from one end of the forty-six-page review to theother without encountering an explanation for how such a system might
have gradually evolved. The topic is off the radar screen.
Logging on to a computer database of the professional literature in thebiomedical sciences allows you to do a quick search for key words in thetitles of literally hundreds of thousands of papers. A search to see whattitles have both evolution and vesicle in them comes up completely empty.
Slogging through the literature the old-fashioned way turns up a few
scattered papers that speculate on how gated transport

FROM HERE TO THERE 115
between compartments of a eukaryotic cell might have developed.4 But
all the papers assume that the transport systems came from preexisting
bacterial transport systems that already had all the components thatmodern cells have. This does us no good. Although the speculations may
have something to do with how transport systems could be duplicated,
they have nothing to do with how the initial systems got there. At somepoint this complex machine had to come into existence, and it could nothave done so in step-by-step fashion.
Perhaps the best place to get an overview of vesicle transport is fromthe textbook Molecular Biology of the Cell by National Academy of Science
President Bruce Alberts, Nobel Prize winner James Watson, and several
more coauthors. The textbook spends 100 pages on the elegant detailsof gated and vesicular transport.5 In that 100 pages there is a one-and-ahalf-page section entitled «The Topological Relationships of MembraneBounded Organelles Can Be Interpreted in Terms of Their Evolutionary
Origins.» In this section the authors point out that if a vesicle pinches offfrom the cell membrane and into the cell, then its inside is equivalent to
the outside of the cell. They then suggest that the nuclear membrane, ER,
Golgi, and lysosomes first arose when parts of the cell membrane pinched
off. This may or may not be true, but it does not even address the origin ofprotein transport, either vesicular or gated. Clathrin is not mentioned inthis short section, nor are the problems of loading the correct cargo into
the correct vesicle and targeting it to the correct compartment. In short,the discussion is irrelevant to the questions we are asking. At the end of
our literature search, we know no more than when we started.

SUMMING UP AND LOOKING AHEAD

Vesicular transport is a mind-boggling process, no less complex thanthe completely automated delivery of vaccine from a storage area toa clinic a thousand miles away. Defects in vesicular transport can havethe same deadly consequences as the failure to deliver a needed vaccine
to a disease-racked city. An analysis shows that vesicular transport isirreducibly complex, and so its development staunchly resists gradualistic
explanations, as Darwinian evolution would have it. A search of theprofessional biochemical literature and textbooks shows that no116 EXAMINING THE CONTENTS OF THE BOX
one has ever proposed a detailed route by which such a system could
have come to be. In the face of the enormous complexity of vesiculartransport, Darwinian theory is mute.
In the next chapter I will examine the art of self-defense—but, ofcourse, on a molecular scale. Just as machine guns, battle cruisers, andnuclear bombs are necessarily sophisticated machines in our larger world,
we will see that tiny cellular defense mechanisms are quite complex, too.
Few things are simple in Darwin's black box.

CHAPTER 6

A DANGEROUS WORLDALL SHAPES AND SIZES

Enemies abound. Paranoia has nothing to do with it; we are surroundedby creatures that, for one reason or another, want to do us in. Since mostpeople don't want to die just yet, they take steps to defend themselves.
Threats of aggression can come in all shapes and sizes, so defenses haveto be versatile. The largest-scale threat is war between nations. Rulers ofnations always seem to be wanting the resources of neighboring countries,
so threatened countries have to defend themselves or suffer unpleasantconsequences. In modern times, countries can have very sophisticatedmeans of defense indeed. The United States has stockpiled atomic bombs;
if some other country shakes its proverbial fist at us, we can rattle ourbombs at them. If threats escalate to violence and we don't wish to use
atomic bombs for one reason or another, then other machines can be
deployed: jets that drop «smart» bombs, AWACS planes that monitor the
air space for many miles, tanks equipped for night combat, surface-to-airmissiles that shoot down surface-to-surface missiles, and much more. To
the techno-war-monger, we live in a golden age.

117

118 EXAMINING THE CONTENTS OF THE BOX
Big threats like war are important, but other types of aggression cankill, too. Terrorist bombings of planes or gas attacks on subways have,
unfortunately, become too frequent for comfort. Worse, none of theweapons mentioned above will help much to prevent a subway gas attack.
When the nature of the enemy changes dramatically—from a foreigncountry to a domestic terrorist group—the nature of the defense must alsochange. Instead of bombs, government officials install metal detectors at
airports and place guards with guns at strategic locations.
Terrorism and war threaten us, but they happen infrequently. On a dayto-day basis more people are assaulted by muggers and mayhem in theirneighborhood than by exotic groups or foreign countries. The streetwisecity dweller will have bars on his window, use an intercom or peephole tosee who is at the door, and carry a can of pepper spray when it's time towalk the dog. In lands where such modern conveniences are unknown,stone or wooden walls can be built around the hut to keep out intruders(both two- and four-footed), and a spear is kept by the bed in case the wallis breached.
A stick, rock, barrier, gun, alarm, tank, and atomic bomb used to help
fend off attacks. Since the circumstances in which each weapon is usefulmight vary considerably, there is a lot of overlap. Both a stick and a pistol
can deter a mugger; a pistol and a tank can threaten a terrorist group; andboth a tank and an atomic bomb can be used against a foreign country.
Looked at this way, we can speak about the «evolution» of defensive
systems. We can talk about an arms race in which the equipment ofcompeting sides becomes more and more sophisticated. We can tell stories
about life being a struggle where people or countries with the best defenses
survive. But before we hop in a box and fly off with Calvin and Hobbes, weneed to recall the distinction between conceptual precursors and physicalprecursors. A rock and a gun can both be used for defense, but a rockcannot be turned into a gun by a series of small steps. A can of pepper
spray is not a physical precursor of a hand grenade. A jet plane cannot
be changed into an atomic bomb one nut and bolt at a time, even thoughboth the plane and the bomb do contain nuts and bolts. In Darwinianevolution, only physical precursors count.
Humans and large animals are not the only threats a person encounters.
There are also Lilliputian aggressors against whom bombs or guns or rocks
are ineffective. Bacteria, viruses, fungi—they all wouldA DANGEROUS WORLD 119
love to eat us if they could. Sometimes they do, but most times they
don't because our bodies have an array of defensive systems to deal withmicroscopic attacks. The first line of defense is the skin. Like a stockade
fence, the skin works by a relatively low-tech method: it's a barrier that is
hard to breach. Burn victims often succumb to massive infections because
the skin barrier has been broken and the internal defenses can't cope withthe overwhelming numbers of invaders. But although skin is an importantpart of the body's defense, it is not a physical precursor of the immune
system.
To discourage any outsider who manages to climb to the top, sometimes
stockade walls have spikes on them. Where I lived in the Bronx, almost
all of the cyclone fences were topped with razor wire, which apparently
is more effective at lacerating intruders than old-fashioned barbed wire.
Spikes and razor wire are not parts of the fence proper; they are little addons that increase the effectiveness of the barrier. Still, like the fence itself,
razor wire is not a physical precursor to, say, a gun or a landmine.
Skin, too, has add-ons that increase its effectiveness as a barrier. In abiochemistry laboratory you often have to wear gloves to protect yourself
from the material you're handling, but sometimes you have to wear gloves
to protect the material from you. People who work with RNA wear gloves
because human skin excretes an enzyme that chops up RNA. Why? Itturns out that many viruses are made from RNA. To such a virus, theenzyme is like razor wire on the skin: any RNA that tries to breach thebarrier gets lacerated.
There are other types of spikes on the skin. One of the most interestingis a class of molecules called magainins, discovered by a biologist named
Mike Zasloff after he wondered why live laboratory frogs that are cut
open and sewed back up in nonsterile conditions rarely get infections. He
showed that their skin excretes a substance which can kill bacterial cells;
since then, magainins have been discovered in many kinds of animals. But
magainins, like the RNA-destroying enzymes, are not precursors to thesophisticated defense systems under the skin of animals.
To find the heavy weaponry, we have to peek under our skins. Theinternal defense system of vertebrates is dizzyingly complicated. Like themodern U.S. army, it has a variety of different weapons that can overlap intheir use. But like the weapons we discussed above, we120 EXAMINING THE CONTENTS OF THE BOX
must not automatically assume the different parts of the immune system
are physical precursors of each other. Although the body's defenses arestill an active area of research, much is known in detail about particular
aspects. In this chapter I will discuss selected parts of the immune systemand point out the problems they present for a model of gradual evolution.
Those who become intrigued by the cleverness of the systems and wantto know more are encouraged to pick up any immunology text for thedetails.1

THE RIGHT STUFF

When a microscopic invader breaches the outer defenses of the bodythe immune system swings into action. This happens automatically. The
molecular systems of the body, like the Star Wars anti-missile systemthat the military once planned, are robots designed to run on autopilot.
Since the defense is automated, every step has to be accounted for by somemechanism. The first problem that the automated defense system has is
how to recognize an invader. Bacterial cells have to be distinguished fromblood cells; viruses have to be distinguished from connective tissue. Unlike
us, the immune system can't see, so it has to rely initially on something
akin to a sense of touch.
 Antibodies are the «fingers» of the blind immune system—they allow
it to distinguish a foreign invader from the body itself. Antibodies areformed by an aggregation of four chains of amino acids (Figure 6-1): two
identical light chains, and two identical heavy chains. The heavy chainsare about twice as big as the light chains. In the cell, the four chains makea complex that resembles the letter Y. Because the two heavy chains are thesame and the two light chains are the same, the Y is symmetrical: if you
took a knife and cut it down the middle you'd get identical halves, with
one heavy and one light chain in each half. At the end of each pronged tipof the Y there is a depression (called a binding site). Lining the bindingsite are portions of both the light chain and the heavy chain. Binding sites
come in a large variety of shapes. One antibody might have a binding sitewith a piece jutting up here, a hole over there, and an oily patch on theedge. A second antibody might have a positive charge on the left, a crevice
in the middle, and a bump on the right.

A DANGEROUS WORLD 121
FIGURE 6-1
Schematic drawing of an antibody molecule.

If the shape of a binding site just happens to be exactly complementary
to the shape of a molecule on the surface of an invading virus or bacterium,then the antibody will bind to that molecule. To get a feel for it, imagine
a household object with a depression in it and a few knobs poking up outof the depression. My youngest daughter has a doll wagon with front andback seats—something like that will do nicely. Now take the wagon/object,
go around the house, and see how many other articles will fit snugly into
the depression, filling both the front seat and the back seat without leaving
any spaces. If you find even one, you're luckier than I am. Nothing in myhouse fit snugly in the wagon, and neither did anything in my office orlaboratory. I imagine there's some object out in the world with a shapecomplementary to the wagon's, but I haven't found it yet.
The body has a similar problem: the odds of any given antibody binding
to any given invader are pretty slim. To make sure that at least one kindof antibody is available for each attacker, we make billions to trillions ofthem. Usually, for any particular invader; it takes 100,000 to find one
antibody that works.
When bacteria invade the body, they multiply. By the time an an-

122 EXAMINING THE CONTENTS OF THE BOX
tibody binds to a bacterium there may be many, many copies of the
bug floating around. Against this Trojan horse that breeds, the body has
100,000 guns, but only one works. One handgun isn't going to do muchgood against a horde; somehow reinforcements have to be brought in.
There's a way to do this, but first I have to back up and explain a bit more
about where antibodies come from.
There are billions of different kinds of antibodies. Each kind of antibody
is made in a separate cell. The cells that make antibodies are called В cells,
which is easy to remember because they are produced in the bone marrow.2
When а В cell is first born, mechanisms inside of it randomly choose oneof the many antibody genes that are encoded in its DNA. That gene is said
to be «turned on»; all other antibody genes are «turned off.» So the cell
produces only one kind of antibody, with one kind of binding site. The
next cell that's made will in all likelihood have a different antibody gene
turned on, so it will make a different protein with a different binding site.
The principle, then, is one cell, one type of antibody.
Once a cell commits to making its antibody, you might think that theantibody would leave the cell so it could patrol the body. But if the contentsof all В cells were dumped out into the body, there would be no way to tellwhich cell the antibody came from. The cell is the factory that makes theparticular type of antibody; if the antibody finds a bacterium, we need totell the cell to send us reinforcements. But with this hypothetical setup, we
can't get a message back.
Fortunately, the body is smarter than that. When а В cell first makes
its antibody, the antibody anchors in the cell membrane with the prongsof the Y sticking out (Figure 6-2). The cell does this trick by using the genefor the normal antibody, and also using a little piece of a gene that codes
for an oily tail on the protein. Since the membrane is oily, too, the piece
sticks in the membrane. This step is critical, because now the binding siteof the antibody is attached to its factory. The entire В cell factory patrols
the body; when a foreign invader enters, the antibody-with-attached-cellbinds.
Now we have the factory close at hand to the invaders. If the cell could
be signaled to make more of the antibody, then the fight would be helped byreinforcements. Fortunately, there is a way to send a signal; unfortunately,
it's pretty convoluted. When an antibody on а В cell

A DANGEROUS WORLD 123
FIGURE 6-2
Schematic drawing of a B cell.

binds to a foreign molecule it triggers a complex mechanism to swallow
the invader: in effect, the munitions factory takes a hostage. The antibody
then breaks off a piece of membrane to make a little vesicle—a self-madetaxicab. In this taxi, the hostage is brought into the B-cell factory. Inside
the cell (still in the cab) the foreign protein is chopped up, and a pieceof the foreign protein sticks to another protein (called an MHC protein).
The cab then returns to the membrane of the cell. Outside the factory,
along comes another cell (called a helper T cell). The helper T cell binds
to the В cell, which is «presenting» the chopped-up piece of invader (theforeign fragment in the MHC protein) for the T cell's consideration. If
the fit is just right, it causes the helper T cell to secrete a substance calledinterleukin. Interleukin is like a message from the Department of Defense
to the munitions factory. By binding to another protein on the surface ofthe В cell, the interleukin sets off a chain of events that sends a message tothe nucleus of the В cell. The message is: grow!
The В cell begins to reproduce at a rapid rate. T cells continue to124 EXAMINING THE CONTENTS OF THE BOX
secrete interleukin if they are bound to а В cell. Eventually thegrowing B-cell factory produces a series of spinoff factories in the formof specialized cells called 'plasma cells.' Instead of producing a form of theantibody that sticks in the membrane, plasma cells leave off the last oily
piece of the protein. Now free antibody is extruded in large amounts into
the extracellular fluid. The switch is critical. If the new plasma-cell factories
were like the old B-cell factory, the antibodies would all be confined toquarters and would be much less effective at inhibiting the invaders. 

STEP BY STEP

Could this system have evolved step-by-step? Consider the vast poolbillions to trillions of factory В cells. The process of picking the right cell outof a mixture of antibody-producing cells is called clonal selection. Clonal
selection is an elegant way to mount a specific response in great numbers
to a wide variety of possible foreign invaders. The process depends on alarge number of steps, some of which I have not discussed yet. Leaving
those aside for now, let's ask what the minimum requirements are for aclonal selection system, and if those minimum requirements could be
produced step-by-step.
The key to the system is the physical connection of the binding abilityof the protein with the genetic information for the protein. Theoreticallythis could be accomplished by making an antibody where the tail of the
Y bound to the DNA that coded for the protein. In real life, however,such a setup wouldn't work. The protein might be connected to its genetic
information, but because the cell is surrounded by a membrane, theantibody would never come in contact with the foreign material, which isfloating around outside the cell. A system where both the antibody and its
attached gene were exported from the cell would overcome that problem,
only to run into a different one: outside the cell there would be no cellularmachinery to translate the DNA message into more protein.
Anchoring the antibody in the membrane is a good solution to the
problem; now the antibody can mix it up with a foreign cell and still benear its DNA. But although the antibody can bind the foreign material
without floating away from the cell, it does not have direct physicalA DANGEROUS WORLD 125
contact with the DNA. Since the protein and DNA are blind, there must
be a way to get a message from one to the other.
Just for now, for the sake of argument, let's forget about the tortuous waythat the message of binding actually gets to the B-cell nucleus (requiring
the taxicab, ingestion, MHC, helper T cells, interleukin, and so on).
Instead let's imagine a simpler system where there's only one other protein.
Let's say that when the antibody binds to a foreign molecule, something
happens that attracts some other protein—a messenger to take word of ahostage to the factory nucleus. Maybe when the hostage is first found, theshape of the antibody changes, perhaps pulling up a little on the antibody's
tail. Perhaps part of the antibody's tail sticks into the inside of the cell,which is what triggers the messenger protein. The change in the tail could
cause the messenger protein to scuttle into the nucleus and bind to the
DNA at a particular point. Binding to the right place on the DNA is whatcauses the cell to start growing and to start producing antibody without
the oily tail—antibody that gets sent out of the cell to fight the invasion.
Even in such a simplified scheme, we are left with three criticalingredients: (1) the membrane-bound form of the antibody; (2) the
messenger; and (3) the exported form of the antibody. If any of thesecomponents is missing, the system fails to function. If there is no antibody
in the membrane, then there's no way to connect a successful antibody
that binds a foreign invader to the cell containing the genetic information.
If there is no exported form of the antibody, then when the signal isreceived there is nothing to send out into the world to fight. If there isno messenger protein, then there is no connection between binding themembrane antibody and turning on the right gene (making the system
about as useful as a doorbell whose wires had been cut).
A cell hopefully trying to evolve such a system in gradual Darwiniansteps would be in a quandary. What should it do first? Secreting a little
bit of antibody into the great outdoors is a waste of resources if there's no
way to tell if it's doing any good. Ditto for making a membrane-boundantibody. And why make a messenger protein first if there is nobody togive it a message, and nobody to receive the message if it did get one? We
are led inexorably to the conclusion that even this greatly simplified clonal
selection could not have come about in gradual steps.

126 EXAMINING THE CONTENTS OF THE BOX
Even at this simplified level, then, all three ingredients had to evolve
simultaneously. Each of these three items—the fixed antibody, the messenger
protein, and the loose antibodies—had to be produced by a separate
historical event, perhaps by a coordinated series of mutations changing
preexisting proteins that were doing other chores into the components of
the antibody system. Darwin's small steps have become a series of wildly
unlikely leaps. Yet our analysis overlooked many complexities: How does
the cell switch from putting the extra oily piece on the membrane to not
putting it on? The message system then is fantastically more complicatedthan our simplified version. Ingestion of the protein, chopping it up,
presenting it to the outside on an MHC protein, specific recognition ofthe МНС/fragment by a helper T cell, secretion of interleukin, bindingof interleukin to the В cell, sending the signal that interleukin has boundinto the nucleus— the prospect of devising a step-by-step pathway for theorigin of the system is enough to make strong men blanch.

MIX AND MATCH

Factories float around in huge numbers, poised to deliver antibodies
that can stick to an invader with virtually any shape. But how does the
body make all those billions of differently shaped antibodies? It turns outthat there is an elegant trick for making very many different antibodies
without requiring enormous quantities of genetic material to code for theproteins. Over the next few pages I'll describe the system in some detail.
Again, don't be concerned if the details quickly slip your mind; my purpose
here is just to help you appreciate the complexity of the immune system.
 It took a fascinating discovery to lead scientists to puzzle out the fullcomplexity of the immune system. The discovery started with a potentiallycruel, but necessary, experiment. Just to see what would happen, chemists
made some small molecules that do not occur in nature and then attachedthem to a protein. When the protein carrying the synthetic molecules was
injected into a rabbit, the scientists were astonished to find that, yes, therabbit made antibodies that bound tightly to the synthetic molecule. How
could this be? Neither the rabbit nor its ancestors ever met the synthetic
molecule, so how did it know

A DANGEROUS WORLD 127
how to make antibodies against it? Why should it recognize a molecule
it had never seen before?
The puzzle of «antibody diversity» intrigued scientists studying
immunology. Several ideas were floated as possible explanations. Proteins
were known to be flexible molecules, and antibodies are proteins. So
maybe when a new molecule is injected into the body an antibody wraps
around it, molds itself to that shape, and then somehow freezes in that
configuration. Or maybe, because defense is so vitally important, theDNA of organisms contains a vast number of genes for antibodies withmany different shapes—enough to allow them to recognize things they
hadn't seen yet. But such a huge number of antibodies would take up
more than the available coding space in the DNA. So maybe there were
only a few antibodies, and when the cell divided, maybe there was some
way to make a lot of mutations in just the areas coding for the bindingsites of the antibodies. That way each new В cell in the body could carrydifferent mutations, coding for an antibody different from all other В cells.
Or maybe the answer was a combination of these, or maybe it involved
something completely new.
The answer to the problem of antibody diversity had to await anastonishing discovery: a gene coding for a protein didn't always have to bea continuous segment of DNA—it could be interrupted.3 If we compare agene to a sentence, it was as if a protein's code, «The quick brown fox jumps
over the lazy dog» could be altered (without destroying the protein) toread «The quick brdkdjf bufjwkw nhruown fox jumps over the lapfeqmzda
lfybnek sybagjufu zy dog.» The sensible DNA message was broken up bytracts of nonsense letters that somehow were not included in the protein.
Further work showed that for most genes, corrections would be made—splicing out the nonsense—after an RNA copy is made of a DNA gene.
Even with «interrupted» DNA, an edited and corrected message in RNA
could be used by the cell's machinery to make the correct protein. Even
more surprisingly, for antibody genes the DNA itself can also be spliced.
In other words, DNA that is inherited can be altered. Amazing!
Splicing and rearrangement of DNA play a large role in explaining thegreat number of antibodies that the body can produce. The following is abrief description of work that has taken many investigators many

128 EXAMINING THE CONTENTS OF THE BOX
years to accomplish; because of their efforts, the riddle of antibody
diversity is solved.
At conception there are a number of gene pieces in the fertilized cellthat contribute to making antibodies. The genes are arranged into clusters
that I will simply call cluster 1, cluster 2, and so forth. In humans there areapproximately 250 gene segments in cluster 1; a ways down the DNA fromcluster 1 are ten gene segments that form cluster 2; further on down the
DNA road are a group of six segments that comprise cluster 3; and downa piece from that are eight other gene segments that make up cluster 4.
These are the players.
After the youngster grows a bit and sets his mind to getting born, one
thing he wants to do is produce В cells. During the making of В cells, afunny thing happens: the DNA in the genome is rearranged, and some of
it is thrown away. One segment from cluster 1 is picked out, apparently at
random, and joined to one segment from cluster 2. The intervening DNA
is cut out and discarded. Then a segment from cluster 3 is picked, again
apparently at random, and joined to the cluster 1-2 segment.
The recombining of the segments is a little bit sloppy—no what you
usually expect from a cell. Because of the sloppy procedure, the coding
for a few amino acids (remember, amino acids are the building blocks
of proteins) can get added or lost. Once the cluster 1-2-3 segment is put
together, the DNA rearrangement is over.4 When it's time to make anantibody, the cell makes an RNA copy of the cluster 1-2-3 combination
and adds to it an RNA copy of a segment from cluster 4. Now, finally,
the regions that code for contiguous protein segments are themselves in acontiguous arrangement on the RNA.
How does this process explain antibody diversity? It turns out that
portions of the segments from clusters 1,2, and 3 form part of the binding
site—the tips of the Y. Mixing and matching different segments fromthe three different clusters multiplies the number of binding sites withdifferent shapes. For example, suppose that one segment from cluster 1
coded for a bump in the binding site, and another coded for a positive
charge. And suppose that different segments from cluster 2 coded for anoily patch, a negative charge, and a deep depression, respectively. Picking
one segment randomly from cluster 1 and cluster 2, you could have six
possible combinations:A DANGEROUS WORLD 129
a bump next to an oily patch, negative charge, or deep depression; or apositive charge next to an oily patch, negative charge, or deep depression.
(This is essentially the same principle whereby pulling three numbers outof a hat explains the diversity of a state lottery; picking just three numbers
from 0 to 9 gives a total of one thousand possible combinations.) Whenmaking an antibody heavy chain, the cell can pick one of two hundred andfifty segments from cluster 1, one of ten from cluster 2, and one of six fromcluster 3. Furthermore, the sloppiness during recombination «jiggles»
the segments (by crowding another amino acid into the chain, or leaving
one out); this effect adds another factor of about 100 to the diversity. By
mixing and matching DNA segments you get 250 × 10 × 6 × 100, which isabout a million different combinations of heavy-chain sequences. Similar
processes produce about ten thousand different light-chain combinations.
Matching one light-chain gene to one heavy-chain gene at random in eachcell gives a grand total of ten thousand times one million, or ten billion
combinations! The huge number of different antibodies provides so manydifferent binding sites that it's almost certain at least one of them will bind
almost any molecule—even synthetic ones. And all of this diversity comesfrom a total of just about four hundred different gene segments.
The cell has other tricks to tweak upward the number of possible
antibodies. One trick happens after a foreign invasion. When a cell binds
to foreign material, it receives a signal to replicate; during many roundsof replication the cell «intentionally» allows a very high level of mutationin just the variable regions of the heavy- and light-chain genes. This
produces variations on a winning theme. Because the parent cell coded
for an antibody that already was known to bind pretty well, mutating thesequence might produce a stronger binder. In fact, studies have shownthat the antibodies produced by cells late in an infection bind much more
tightly to foreign molecules than antibodies produced early in an infection.
This «somatic hypermutation» adds another several orders of magnitude
to the diversity of possible antibodies. Remember the difference between
B-cell factories and plasma factories? That oily piece of the Y that anchors
the antibody in the B-cell membrane? For a plasma cell, when the RNA
copy of the gene is130 EXAMINING THE CONTENTS OF THE BOX
made, the membrane segment is not copied. The segment is downstream
from the rest of the gene. The DNA can be likened to a message that says
«The quick brdkdjf bufjwkw nhruown fox jumps over the lapfeqmzda
lfybnek sybagjufu zy dog kdjyf jdjkekiwif vmnd and eats the mnaiuw
rabbit.» The final words can be left in or taken out, and the message still
makes some sense. 

INCH BY INCH

An antibody-diversity system requires several components to work. The
first, of course, is the genes themselves. The second is a signal identifying
the beginning and end of gene segments. In modern organisms, eachsegment is flanked by specific signals that tell an enzyme to come along
and join the parts together. This is like a sentence that reads «The quick
brcut here [fjwkw]cut hereown fox jumps over the lacut here [Ifybnek sy]
cut herezy dog»—as long as the beginning and ending are present, the cell
knows to keep it together. The third component is the molecular machinethat specifically recognizes the cutting signals and joins the pieces in theright order. In the absence of the machine, the parts never get cut out
and joined. In the absence of the signals, it's like expecting a machinethat's randomly cutting paper to make a paper doll. And, of course, in
the absence of the message for the antibody itself, the other components
would be pointless.
The need for minimal function reinforces the irreducible complexityof the system. Imagine you were adrift in a life raft on a stormy sea, andby chance a box floated by that contained an outboard motor. Your joy at
the hope of deliverance would be short-lived if, after you affixed it to theboat, the outboard propeller turned at a rate of one revolution per day.
Even if a complex system functions, the system is a failure if the level of
performance is not up to snuff.
The problem of the origin of antibody diversity runs headlong into
the requirement for minimal function. A primitive system with only one
or a few antibody molecules would be like the propeller turning at one
revolution per day: not sufficient to make a difference. (More to the point,
it would be as if the FBI national identification database only contained
two sets of fingerprints. Out of hundreds of thousands of criminals, theFBI could only hope to catch those two.) Because the likelihood is soA DANGEROUS WORLD 131
small for the shape of one antibody being complementary to the shapeof a threatening bacterium—perhaps one in a hundred thousand or so—an animal that spent energy making five or ten antibody genes would be
wasting resources that could have been invested in leaving more progeny,
or building a stronger skin, or making an enzyme for excretion that would
degrade RNA. To do any good, an antibody-generating system would needto generate a very large number of antibodies from the start.

THE HIT MAN

Suppose it is a thousand years ago and you live in a large compoundwith a group of people. Because it is near the coast, you have to worry
about Viking marauders. The compound is surrounded by a strong, highwooden fence; during a raid, pots of boiling oil are poured on folks trying
to climb up ladders. One strange day a traveling wizard knocks on thecompound door. Opening his pack, he offers to sell you a weapon fromthe future. He calls it a «gun.» When the trigger is pulled, he says, the gun
shoots a projectile in the direction you aim it. The gun is portable, and it
could quickly be taken from one side of the compound to the other if theenemy sneakily shifted their attack. You and the other members of thecompound pay the wizard two cows and four goats for the weapon.
Eventually there is a raid on your compound. Boiling oil flows freely,
but the raiders have a battering ram. Hearing it whack the compound gate,
you stride toward the gate confidently, gun in hand. Finally the gate issmashed and the raiders pour through, screaming and waving their battle
axes. You aim the gun and fire at their leader. The projectile flies throughthe air and sticks to the Viking chieftains nose. On the barrel of the gun,in letters you cannot read, is the inscription «Acme Toy Dart Gun.» The
chieftain stops, stares at you, and begins to grin as your smile dissolves.
He and his friends rush at you; fortunately, you are reincarnated as abiochemist in the twentieth century.
Antibodies are like toy darts: they harm no one. Like a «Condemned»
sign posted on an old house or an orange «X» painted on a tree to be
removed, antibodies are only signals to other systems to destroy themarked object. It is surprising to think that after the body132 EXAMINING THE CONTENTS OF THE BOX
has gone to all the trouble to develop a complex system to generate
antibody diversity, and after it has laboriously picked a few cells by theroundabout process of clonal selection, it is still virtually helpless against
the onslaught of invaders.
 Much of the actual killing of foreign cells that are marked by
antibodies is done by the «complement» system, which is called thisbecause it complements the action of antibodies in getting rid of invaders.
The pathway is remarkably complex (Figure 6-3); in many ways, it issimilar to the blood-clotting cascade discussed in Chapter 4. It consistsof about 20 kinds of proteins that form two related pathways, called theclassical pathway and the alternative pathway. The classical pathway starts
when a large aggregate of proteins, called C1, binds to an antibody that isitself bound to the surface of a foreign cell. It is crucial that the C1 complex
recognize only bound antibody; if C1 attached itself to antibody that was
floating around in the bloodstream, then all of the C1 would be sopped
up and unavailable for action against enemies. Or, if C1 bound to themembrane-attached antibodies of В cells, it would initiate reactions that
ultimately would end up killing good cells.
C1 is made up of 22 protein chains. These can be divided into threegroups. The first is called C1q. It contains six copies of three
FIGURE 6-3
The complement pathway.

A DANGEROUS WORLD 133
different types of proteins, for a total of 18. The other two groups arecalled C1r and С1s. They both have two copies each of different proteins.
The three different types of proteins in C1q all begin with a special aminoacid sequence that resembles the sequence of the skin protein collagen. The
sequence allows the tails of the three types of C1q proteins to wrap aroundeach other like braids. This arrangement holds one of each type of protein
in a mini-complex. The remainder of the protein chains then fold up into
complex, globular shapes at the top of the braid. Six of the minicomplexes
then come together. The six braids stick to each other lengthwise to createa central stalk, out of which protrude six heads. Pictures of C1q takenwith an electron microscope show something resembling a hydra-headed
monster. (Other people have likened it to a bouquet of tulips, but I likemore dramatic images.) The C1q heads attach to the antibody-foreign cellcomplex. At least two of the heads have to be attached before the pathway
is initiated. Once they stick, something in C1q changes, and the change in
C1q causes C1r and С1s to bind more tightly to C1q. When this happens
C1r cuts itself (headline: Dog bites dog!) to give C1r. («Activated» proteinsare designated by an upper bar over the number and lower case letter.) C1r
then is able to cut С1s to yield С1s.
After С1s is cleaved, we still have a long way to go before the work ofdestroying the invading cell is finished. The proteins of C1 are collectively
called the «recognition unit.» The next group of proteins (named C2, C3,
and C4) is called the «activation unit.» Unlike the recognition unit, theactivation unit is not already together in one piece; it has to be assembled.
The first step in forming the activation unit is the cleavage of C4 by C1s.
When C4 is cut by C1s, a very reactive group that was inside one piece(C4b) is exposed to the surroundings. If the group is close to a membrane,
it can chemically react with it. The attachment of C4b is necessary so therest of the proteins in the activation unit can have an anchor to hold themclose to the invader. In contrast, if C4b is pointed in the wrong direction
or is floating around in solution, then the reactive group quickly decays
without attaching to the correct membrane.
After C4b has attached itself to the target membrane, in association
with C1s it cleaves C2 into two pieces. The larger piece, C2a,134 EXAMINING THE CONTENTS OF THE BOX
remains stuck to C4b to yield C4b,2a, also known as «C3 convertase.»
C3 convertase has to act quickly, or it falls apart and C2a floats away. If amolecule of C3 is in the vicinity, C3 convertase cleaves it into two pieces.
C3b sticks to C3 convertase to form C4b,2a,3b, which is also called «C5convertase.» The final reaction of the activation unit is the cleavage of C5
into two fragments.
At this point the system is finally ready to stick a knife in the invader.
One of the pieces of C5 sticks to C6 and C7. This structure has theremarkable property of being able to insert itself into a cell membrane.
C5b,6,7 then binds to a molecule of C8 and a variable number (from one toeighteen) of molecules of C9 adds to it. The proteins, however, do not form
an undifferentiated glob. Rather, they organize themselves into a tubularform that punches a hole in the membrane of the invading bacterial cell.
Because the insides of cells are very concentrated solutions, osmoticpressure causes water to rush in. The in-rushing water swells the bacterialcell till it bursts.
There is an alternative pathway for the activation of the membraneattack complex that can act quickly after infection, not needing to wait
for the production of specific antibodies. In the alternative pathway asmall amount of C3b, which apparently is produced continuously in low
amounts, binds with a protein called factor B. C3b,B can then be cut
by another protein, factor D, to give C3b,Bb. This can now act as a C3
convertase. When more C3b is made, a second molecule of C3b can attach
to yield (C3b)2Bb. Remarkably, this is now a C5 convertase, which produces
C5b, which then goes on to start the formation of the membrane-attack
complex in the way described above for the first pathway.
C3b is a dangerous protein to have floating around, since it can activate
the destructive end of the complement pathway. In order to minimize
random damage, two proteins (factors I and H), search out, stick to,
and destroy C3b in solution. But if C3b is on the surface of a cell, thenanother protein (properdin), binds to and protects C3b from degradation
so that it can do its job. How does C3b target foreign cells in the absenceof antibodies? C3b is effective only if it sticks to the surface of a cell. The
chemical reaction by which it does so goes faster in the presence of themolecules typically found on the surface of many bacteria and viruses. A DANGEROUS WORLD 135

PROBLEMS, PROBLEMS

Like the blood-clotting pathway, the complement pathway is a cascade.
Inevitably, in both cases one encounters the same problems trying toimagine their gradual production. It is not the final activity of a cascadethat is the problem. The formation of a hole in a membrane does notnecessarily require several different components; one killer protein could
conceivably do the job. Nor does the formation of a protein aggregate, suchas in blood clotting, necessarily require multiple components; under theright conditions, any protein will aggregate. (The particular shapes of thecomplement hole-complex and fibrin aggregate, however, are particularly
suited to the jobs they do and need to be explained.) And as we saw in
Chapter 4, a telephone pole by itself could bop Foghorn Leghorn.
It is the control systems that are the problem. At each control point both
the regulatory protein and the masked protein that it activates have to bepresent from the beginning. If C5b were present, the rest of the cascade
would immediately be touched off; but if C5 were present with nothing
to activate it, then the whole pathway would always be shut off. If C3b
were present, the rest of the cascade would immediately be touched off;
but if C3 were present with nothing to activate it, then the whole pathway
would always be shut off. Even if one imagines a much shortened pathway(where, say, Cls directly cuts C5), insertion of additional control points
into the middle of the cascade runs into the same problem: the irreducible
complexity of the switches.
 In addition to the generic problems of setting up a cascade, thecomplement pathway shares another problem with the blood-clotting
cascade: attachment of proteins to membranes is crucial. Several clotting
factors must first be modified to synthesize Gla residues so that they
could stick to a membrane. In the complement pathway, both C3 andC4 have unusual, highly reactive internal groups that chemically attach
to the membrane after the proteins are cleaved by other factors. These
special features have to be available before the pathway is functional,
adding a further severe barrier to their gradual development.
Numerous little features of the complement system are stumbling
blocks to gradual development. Let's consider some subtle characteristics
of just the C1 system. The three types of proteins in136 EXAMINING THE CONTENTS OF THE BOX
C1q braid around each other, but do not braid with themselves. Ifthey did, then the ratio of different types of chains in the complex would
be changed, and there would be a much smaller chance of getting thereal C1q complex with six copies of three different chains. If the bindingof C1q to the antibody-foreign cell did not trigger C1r's self-scission,then the cascade would be stopped in its tracks. Conversely, if C1r cut
itself before C1q bound to the antibody complex, then the cascade would
be prematurely triggered. And so on. 

SISYPHUS WOULD SYMPATHIZE

The proper functioning of the immune system is a prerequisite forhealth. Major illnesses such as cancer and AIDS have either their cause or
their cure, or both, in the vagaries of the system. Because of its impact on
public health, the immune system is a subject of intense interest. Thousandsof research laboratories around the world work on various aspects of theimmune system. Their efforts have already saved many lives and promise
to save many more in the future.
Although great strides have been made in understanding how theimmune system works, we remain ignorant of how it came to be. Noneof the questions raised in this chapter has been answered by any of thethousands of scientists in the field; few have even asked the questions. A
search of the immunological literature shows ongoing work in comparative
immunology (the study of immune systems from various species). Butthat work, valuable though it is, does not address in molecular detail thequestion of how immune systems originated. Perhaps the best efforts atdoing that so far have been in two short papers. The first, by Nobel laureate
David Baltimore and two other prominent scientists, is tantalizingly
entitled «Molecular Evolution of the Vertebrate Immune System.» But it's
hard to live up to such a title in just two pages. The authors point out thatfor any organism to have an immune system akin to that seen in
mammals, the minimally required molecules are the antigen receptors(immunoglobulin and TCR), the antigen presentation molecules (MHC),
and the gene rearranging proteins.5

A DANGEROUS WORLD 137(Immunoglobulins are antibodies. TCR molecules are akin to
antibodies.) The authors then argue that sharks, which are very distantly
related to mammals, appear to have all three components. But it's one thing
to say an organism has a completed, functioning system, and another tosay how the system developed. The authors certainly realize this. Theynote that
immunoglobulin and TCR genes both require RAG proteins forrearrangement. On the other hand, RAG proteins require specificrecombination signals to rearrange immunoglobulin and TCR genes.

(RAG is the component that rearranges the genes.) They make a valiant
stab at accounting for the components, but in the end, it is a hop in thebox with Calvin and Hobbes. The authors speculate that a gene from abacterium might have luckily been transferred to an animal. Luckily, theprotein coded by the gene could itself rearrange genes; and luckily, in the
animal's DNA there were signals that were near antibody genes; and so on.
In the final analysis the authors identify key problems with gradualistic
evolution of the immune system, but their proffered solutions are reallyjust a disguised shrug of their shoulders.
Another paper that gamely tries to account for a piece of the immune
system is entitled «Evolution of the Complement System.»6 Like the paper
discussed above, it is very short and is a commentary article—in otherwords, not a research article. The authors make some imaginative guesses
about what might come first and second, but inevitably they join Russell
Doolittle in proposing unexplained proteins that are «unleashed» and«spring forth» («At some point a critical gene fusion created a protease witha binding site for the primitive C3b»; «Evolution of the other alternative
pathway components further improved the amplification and specificity»;and «C2, created by the duplication of the factor В gene, would then haveallowed further divergence and specialization of the two pathways»). No
quantitative calculations appear in the paper. Nor does an acknowledgmentthat gene duplications would not immediately make a new protein. Nordoes any worry about a lack of controls to regulate the pathway. But then,it would be hard to fit those concerns in the four paragraphs of the paperthat deal with molecular mechanisms.

138 EXAMINING THE CONTENTS OF THE BOX
There are other papers and books that discuss the evolution of theimmune system.7 Most of them, however, are at the level of cell biology
and thus unconcerned with detailed molecular mechanisms, or else they
are concerned simply with comparison of DNA or protein sequences.
Comparing sequences might be a good way to study relatedness, but theresults can't tell us anything about the mechanism that first produced thesystems.
We can look high or we can look low, in books or in journals, but theresult is the same. The scientific literature has no answers to the questionof the origin of the immune system.
In this chapter I have looked at three features of the immune system—
clonal selection, antibody diversity, and the complement system—anddemonstrated that each individually poses massive challenges to a putative
step-by-step evolution. But showing that the parts can't be built step bystep only tells part of the story, because the parts interact with each other.
Just as a car without steering, or a battery, or a carburetor isn't going to
do you much good, an animal that has a clonal selection system won't get
much benefit out of it if there is no way to generate antibody diversity. A
large repertoire of antibodies won't do much good if there is no system tokill invaders. A system to kill invaders won't do much good if there's no
way to identify them. At each step we are stopped not only by local systemproblems, but also by requirements of the integrated system.
We have looked at some positive features of the immune system, butthere are also drawbacks to carrying around loaded weapons. You haveto make sure you don't shoot yourself in the foot. The immune system
has to discriminate between itself and the rest of the world. When, say,a bacterium invades, why does the body make antibodies against it but
not against the red blood cells that are continually circulating in the
bloodstream, or any of the other tissues that antibody cells constantly
bump up against? When the body does make self-directed antibodies, it isgenerally a disaster. For example, people suffering from multiple sclerosis
make antibodies that are directed against the insulation that surrounds
nerves. That causes the immune system to destroy the insulation, exposing
and short-circuiting nerves, and leading to paralysis. In juvenile diabetes,
antibodies are made against the β cells of the pancreas, leading to theirdestruction. The unfortunate person can no longer make insulin andusually dies unless insulin

A DANGEROUS WORLD 139
is supplied artificially. How the body acquires tolerance to its own
tissues is still obscure, but whatever the mechanism, we know one thing:a system of self-toleration had to be present from the start of the immune
system.
Diversity, recognition, destruction, toleration—all these and moreinteract with each other. Whichever way we turn, a gradualistic accountof the immune system is blocked by multiple interwoven requirements. As
scientists we yearn to understand how this magnificent mechanism cameto be, but the complexity of the system dooms all Darwinian explanations
to frustration. Sisyphus himself would pity us.
It is perhaps not surprising to discover unremitting complexity in such
Star Wars-like machines as comprise the immune system. But what about
humbler systems? What about the factories that manufacture the nuts
and bolts out of which molecular machines are made? In a final evidence
chapter I will examine the system that makes one of the «building blocks.»
We will see that complexity reaches down to the very bottom of the cell.

CHAPTER 7

ROAD KILLLOOK BOTH WAYS

My family and I live about five miles from campus on one of the many
beautiful mountains that grace Pennsylvania. The area, although close totown, is rural, with a thick forest wherever space has not yet been cleared
for a house. Leading to our home is a narrow country road, winding thisway and that as it makes its way up the mountain. As I drive to work in themorning or home at night I always see a few little animals crouching by
the side of the road, ready to make a run for it. Whether they are taking adare, trying to impress the opposite sex, or just anxious to get home, I do
not know. But it is a dangerous game they play, and some pay the price.
Squirrels are the worst. Unlike more sensible animals, squirrels don't
just cross over. While far away you can spot them sitting on one side of theroad. As you get closer, they dash over to the other side, stop, reverse, andscramble back to the center. Closer and closer you get, and they're still in
the road. Finally, as you drive by, they decide that your side is where they
really want to be. Squirrels can fit under the car, so there's always hope as
they disappear under the front end that you might see

140

ROAD KILL 141
them in the rearview mirror, scurrying to safety. Sometimes they makeit; sometimes they don't.
Groundhogs generally travel in a straight line across the road, making
their position easy to anticipate, but you don't get much warning. Usually
you're driving along, thinking about dinner, when all of a sudden a small,round shape waddles out of the darkness into your lane. At that point all
you can do is grit your teeth and wait for the bump— unlike squirrels,
groundhogs don't fit under the car. The next morning all that's left is a little
stain on the road, other cars having obliterated the carcass. Nature red in
tooth, claw, and tarmac.
Although traffic has picked up on the road lately, it's still pretty slow—
one car every few minutes during the day, one every half hour at night.
So most animals that cross the road easily make it to the other side. That's
not true everywhere. The Schuylkill Expressway, the main highway into
Philadelphia from the northwest, is eight or ten lanes wide in certain
stretches. The volume of traffic can easily be thousands of times what itis on the road by my house. It would not be smart to bet on a groundhog
starting from one side of the Schuylkill during rush hour getting to theother side.
Suppose you were a groundhog sitting by the side of a road several
hundred times wider than the Schuylkill Expressway. There are a thousand
lanes going east and a thousand lanes going west, each filled with trucks,
sports cars, and minivans doing the speed limit. Your groundhog
sweetheart is on the other side, inviting you to come over. You notice thatthe remains of your rivals in love are mostly in lane one, with some in lane
two, and a few dotted out to lanes three and four; there are none beyond
that. Furthermore, the romantic rule is that you must keep your eyes closed
during the journey, trusting fate to deliver you safely to the other side.
You see the chubby brown face of your sweetie smiling, the little whiskers
wiggling, the soft eyes beckoning. You hear eighteen-wheelers screaming.
And all you can do is close your eyes and pray.
The example of groundhogs crossing a road illustrates a problem forgradualistic evolution. Up until this point in the book I have emphasized
irreducible complexity—systems that require several components tofunction, and so are mammoth barriers to gradual evolution. I discussed anumber of examples; more can be seen just by paging through a142 EXAMINING THE CONTENTS OF THE BOX
biochemistry textbook. But some biochemical systems are notirreducibly complex. They do not necessarily require several parts tofunction, and there seem to be (at least at first blush) ways to assemble
them step-by-step. Nonetheless, upon closer examination nasty problems
pop up. Supposedly smooth transitions turn out to be ephemeral whenchecked in the light of day. So even though some systems are not irreduciblycomplex, it does not necessarily mean that they have been put together ina Darwinistic manner. Like a groundhog trying to cross a thousand-lane
highway, there is no absolute barrier to putting together some biochemicalsystems gradually. But the opportunities to go wrong are overwhelming.

THE BUILDING BLOCKSThe big molecules that do the work in the cell—proteins and nucleic
acids—are polymers (that is, they are made of discrete, units strung
together in a row). The building blocks of proteins are amino acids, and thebuilding blocks of nucleic acids are nucleotides. Much like a child's snaplock beads, amino acids or nucleotides can be strung to give an almost
infinite variety of different molecules. But where do the beads come from?
Snap-lock beads are made in a factory; they aren't just found lying aroundin the woods. The factory makes the beads in specific shapes so that thelittle hole in one end is the right size for the knob sticking out of the otherend. If the knob were too big, the beads could not be joined; if the holes
were too big, the string of beads would fall apart. The manufacturer of
snap-lock beads takes great care to mold them in the right shape and touse the right kind of plastic. The cell takes much care in manufacturing its
building blocks, too.
DNA, the most famous of nucleic acids, is made up of four kinds ofnucleotides: A, C, G, and T.1 In this chapter I will talk mostly about thebuilding block A. When the building block is not connected to a polymer,
it can be in several forms, designated AMP, ADP or ATP. The form that isfirst synthesized in the cell is AMP. Like snap-lock beads, AMP has to bemade carefully. Most molecules in biological organisms are made of justa few different kinds of atoms, and AMP is no exception. It is comprisedof five different kinds: ten carbons, eleven hydrogens, seven oxygens, four
nitrogens, and one phosphorus. I've used the analogy of snap-lock beads
to convey how amino acids and nucleotides are put together into long

ROAD KILL 143
chains. To understand how AMP is synthesized, let's think of something
like Tinkertoys. For those readers who are unfamiliar with them,Tinkertoys have two kinds of pieces—a wooden wheel with holes drilled
into the rim and center, and wooden sticks that have the same diameteras that of the holes. By pushing the sticks into the holes, you can connect
several wheels. By using more sticks and wheels you can build up a wholenetwork. The structures you can make from just those two types of pieces,from castles and cars to dollhouses and bridges, are limited only by yourimagination. Atoms are like the pieces of a Tinkertoy set: the atoms are thewooden wheels, and the chemical bonds formed between atoms are thesticks. Like Tinkertoys, atoms can be put together to form many different
shapes. A big difference is that the cell is a machine, however, so themechanism to assemble the molecules of life must be automated. Imagine
the complexity of a machine that could automatically assemble Tinkertoys
into, say, the shape of a castle! The mechanism that the cell uses to make
AMP is automated, and as expected, it is far from simple.
Atoms are almost always found in molecules; they're not lying free
like tinker toy pieces. So to make a new molecule you generally have totake old molecules and join parts of them together. It's like taking a turretoff of a Tinkertoy castle to use as a car body, using a propeller from a
Tinkertoy airplane as a car wheel, etc. Similarly, new molecules are built
up from pieces of old molecules. The molecules that are used to build up
AMP all have rather long and tedious chemical names; I won't use themin the description unless I have to. Instead I'll just describe the molecules
in words and give them innocuous names like «Intermediate III» and«Enzyme VII.»
Figure 7-1 shows the molecules that are involved in the step-by-step
synthesis. Most readers will probably find my description on the next
several pages easier to follow by referring frequently to the figure. Don't
worry, though—I'm not going to talk about any esoteric concepts; just
who is connected to whom. The point is to appreciate the complexity ofthe system, to see the number of steps involved, to notice the specificityof the reacting components. The formation of biological molecules does
not happen in some fuzzy-minded Calvin and Hobbes way; it requires
specific, highly sophisticated molecular robots to get the job done. I urge
you to skim along through the next two sections and marvel.

144 EXAMINING THE CONTENTS OF THE BOX
FIGURE 7-1
Biosynthesis of AMP. The figure starts with Intermediate III.
F represents the «foundation»- ribose-5-phosphate. White
boxes are nitrogen atoms, black are carbon atoms, and grayare oxygen atoms. the atoms are numbered in the order they
become attached. only atoms that will be part of the final
product are numbered. atoms that become attached but aresubsequently replaced or cut off are marked with an x.

ROAD KILL 145 То build a house you need energy. Sometimes the energy is just in
the muscles of the workers, but sometimes it is in the gasoline that powers
bulldozers or electricity that turns drills. The cell needs energy to make
AMP. The cell's energy comes, in discrete packages; I'll call them «energy
pellets.» Think of them as molecular candy bars, to provide energy formuscles, or gallon cans of gasoline, to power machines. There are several
different types of energy pellets, including ATP and GTP. Don't worry
about what they look like or how they work; I'll just note at which steps weneed them.
The first two steps in the synthesis of AMP aren't shown in Figure
7-1—they happen offstage. Just as the building of a house starts with thefoundation, so does the synthesis of AMP. The foundation is a complicatedmolecule whose synthesis I will not discuss. It consists of a ring of atoms;
four carbons and one oxygen. To three of the ring carbons are attachedoxygen atoms. To the fourth carbon in the ring is attached another carbon,
to which is hooked an oxygen, to which is attached a phosphorus with threeoxygens. In the first step of the synthesis of AMP a group consisting of two
atoms of phosphorus and six atoms of oxygen is transferred by Enzyme I,
en masse, to one of the oxygens of the foundation to make Intermediate II.
This requires an energy pellet of ATP. Intermediate II is used by the bodyas the starting point for making several different molecules, including
AMP.
In the next step Enzyme II takes a nitrogen atom from the amino acidglutamine and places it on a ring carbon to give Intermediate III. In thesame step the phosphorus/oxygen group that was attached in the last stepis kicked off. This is the point at which Figure 7-1 takes up the story. To
make the figure easier to follow, I will just represent the foundation by theletter F. So at this point in Figure I we see a a nitrogen atom attached to aletter F.2 Nitrogen atoms are colored white in the figure, carbons are black,and oxygens are gray. The atoms that will end up in the final product(AМР) are numbered according to the order in which they are attached.
Atoms that won't end up in AMP are marked with an «X.»
Under the guidance of Enzyme III, an amino acid called glycine(consisting of a nitrogen atom that is attached to a carbon, which is146 EXAMINING THE CONTENTS OF THE BOX
attached to another carbon attached to two oxygens) glides in andhooks on to the nitrogen of Intermediate III through one of its carbon
atoms. This uses an energy pellet of ATP. In the process one of the twooxygens originally attached to carbon #2 is kicked out. At this point themolecule looks like the foundation has a tail waving in the breeze. The
finished product, AMP is going to look very different: a couple of stiff,
fused rings attached to the foundation. In order to get there from where
we are now, the molecule has to be chemically prepared in the right order.
In the next step a molecule of formic acid (actually the related ion,formate), consisting of two atoms of oxygen attached to an atom of carbon,
is stuck onto nitrogen #4 of Intermediate IV to make Intermediate V. In
the process one of the formate oxygens is kicked out. Ordinarily formate
is unreactive, so getting it to hook onto other molecules requires some
preparation. A biochemistry textbook emphasizes the problem:
Formate ... is quite unreactive under physiological conditions and mustbe activated to serve as an efficient formylating agent.... The fundamental
importance of [THF] is to maintain formaldehyde and formate in chemicallypoised states, not so reactive as to pose toxic threats to the cell but available
for essential processes by specific enzymatic action.

Thankfully, as the quote points out, formate is not just floating aroundin solution. It is first attached to a vitamin called THF, a cousin of the Вvitamin folic acid (don't even ask how the vitamin is synthesized). When it
is attached by an enzyme to the vitamin (in a reaction requiring an energy
pellet of ATP), formate is revved up and made ready for action. The THFformate complex, however, would not join up with Intermediate IV to giveIntermediate V unless directed to do so by Enzyme IV; it would float awayin the cell until it reacted with something else or decayed, and that would
mess up our synthesis of AMP. That doesn't happen, however, because the
enzyme guides the reaction to the correct products.
The next step is to replace the oxygen atom that is hooked onto carbon#2 of Intermediate V with a nitrogen atom. This can be done chemicallyby exposing the molecule to ammonia—but you can't just throw ammonia
into the cell, because it would react willy-nilly with a lot of things that

ROAD KILL 147
it shouldn't react with. So part of an amino acid is used to donate thenitrogen atom that's needed. The amino acid glutamine, under the watchfuleyes of Enzyme V sidles up to Intermediate V so that the nitrogen of theamino acid is close to the first oxygen of Intermediate V. Through thecatalytic wizardry that enzymes are famous for, the nitrogen hops off theamino acid, the oxygen is kicked out of Intermediate V and the nitrogentakes its place to make Intermediate VI. This step uses an energy pellet ofATP. 

RING AROUND THE ROSIE The next step in building ourselves a molecule of AMP is in someways like the last step. Again we're going to take a nitrogen atom and use
it to replace an oxygen atom that's attached to a carbon, and again thisstep uses an energy pellet of ATP. But this time we don't have to bring in anitrogen from the outside. Instead we'll use nitrogen #1, which is alreadyin our molecule. The first nitrogen that was put on the foundation—the
one that kicked out the phosphorus/oxygen group a number of steps
ago—now comes into play. It takes the place of the oxygen atom that is lastin the chain. But unlike the nitrogen that came from the amino acid in
the previous step, this nitrogen doesn't break any of its bonds with otheratoms. It just makes a new one, as seen in Intermediate VII. An interesting
thing about this arrangement is that it now makes a ring of atoms; thering has five members, with two groups sticking off of it. The first group isnitrogen #6, which was introduced in the last step, and the second groupis the foundation.
When you shake a can of soda and open the lid, usually you get soakedby a spray of liquid. The spray is powered by the sudden release of carbon
dioxide gas that had been dissolved in the liquid. Some carbon dioxide
is also dissolved in cellular fluid (although an animal usually doesn't fizz
when shaken) and can be used in biochemical reactions. That's good,
because the next step in the synthesis of AMP needs carbon dioxide.
In the reaction the gas molecule (actually its water-logged counterpart,
bicarbonate) is placed by Enzyme VII onto carbon #3 to make Intermediate
VIII. An energy pellet of ATP powers this step.4
And now it's time for another ammonia to be added. This step will also

148 EXAMINING THE CONTENTS OF THE BOX
use an ATP energy pellet. Like the last time ammonia added, it won't
be found floating around free in solution (like the carbon dioxide was); it
will be donated by an amino acid. But this time it will be the amino acidcalled aspartic acid. And, in another twist, the nitrogen does not leave theamino acid when it reacts Intermediate VIII: we get the nitrogen we want,
but also an ugly extra chain of atoms dangling off the end of Intermediate
IX. Enzyme IX removes the unwanted appendage, sawing off only the
extraneous part.
The result, Intermediate X, is a half-built molecule. Another molecule ofactivated formate—again hooked on to a vitamin—is attached to nitrogen#6 of Intermediate X to give Intermediate XI. In the next step, Enzyme
XI directs nitrogen #8 to kick out the oxygen of the formate that was just
attached and to make a bond to carbon #9; this gives Intermediate XII.
Because the reacting nitrogen does not break its bond with the carbon
to which it was initially attached, the reaction forms another ring. The
two fused rings of Intermediate XII are rigid, not floppy like the chainsof atoms that preceded ring formation. The formation of the six-member
ring in this step is similar to the formation of the five-member ring several
steps ago, and the reaction of formate in the last step is chemically similar
to the previous addition of formate. But even though the two sets of steps
are similar; they are catalyzed by two different sets of enzymes. This isnecessary because the shape of the molecule has changed during synthesis,
and enzymes are frequently sensitive to shape changes.
Intermediate XII is a nucleotide called IMP, which is used in somebiomolecules (for example, one special type of RNA that helps to makeprotein contains a little bit of IMP). To make AMP from IMP requires
a couple of different steps, which are shown in Figure 7-1. In a step
reminiscent of an earlier one, Enzyme XII attaches a molecule of the aminoacid aspartic acid to the six-membered ring, kicking out the oxygen atomwith the nitrogen atom оf the incoming molecule. This gives Intermediate
XIII. The reaction uses an energy pellet, but not ATP; instead, for reasons
I will discuss later, it uses GTP. Again, as happened last time that aspartic
acid was attached, this leaves us with an ugly, detrimental appendage.

ROAD KILL 149
Enzyme IX comes back (the only enzyme to be used twice in thepathway) to saw off the unnecessary part and leave behind the required
nitrogen atom.
Finally we have AMP—one of the 'building blocks' of nucleic acids. 

GETTING THERE

I assume I've lost most readers in the labyrinth by now, so let me playaccountant and summarize the biosynthesis of AMP. The synthesis takes
thirteen steps and involves twelve enzymes; one of the enzymes, IX,
catalyzes two steps. Besides the foundation molecule, ribose-5-phosphate,the synthesis requires five molecules of ATP to provide the energy to drive
chemical reactions at different steps, one molecule of GTP, one moleculeof carbon dioxide, two molecules of glutamine to donate nitrogen atoms
at different steps, a molecule of glycine, two formyl groups from THF atseparate steps, and two molecules of aspartic acid to donate nitrogen atoms
at another two steps. Additionally, at two separate steps the remains ofaspartic acid molecules have to be cut off, and at two separate steps partsof the growing molecule have to be reacted with each other to close thetwo rings. All thirteen steps occur to produce just one kind of molecule.
The precursor molecules along the synthetic pathway—Intermediates III
to XI—play no independent role; they are used for nothing but to make
AMP or GMP.
All roads lead to Rome, it is said, and similarly there are many ways tosynthesize AMP. A book for chemists that I have on my shelf lists eight
different ways to make adenine (which is the top part of AMP, without
the foundation);5 the remainder of the molecule can be put together in avariety of ways also. Chemists who want to synthesize adenine, however,use completely different routes from that used by cells. Because they
involve reactions in oily liquids at extremes of acidity, these conditions
would cause the quick demise of any known organism.
In the early 1960s scientists who were interested in the origin of life
discovered an interesting way to synthesize adenine.6 They saw that thesimple molecules hydrogen cyanide and ammonia—which are thought tohave been plentiful in the early days of earth—will form adenine under150 EXAMINING THE CONTENTS OF THE BOX
the right conditions. The ease of the reaction so impressed Stanley
Miller that he called it «the rock of the faith» for origin-of-life researchers.7
But there's a problem lurking in the back ground: hydrogen cyanide andammonia are not used in biosynthesis of AMP. But even if they were on
the ancient earth, and even if that had something to do with the origin oflife (which is ргоblematic on a number of other grounds), the synthesis ofadenine from simple molecules in a chemist's flask gives us absolutely no
information about how the route for making the molecule first developedin the cell.
Stanley Miller was impressed by the ease of synthesis of adenine from
simple molecules, but the cell eschews simple synthesis. In fact, if we
dissolved in water (using the formal chemical names) ribose-5-phosphate,glutamine, aspartic acid, glycine, N10-formyl-THF, carbon dioxide, andenergy packets of ATP and GTP—all the small molecules that are used by
the cell to build AMP—and let them sit for a long time (say, a thousand
or a million years) we would not get any AMP.8 If Stanley Miller mixed
these chemicals hoping for another rock of the faith, he would be quite
disappointed.
Shoes might be all we need to get to Rome from Milan. But we will needmore than shoes to get to Rome from Sicily; we will need a boat. And to getto Rome from Mars, we need very high-tech equipment indeed. To make
AMP from the ingredients that the cell uses we also need very high-techequipment: the enzymes that catalyze the reactions of the pathway. In theabsence of the enzymes, AMP is simply not made by the reactions shownin Figure 7-1. The point is that even if adenine or AMP can be made bysimple pathways, those pathways are no more precursors to the biologicalroute of synthesis than shoes are precursors to rocket ships.

ABCD

Consider a metabolic pathway where compound A is transformed into
compound D by way of intermediates В and C. Could the pathway have
evolved gradually? It depends. If А, В and С are useful compounds forthe cell, and if neither В, C, nor D are essential from the beginning, thenperhaps a slow development is possible. In that stance we can imagine acell that made A leisurely mutating so that, serendipitously, compoundROAD KILL 151
В was produced. If it did no harm, then perhaps over time the cellwould find a use for compound B. And then perhaps the scenario could be
repeated. A random mutation causes the cell to produce some С from B, a
use is found for C, and so on.
However, suppose D is necessary from the beginning. AMP is required
for life on earth: it is used to make DNA and RNA, as well as a numberof other critical molecules. There may be some way to construct a living
system that does not require AMP, but if there is, no one has a clue how
to do so. The problem for Darwinian evolution is this: if only the end
product of a complicated biosynthetic pathway is used in the cell, how
did the pathway evolve in steps? If A, B, and С have no use other thanas precursors to D, what advantage is there to an organism to make just
A? Or, if it makes A, to make B? if a cell needs AMP, what good will it
do to just make Intermediate III, or IV, or V? On their face, metabolic
pathways where intermediates are not useful present severe challenges toa Darwinian scheme of evolution. This goes in spades for something like
AMP, because the cell has no choice: AMP is required for life. Either it
immediately has a way to produce or obtain AMP or the cell is dead.
A few textbooks mention this problem. The typical explanation is
economically expressed by Thomas Creighton:
How might the biochemical complexity of metabolic pathways have
evolved? In the case of the biosynthetic pathways that produce thebuilding blocks of amino acids, nucleotides, sugars, and so forth, it is likelythat these building blocks were originally present in the primordial soup
and were used directly. As organisms increased in number, however, these
constituents would have become scarce. Any organism that could produce
one of them from some unused component of the primordial soup, using
a newly evolved enzyme, would have had a selective advantage. Oncethe availability of that component became limiting, there would havebeen selection for any organism that could produce it from some othercomponent of the primordial soup. According to this scenario, the enzymes
of metabolic pathways would have evolved in a sequence opposite to the
one they have in the modern pathway.9

Simply put, Creighton says that if we find a reaction pathway in amodern organism that goes ABCD, then D was available in theprimordial soup—synthesized by simple chemical precursors without

152 EXAMINING THE CONTENTS OF THE BOX
benefit of enzymes. As the supply of D ran low, some organism would«learn» to make D from C. As С ran out, it would make C from B. When
famine threatened again, it would learn to make В from A, and so on. The
same scheme is described in Molecular Biology of the Cell, a popular text
written by Nobel laureate James Watson, president of a National Academyof Sciences, Bruce Alberts, and several other coauthors. We are told in a
figure legend that the primordial cellis provided with a supply of related substances (A, B, C, and D) produced
by prebiotic synthesis. One of these, substance D, is metabolically useful.
As the cell exhausts the available supply of D, a selective advantage is
obtained by the evolution of a new enzyme that is able to produce D fromthe closely related substance C.10

Yes, everybody agrees that, if you run out of D, the thing to do is tomake it from C. And of course, it should be a simple matter to convert В
to C. After all, they're right next to each other in the alphabet. And where
do we get A, B, and the rest? From the primordial alphabet soup, of course.
The fact is that no one ever puts real chemical names on any of themythical letters in the ABCD story. In the textbooks mentioned
above, the cartoon explanations are not developed any further, eventhough the books are used to teach Ph.D. students who could easily
follow detailed explanations. It is certainly no trouble to imagine thatthe primordial soup might have some С floating around which could
easily be converted to D; Calvin and Hobbes could imagine that without
any difficulty whatsoever. It is, however, much more difficult to believe
there was much adenylosuccinate (Intermediate XIII) to be converted
to AMP. And it is even harder to believe that carboxyaminoimidazole
ribotide (Intermediate VIII) was sitting around waiting to be converted to
5-aminoimidazole-4-(N-succinylocarboxamide) ribotide (Intermediate
IX). It is difficult to believe because, when you put real names on thechemicals, then you have to come up with a real chemical reaction that
could make them. No one has done.
The problems with the ABCD theory are legion. Let's lookat a few of the more prominent ones. First, except for Intermediate X,
prebiotic synthesis experiments have yielded none of the intermediates
in the biosynthesis of AMP.11 Although adenine can be made by reacting
ammonia and hydrogen cyanide, biochemical precursors to adenine

ROAD KILL 153
can not. Second, there are good chemical reasons to think thatintermediates in the biochemical pathway can't be made except under
careful guidance of enzymes. For example, if the right enzymes were notavailable to steer the reactions to Intermediates V and XI, formate would
more likely react in nonproductive ways than in the ways required to make
AMP. Note that those enzymes would have to be available before enzymes
for the succeeding steps could be developed, else the later enzymes would
have nothing to work on. Furthermore, the steps that require energy
pellets have to be carefully guided so that the energy isn't squandereddoing something useless. For example, the energy of gasoline can make a
car move because it is channeled in the right way by a complex machine;burning gasoline in a pool under the car doesn't move it at all. Unless there
was an enzyme guiding the use of the ATP energy pellet, the energy would
be squandered. Notice once more that the enzymes needed to guide thesesteps would be required before the organism would have the chemical thatis made in the next step of the pathway.
A third problem with the ABCD story is that some of theintermediates in the pathway are chemically unstable. So even if, against
all hope, they were made in an undirected pxebiotic reaction, they would
either quickly fall apart or quickly react in the wrong way; again theywould not be available to continue the pathway. Other reasons could be
advanced against the ABCD story, but this will suffice.

THEN AND NOW

A few years ago I read The Closing оf the American Mind by Allan
Bloom. I was startled by his claim that many modern Аmerican ideas
actually have their roots in old European philosophies. In particular I was
surprised that the song «Mack the Knife» was a translation of a Germansong, «Mackie Messer,» whose inspiration Bloom traces to a murderer's«joy of the knife» that Nietzsche describes in Thus Spake Zarathrusta.12
Most of us like to think that our ideas are our own—or at least they were
proposed by someone else, that we only agreed to them after conscious
review and assent. It's unnerving to think, as Bloom maintained, that manyof our important ideas about the way the world works were simply pickedup unreftectively from the cultural milieu in which we found ourselves.

154 EXAMINING THE CONTENTS OF THE BOX
The ABCD story is an old idea that has been passed on
unreflectively. It was first proposed in 1945 by N. H. Horowitz in theProceedings of the National Academy of Sciences. Horowitz sees the
problem:Since natural selection cannot preserve nonfunctional characters, the mostobvious implication of the facts would seem to be that a stepwise evolutionof biosyntheses, by the selection of a single gene mutation at a time, is
impossible.13

But there is hope:
In essence, the proposed hypothesis states that the evolution of the basic
syntheses proceeded in a stepwise manner, involving one mutation at atime, but that the order of attainment of individual steps has been in thereverse direction from that in which the synthesis proceeds, i.e., the last
step in the chain was the first to be acquired in the course of evolution, thepenultimate step next, and so on. This process requires for its operation a
special kind of chemical environment; namely, one in which end products
and potential intermediates are available. Postponing for the moment thequestion of how such an environment originated, consider the operation of
the proposed mechanism. The species is at the outset assumed to (require)
an essential organic molecule, D. ... As a result of biological activity, theamount of available D is depleted to a point where it limits the further
growth of the species. At this point, a marked selective advantage will beenjoyed by mutants which are able to carry out the reaction B + C = D... . In
time B may become limiting for the species, necessitating its synthesis fromother substances.14

Here is the source for the explanation of the development of biochemical
pathways given by modem textbooks. But what was the state of science inHorowitz's day? In 1945, when his article appeared, the nature of a gene
was unknown, as were the structures of nucleic acids and proteins. No
experiments had yet been done to see if the «special kind of chemical
environment» Horowitz postulated was possible. In the intervening years
biochemistry has progressed tremendously, but no advance encourages
his hypothesis. The structures of genes and proteins are known to bemuch more complicated than thought in Horowitz's day. There are goodchemical reasons for thinking that the intermediates in AMP synthesis
would not be available outside of a living cell, and no experiment has
shown otherwise. The «moment for which Horowitz postponed

ROAD KILL 155«the question of how such an environment originated» has now
stretched past fifty years. Despite the manifest difficulties, the old story
is repeated in textbooks as if it were as obvious as the nose on your face;
the progress of five decades can't put a dent in received wisdom. Reading
modern texts, you can almost hear the haunting strains of «Mack theKnife.»
Although textbooks carry the standard idea, some people are restless.
Nobel laureate Christian de Duve, in his book Blueprint for a Cell, expresses
skepticism of the importance of the hydrogen cyanide/ammonia pathway.
Instead he proposes that AMP arose through «protometabolic pathways»
in which a lot of little proteins just happened to have the ability to make a
lot of different chemicals, some of which were intermediates in the AMP
pathway. To illustrate his theory he has a figure in which arrows point fromthe words abiotic syntheses to the letters А, В, C, and D. But, breaking
new ground, he has arrows pointing from А, В, C, and D to M, N, S, T
and W and from there to P, O, Q, R, and U. Beside each of the arrows he
has written Cat (as an abbreviation for «catalyst») to show how the lettersoriginated, but that is no explanation: the only «evidence» for the scheme
is the figure! Nowhere does he or any other researcher attach names ofreal chemicals to the mythical letters. Origin-of-life workers have neverdemonstrated that the intermediates in the synthesis of AMP either would
have or even could have existed in a prebiotic soup, let alone sophisticatedenzymes for interconverting the intermediates. There is no evidence thatthe letters exist anywhere outside of de Duve's mind.
Another restless scientist is Stuart Kauffman of the Santa Fe Institute.
The complexity of the metabolism of living organisms makes him doubtthat a step-by-step approach would work:
In order to function at all, a metabolism must minimally be a connected
series of catalyzed transformations leading from food to needed products.
Conversely, however, without the connected web to maintain the flow ofenergy and products, how could there have been a living entity to evolve
connected metabolic pathways?15

To answer his question he proposes, in very mathematical terms,
something similar to what de Duve toyed with: a complex mixture inwhich some chemicals happen to be transformed into other chemicals thatare transformed into still others, and somehow this forms a self-

156 EXAMINING THE CONTENTS OF THE BOX
sustaining network. It is clear from his writings that Kauffman is a very
smart guy, but the connection of his mathematics to chemistry is tenuousat best. Kauffman discusses his ideas in a chapter entitled «The Origin of
a Connected Metabolism,» but if you read the chapter from start to finish
you will not find the name of a single chemical—no AMP, no aspartic acid,no nothing. In fact, if you scan the entire subject index of the book, you will
not find a chemical name there either. John Maynard Smith, Kauffman's
old mentor, has accused him of practicing «fact-free science.»16 That is aharsh accusation, but the complete lack of chemical details in his bookappears to justify the criticism.
Kauffman and de Duve identify a real problem for gradualistic evolution.
The solutions they propose, however, are merely variations on Horowitz's
old idea. Instead of ABCD, they simply propose ABCD times
one hundred. Worse, as the number of imaginary letters increases, thetendency is to get further and further away from real chemistry and to gettrapped in the mental world of mathematics.

TOO MUCH OF A GOOD THING

Every child at one time or another hears the tale of King Midas. The
greedy king loved gold more than anything, or so he thought. When he
was first given the magical gift of turning anything to gold by his touch,he was delighted. Old vases, worthless stones, used clothing, all became
beautiful and priceless by mere contact with him. However, storm clouds
could be sighted when Midas touched already-beautiful flowers, whichthen lost their fragrance. He knew he was in deep trouble when the foodhe tried to eat turned to gold. Finally, folly led to grief when his daughter,little Marygold, hugged her father and turned into a golden statue.
The story of King Midas teaches some obvious lessons: don't be greedy,
love is worth more than money, and so forth. But there is another, lessobvious lesson about the importance of regulation. It is no enough to havea machine or process (magical or otherwise) that does something; youhave to be able to turn it on or off as needed. If the king had wished forthe golden touch and the ability to switch it on оr off when he wanted,
he could have transmuted a few rocks into gold nuggets but not zap his
daughter. He could turn the plates to gold, but not the food.

ROAD KILL 157
The need for regulation is obvious for machines we use in our daily
lives. A chain saw that couldn't be turned off would be quite a hazard, anda car with no brakes and no neutral gear would be of little use. Biochemicalsystems are also machines we use in our daily lives (whether we think ofthem or not), and so they too have to be regulated. To illustrate this, let's
spend the next three paragraphs looking at the ways in which the synthesisof AMP is regulated (outlined in Figure 7-2).
 Enzyme I requires an ATP energy pellet to transform ribose-5phosphate (the foundation) into Intermediate II. The enzyme has
FIGURE 7-2
Regulation of the AMP pathway. Heavy white arrows indicatecompounds that slow down synthesis; heavy black arrows
indicate compounds that speed up synthesis.

158 EXAMINING THE CONTENTS OF THE BOX
an area on its surface that can bind either ADP or GDP when there
is an excess of those chemicals in the cell. The binding of ADP or GDP
acts as a valve, decreasing the activity of the enzyme and slowing thesynthesis of AMP. This makes good physiological sense: since ADP is theremains of a spent ATP (like a bullet shell after a gun has been fired), highconcentrations of ADP in the cell means that the concentration of ATP,the cellular energy pellet, is low. Instead of making AMP, Intermediate I isthen used as fuel to produce more ATP.
Commonly in biochemistry, the first enzyme that irrevocably starts amolecule down a particular metabolic pathway is highly regulated. The
AMP pathway is no exception. Although Intermediate II can be used forother things, once it is transformed into Intermediate III the molecule isinevitably swept on to either AMP or GMP by the other enzymes of thepathway. So the enzyme that catalyzes the critical reaction (Enzyme II)
is also regulated. Enzyme II, in addition to binding sites for the reacting
molecules, has two other binding sites on its surface: one that will hold
either AMP, ADP or ATP, and a second site that will hold either GMP,
GDP, or GTP. If one site is filled, the enzyme works more slowly; if bothsites are filled, it works more slowly yet. Furthermore, in addition to thesite where reaction takes place, Enzyme II contains another site that binds
Intermediate II, itself a reactant. Binding of Intermediate II to the secondsite makes the enzyme work faster. Again this makes physiological sense:
if there is so much Intermediate II around that it binds to both sites of the
enzyme, then the cell is behind in its synthetic work and needs to process
Intermediate II more quickly.
Synthesis is regulated at several other places as well. After IMP is
made the pathway splits to build either AMP or GMP. Enzyme XII,
which catalyzes the first step from IMP to AMP, is itself slowed down byexcess amounts of AMP. Similarly, the catalysis of the first step from IMP
to GMP is inhibited by excess GMP. (Unlike King Midas, the enzymes
can tell when they have too much of a good thing.) Finally, Enzyme XII
uses GTP as an energy pellet because, if a lot of GTP is around, more«A» nucleotides (AMR, ADP and ATP) are needed to keep the supply inbalance. The final step in the synthesis of GMP uses ATP as an energy
source for similar reasons. ROAD KILL 159

REGULATORY FAILURE

When the regulation of metabolism fails, the result is illness ordeath. An example is diabetes; the uptake of sugar into cells is slowed,
even though sugar molecules that manage to get into cells are otherwise
metabolized normally. A disease, much less common than diabetes, that
results from a failure to regulate AMP synthesis is called Lesch-Nyhan
syndrome. In Lesch-Nyhan syndrome an enzyme needed to recycle
used nucleotides from degraded DNA or RNA is missing or inactive;
this indirectly causes Intermediate II to accumulate. Unfortunately, as
mentioned above, Intermediate II stimulates Enzyme II, which in turnincreases the synthesis of AMP and GMP. The increased synthesis leads
to the production of excess uric acid (the breakdown product of AMP and
GMP), which comes out of solution and crystallizes. Random deposits ofuric acid crystals can disrupt normal body functions, as they do in gout. In
Lesch-Nyhan syndrome, however, the consequences are more severe. They
include mental retardation and a compulsion toward self-mutilation—thepatient bites his own lips and fingers.
The regulation of AMP biosynthesis is a good example of the intricate
mechanisms needed to keep the supply of biomolecules at the right level:
not too much, not too little, and in the right ratio with related molecules.
The problem for Darwinian gradualism is that cells would have no reason
to develop regulatory mechanisms before the appearance of a new catalyst.
But the appearance of a new, unregulated pathway, far from being a boon,
would look like a genetic disease to the organism. This goes in spades
for fragile ancient cells, putatively developing step by step, that would
have little room for error. Cells would be crushed between the Scylla ofunavailability and the Charybdis of regulation.
No one has a clue how the AMP pathway developed. Although a few
researchers have observed that the pathway itself presents a severe challenge
to gradualism, no one has written about the obstacle posed by the needto regulate a cell's metabolic pathway immediately at its inception. Small
wonder—no one wants to write about road kill.
In the distant past, a cell gazes across the wide highway. On the otherside is a brand new metabolic pathway. The chemical trucks,

160 EXAMINING THE CONTENTS OF THE BOX
buses, station wagons, and motorcycles zoom by without noticing thelittle fellow. In the first lane, marked «intermediates not found in soup,» hesees the remains of most earlier cells that heard the siren call. There are a
few cellular remains in lane two, marked «guiding mechanism required.»
One or two are in the third lane, «instability of intermediates.» There areno cell bodies in lane 4, «regulation»; none made it that far. The other sideis very distant indeed.

STRICT CONSTRUCTION

The Ninth Amendment to the Constitution of the United States
stipulates that «The enumeration in the Constitution, of certain rights,
shall not be construed to deny or disparage others retained by the people.»That's a handy way to say that a short document can't hope to cover allbases, so nothing is implied about things that have not been discussed.
I would like to make a similar disclaimer about this book. In Chapters
3 to 6 I discussed several irreducibly complex biochemical systems,
going into a lot of detail to show why they could not be formed in a
gradualistic manner. The detail was necessary so that the reader could
understand exactly what the problems are. Because I spent a lot of time on
those systems I didn't have time to get on to other biochemical systems,
but this does not imply that they are not also problems for Darwinism.
Other examples of irreducible complexity abound, including aspects of
DNA replication, electron transport, telomere synthesis, photosynthesis,
transcription regulation, and more. The reader is encouraged to borrow abiochemistry textbook from the library and see how many problems forgradualism he or she can spot.
This chapter was somewhat different. In this chapter I wanted toshow that it is not only irreducibly complex systems that are a problem
for Darwinism. Even systems that at first glance appear amenable
to a gradualistic approach turn out to be major headaches on closer
inspection—or when the experimental results roll in—with no reason to
expect they will be solved within a Darwinian framework.
The idea originally offered by Horowitz was a good one in its day.
It could have worked; it might have been true. Certainly if a complex
metabolic pathway ever arose gradually, the scheme Horowitz outlined
must have been the way it happened. But as the years passed and scienceROAD KILL 161
advanced, the prerequisites for his scheme crumbled. If there is adetailed Darwinian explanation for the production of AMP out there, no
one knows what it is. Hard-nosed chemists have begun to drown theirfrustrations in mathematics.
AMP is not the only metabolic dilemma for Darwin. The biosynthesisof the larger amino acids, lipids, vitamins, heme, and more run into thesame problems, and there are difficulties beyond metabolism. But theother problems will not concern us here. I will now turn my attention
away from biochemistry per se and focus on other issues. The scientificobstacles discussed in the last five chapters will serve as stark examplesof the mountains and chasms that block a Darwinian explanation of life.

PART III

WHAT DOES THE BOX TELL US?

CHAPTER 8

PUBLISH OR PERISH

THE JOURNAL OF MOLECULAR EVOLUTION

In Chapters 3 through 7, I showed that no one has explained theorigin of the complex biochemical systems I discussed. There are tens of
thousands of scientists in the United States, however, who are interested in
the molecular basis of life. Most of them spend their time in the hard workof isolating proteins, analyzing structures, and sorting out the details of
the ways that Lilliputian things work. Nonetheless, some scientists areinterested in evolution and have published a large amount of work in theprofessional literature. If complex biochemical systems are unexplained,
what type of biochemical work has been published under the heading of«evolution»? In this chapter you will see what has been studied—and what
hasn't.
When the molecular basis of life was discovered, evolutionary thoughtbegan to be applied to molecules. As the number of professional research
papers in this area expanded, a specialty journal, the Journal of Molecular
Evolution, was set up. Established in 1971, JME is devoted exclusively toresearch aimed at explaining how life at the molecular level came to be. It
is run by prominent figures in the field. Among the more than fifty people
who make up the editorial staff and board, are about a dozen members
165166 WHAT DOES THE BOX TELL US?
of the National Academy of Sciences. The editor is a man named
Emile Zuckerkandl, who (along with Linus Pauling) first proposed thatdifferences in the amino acid sequences of similar proteins from different
species could be used to determine the time at which the species last shared
a common ancestor.
Each monthly issue of JME contains about ten scientific papers on
various aspects of molecular evolution. Ten papers per month means
about a hundred papers per year, and about a thousand papers per decade.
A survey of a thousand papers in a particular area can give you a pretty
good idea of what problems have been solved, what problems are being
addressed, and what problems are being ignored. A look back over the last
decade shows that the papers in JME can be divided pretty easily into three
separate categories: chemical synthesis of molecules thought necessary forthe origin of life, comparisons of DNA or protein sequences, and abstract
mathematical models.

IN THE BEGINNING

The origin-of-life question is tremendously important and interesting.
Biology must ultimately deal with the question: even if life evolves bynatural selection acting on variation, how did life get there in the firstplace? Publications concerned with the chemical synthesis of molecules
thought to be necessary for the origin of life constitute about 10 percent of
all papers in JME.
The story of Stanley Miller is one of the best known in all of modern
science. As a young graduate student after World War II working in thelaboratory of Nobel laureate Harold Urey at the University of Chicago,
Miller wanted to determine what chemicals might have been present
billions of years ago on the ancient, lifeless earth. He knew that hydrogenis the predominant element in the universe. When hydrogen reacts withcarbon, nitrogen, and oxygen—common elements on the earth—it forms
methane, ammonia, and water. So Miller decided to see what chemicals
could be produced by a simulated atmosphere that contained methane,ammonia, water vapor, and hydrogen.1
Methane, ammonia, water vapor, and hydrogen are generally unreactive. Miller knew that, to get the gases to produce potentially interestingchemicals, he would have to pump some energy into the system to jumble
things up. One source of energy that would have been available on

PUBLISH OR PERISH 167
the old earth is lightning. So Miller constructed an apparatus in hislaboratory that contained the gases he expected to be present on the early
earth, plus a pool of water, as well as sparking electrodes to simulate
lightning.
Miller boiled the water and sparked the mixture of gases for about aweek. During that time an oily, insoluble tar built up on the sides of theflask, and the pool of water became more and more reddish as material
accumulated in it. At the end of the week Miller analyzed the mixture ofchemicals dissolved in the water and saw that it contained several kindsof amino acids. The result electrified the world. Since amino acids are thebuilding blocks of proteins, it appeared at first blush that the materials
for making the machines of life would be plentiful on the early earth.
Excited scientists had no difficulty imagining that natural processes
might induce amino acids to come together to form proteins, that someof the proteins would catalyze important chemical reactions, that theproteins would get trapped inside small cell-like membranes, that nucleic
acids would be produced by similar processes, and that gradually the first
truly self-replicating cell would be born. As with Mary Shelley's fictionalFrankenstein, it appeared that electricity coursing through inanimate
matter could indeed produce life.
Other experimenters rushed to build on the seminal work of Stanley
Miller. He had detected a few different types of amino acids in his
experiment, but living organisms contain twenty different kinds. Other
researchers varied Miller's experimental conditions. The mix of gases inthe simulated atmosphere was altered, the source of energy was changed
from an electric spark to ultraviolet radiation (to simulate sunlight) orvery strong pulses of pressure (to simulate explosions.) More sophisticatedanalytical methods detected chemicals that were present in very small
amounts. Sustained effort by a number of workers eventually paid off;
almost all of the twenty naturally occurring types of amino acids havebeen detected in origin-of-life experiments.
Other successes were reported in the early years of research on theorigin of life. Perhaps the most notable achievement was by the laboratoryof Juan OrÒ. They showed that the simple chemical hydrogen cyanide
would react with itself to yield a number of products including adenine,
which is a component of one of the building blocks of nucleic acids. The
result cracked open DNA and RNA as targets for chemical investigation

168 WHAT DOES THE BOX TELL US?
of life's origin. Over the years other сomponents of nucleic acids—theother «bases,» as well as the sugar ribose which forms part of RNA—were
produced by chemical simulation experiments.
In light of these well-publicized successes an outsider can be excusedfor feeling a sense of shock when he stumbles across pessimistic reviews oforigin-of-life research in the professional literature, such as one written by
Klaus Dose, a prominent worker in the field. In his assessment of the stateof the problem, Dose pulls no punches.
More than 30 years of experimentation on the origin of life in the fields ofchemical and molecular evolution have led to a better perception of theimmensity of the problem of the origin of life on Earth rather than to its
solution. At present all discussions on principal theories and experimentsin the field either end in stalemate or in a confession of ignorance.2

What leads a professional in the field to such a bleak view, especiallyafter the progress in the heady days following Miller's trailblazing
experiment? It turns out that the successes, although real, paper over aplethora of problems that can only be appreciated when you move beyond
the simple chemical production of some of the bare components of life.
Let's look at a few of those problems.
Making the molecules of life by chemical processes outside of a cell isactually rather easy. Any competent chemist can buy some chemicals froma supply company, weigh them in the correct proportion, dissolve them in
an appropriate solvent, heat them in a flask for a predetermined amountof time, and purify the desired chemical produce away from unwanted
chemicals produced by side reactions. Not only can amino acids andnucleotides—the building blocks—be made, but a chemist can then takethese and produce the buildings themselves: proteins and nucleic acids.
As a matter of fact, the process for doing this has been automated, andmachines that mix and react chemicals to give proteins and nucleic acids
are sold by a number of commercial firms. Any undergraduate can readthe instruction manual and produce a long piece of DNA—perhaps thegene coding for a known protein—in a day or two.
Most readers will quickly see the problem. There were no chemists
four billion years ago. Neither were there any chemical supply houses,
distillation flasks, nor any of the many other devices that the modern

PUBLISH OR PERISH 169
chemist uses daily in his or her laboratory, and which are necessary
to get good results. A convincing origin-of-life scenario requires that
intelligent direction of the chemical reactions be minimized as far as
possible. Nonetheless, the involvement of some intelligence is unavoidable.
Reasonable guesses about what substances were available on the early
earth—such as Stanley Miller made—are a necessary starting point. The
trick for the researcher is to choose a probable starting point, then keep
his hands off.
As an analogy, suppose a famous chef said that random naturalprocesses could produce a chocolate cake. In his effort to prove it, we
would not begrudge him taking whole plants—including wheat, cacao,and sugar cane—and placing them near a hot spring, in the hope thatthe heated water would extract the right materials and cook them. But
we would become a little wary if the chef bought refined flour, cocoa, andsugar at the store, saying that he didn't have time to wait for the hot water
to extract the components from the plants. We would shake our heads if
he then switched his experiment from a hot spring to an electric oven,to «speed things up.» And we would walk away if he then measured theamounts of the components carefully, mixed them in a bowl, placed themin a pan, and baked them in his oven. The results would have nothing to
do with his original idea that natural processes could produce a cake.
The experiment that Stanley Miller reported in 1952 stunned the world.
As Miller has readily explained, however, that experiment was not thefirst such one he tried. Earlier he had set up his apparatus in a somewhat
different manner and found that some oil was formed, but no amino acids.
Since he thought amino acids would be the most interesting chemicals
to find, he jiggled the apparatus around in hopes of producing them. Of
course, if conditions on the ancient earth actually resembled Miller's
unsuccessful attempts, then in reality no amino acids would have been
produced.
Moreover, joining many amino acids together to form a protein with auseful biological activity is a much more difficult chemical problem thanforming amino acids in the first place. The major problem in booking aminoacids together is that, chemically, it involves the removal of a molecule ofwater for each amino acid joined to the growing protein chain. Conversely,
the presence of water strongly inhibits amino acids from forming proteins.
Because water is so abundant on the earth, and because amino acids

170 WHAT DOES THE BOX TELL US?
dissolve readily in water, origin-of-life researchers have been forced topropose unusual scenarios to get around the water problem. For example,
a scientist named Sidney Fox proposed that perhaps some amino acids got
washed up from the primordial ocean onto a very hot surface, such as therim of an active volcano. There, the story goes, they would be heated above
the boiling point of water; with the water gone, the amino acids could join
together. Unfortunately, other workers had earlier shown that heating dry
amino acids gives a smelly, dark brown tar, but no detectable proteins.
Fox, however, demonstrated that if an extra-large portion of one of threedifferent amino acids is added to a mix of purified amino acids and heatedin a laboratory oven, then the amino acids do join. But even then they do
not join to give proteins—the structure they form is chemically different.
So Fox and collaborators called the structures «proteinoids,» then went on
to show that the proteinoids had some interesting properties, including
modest catalytic abilities, that were reminiscent of real proteins.
The scientific community has remained deeply skeptical of theseexperiments. As with our imaginary baker, a heavy odor of investigator
involvement hangs over proteinoids. The special circumstance needed
to make them—hot, dry conditions (putatively representing rare spots
such as volcano rims) with exact amounts of already-purified aminoacids weighed out in advance—casts dark shadows over the relevance ofthe experiments. Worse, because proteinoids are not really proteins, theconsiderable problem of producing authentic proteins remains. In his bookreviewing the difficulties of origin-of-life theories, Robert Shapiro notesthat work on proteinoids has produced a startling unanimity of opinion:[The proteinoid theory] has attracted a number of vehement critics,
ranging from chemist Stanley Miller ... to Creationist Duane Gish. On
perhaps no other point in origin-of-life theory could we find such harmony
between evolutionists and Creationists as in opposing the relevance of theexperiments of Sidney Fox.3

Other researchers have proposed some other ways whereby aminoacids might join to give proteins. All suffer more or less from the problems
that plague proteinoids, and none has attracted much support from thescientific community.

PUBLISH OR PERISH 171

THE RNA WORLDIn the 1980s a scientist named Thomas Cech showed that some RNA
has modest catalytic abilities.4 Because RNA, unlike proteins, can act
as a template and so potentially can catalyze its own replication, it was
proposed that RNA—not protein—started earth on the road to life. Since
Cech's work was reported, enthusiasts have been visualizing a time when
the world was soaked with RNA on its way to life; this model has been
dubbed «the RNA world.» Unfortunately, the optimism surrounding the
RNA world ignores known chemistry. In many ways the RNA-world fadof the 1990s is reminiscent of the Stanley Miller phenomenon during the
1960s: hope struggling valiantly against experimental data.
Imagining a realistic scenario whereby natural processes may havemade proteins on a prebiotic earth—although extremely difficult—is awalk in the park compared to imagining the formation of nucleic acids
such as RNA. The big problem is that each nucleotide «building block» isitself built up from several components, and the processes that form thecomponents are chemically incompatible. Although a chemist can makenucleotides with ease in a laboratory by synthesizing the components
separately, purifying them, and then recombining the components toreact with each other, undirected chemical reactions overwhelmingly
produce undesired products and shapeless goop on the bottom of the test
tube. Gerald Joyce and Leslie Orgel—two scientists who have worked longand hard on the origin of life problem—call RNA «the prebiotic chemist'snightmare.» They are brutally frank:
Scientists interested in the origins of life seem to divide neatly into twoclasses. The first, usually but not always molecular biologists, believe thatRNA must have been the first replicating molecule and that chemists are
exaggerating the difficulties of nucleotide synthesis.... The second groupof scientists are much more pessimistic. They believe that the de novo
appearance of oligonucleotides on the primitive earth would have beena near miracle. (The authors subscribe to this latter view). Time will tellwhich is correct.3

Even if the miracle-like coincidence should occur and RNA be
produced, however, Joyce and Orgel see nothing but obstacles ahead. In

172 WHAT DOES THE BOX TELL US?
an article section entitled «Another Chicken-and-Egg Paradox» they
write the following:This discussion ... has, in a sense, focused on a straw man: the myth of aself-replicating RNA molecule that arose de novo from a soup of randompolynucleotides. Not only is such a notion unrealistic in light of our current
understanding of prebiotic chemistry, but it should strain the credulity ofeven an optimist's view of RNA's catalytic potential...Without evolution it
appears unlikely that a self-replicating ribozyme could arise, but withoutsome form of self-replication there is no way to conduct an evolutionary
search for the first, primitive self-replicating ribozyme.

In other words, the miracle that produced chemically intact RNA
would not be enough. Since the vast majority of RNAs do not have usefulcatalytic properties, a second miraculous coincidence would be needed toget just the right chemically intact RNA.
Origin-of-life chemistry suffers heavily from the problem of roadkill, discussed in the last chapter. Just as there is no absolute barrier to agroundhog crossing a thousand-lane highway during rush hour; so there
is no absolute barrier to the production of proteins, nucleic acids, or any
other biochemical by imaginable, natural chemical processes; however,the slaughter on the highway is unbearable. The solution of some prebiotic
chemists is a simple one. They release a thousand groundhogs by the sideof the road, and note that one makes it across the first lane. They then put
a thousand fresh groundhogs in a helicopter, fly them to the beginningof lane two, and lower them onto the highway. When one survives the
crossing from lane two to lane three, they helicopter another thousandto the edge of lane three. Proponents of the RNA world, who start theirexperiments with long, purified, investigator-synthesized RNA, fly thegroundhogs out to lane 700 and watch as one crosses to lane 701. It is avaliant effort, but if they ever reach the other side, the victory will be quite
hollow.
Scientists working on the origin of life deserve a lot of credit; they haveattacked the problem by experiment and calculation, as science should.
And although the experiments have not turned out as many hoped,
through their efforts we now have a clear idea of the staggering difficulties
that would face an origin of life by natural chemical processes.
In private many scientists admit that science has no explanation for

PUBLISH OR PERISH 173
the beginning of life.7 On the other hand many scientists think thatgiven the origin of life, its subsequent evolution is easy to envision, despite
the major difficulties outlined in this book. The reason for this peculiar
circumstance is that while chemists try to test origin-of-life scenarios
by experiment or calculation, evolutionary biologists make no attempt
to test evolutionary scenarios at the molecular level by experiment or
calculation. As a result, evolutionary biology is stuck in the same frame ofmind that dominated origin-of-life studies in the early fifties, before mostexperiments had been done: imagination running wild. Biochemistry has,in fact, revealed a molecular world that stoutly resists explanation by thesame theory so long applied at the level of the whole organism. Neither of
Darwin's starting points—the origin of life, and the origin of vision—has
been accounted for by his theory. Darwin never imagined the exquisitely
profound complexity that exists even at the most basic levels of life.
Over the years the Journal of Molecular Evolution has published originof-life research concerning many questions, such as the following: Could
other amino acids not found by Miller also be produced? What if carbon
dioxide predominated in the ancient atmosphere instead of methane?
Could nucleotides other than modern ones have started life? Suchquestions have been addressed in JME in papers with titles like «Prebiotic
Syntheses in Atmospheres Containing CH4, CO, and C02»8 «Radiolysis of
Aqueous Solutions of Hydrogen Cyanide (pH 6): Compounds of Interestin Chemical Evolution Studies,»9 «Alternative Bases in the RNA World:
The Prebiotic Synthesis of Urazole and Its Ribosides,»10 and «Cyclizationof Nucleotide Analogues as an Obstacle to Polymerization.»11 These areinteresting questions for scientists, but they do not begin to answer thechallenge to evolution posed by blood clotting, cellular transport, ordisease fighting.

THE MISSING PAPERS

The second category of papers commonly found in the Journal of
Molecular Evolution, accounting for about 5 percent of the total, concerns
Mathematical models for evolution or new mathematical methods forcomparing and interpreting sequence data. This includes papers withtitles such as «A Derivation of All Linear Invariants for a Nonbalanced
Transversion Model»12 and «Monte Carlo Simulation in Phylogenies:174 WHAT DOES THE BOX TELL US?
An Application to Test the Constancy of Evolutionary Rates.»13
Although useful for understanding how gradual processes behave overtime, the mathematics assumes that real-world evolution is a gradualrandom process; it does not (and cannot) demonstrate it.
By far the largest category of papers published in JME, accounting for
more than 80 percent of all manuscripts, is that of sequence comparisons.
A sequence comparison is an amino-acid-by-amino-acid comparison of
two different proteins, or a nucleotide-by-nucleotide comparison of two
different pieces of DNA, noting the positions at which they are identical orsimilar, and the places where they are not.
When methods were developed in the 1950s to determine thesequences of proteins, it became possible to compare the sequence of
one protein with another. A question that was immediately asked waswhether analogous proteins in different species, like human hemoglobin
and horse hemoglobin, had the same amino acid sequence. The answer
was intriguing: horse and human hemoglobin were very similar, but not
identical. Their amino acids were the same in 129 out of 146 positions in
one of the protein chains of hemoglobin, but different in the remaining
positions. When the sequences of the hemoglobins of monkey, chicken,
frog, and others became available, their sequences could be comparedwith human hemoglobin and with each other. Monkey hemoglobin
had 5 differences with that of humans; chickens had 26 differences; andfrogs had 46 differences. These similarities were highly suggestive. Many
researchers concluded that similar sequences strongly supported descentfrom a common ancestor.
For the most part it was shown that analogous proteins from species thatwere already thought to be closely related (like man and chimp, or duckand chicken) were pretty similar in sequence, and proteins from species
thought to be distantly related (such as skunk and skunk cabbage) were
not that similar. In fact, for some proteins one could correlate the amountof sequence similarity with the estimated time since various species
were thought to have last shared a common ancestor, and the correlation
was quite good. Emile Zuckerkandl and Linus Pauling then proposed
the molecular clock theory, which says that the correlation is caused byproteins accumulating mutations over time. The molecular clock has been
vigorously debated since it was proposed, and many issues surrounding it
are still contended. Overall, however, it remains a viable possibility.

PUBLISH OR PERISH 175
In the late 1970s, quick and easy methods became available forsequencing DNA. Thus one could study not only the sequence of a protein
but also the gene for the protein, as well as the DNA surrounding the genethat contained control regions and other features. Genes from higherorganisms were shown to contain interruptions (called introns) in thecoding sequence. Some genes had dozens of introns; other genes just one
or two. So now a biochemist could publish comparisons of the sequencesof the introns in genes from different species, as well as studies of the total
number of introns, their relative positioning in the gene, their length andbase composition, and a dozen other factors. Other aspects of the genetic
apparatus could also be compared: the position of genes relative to othergenes, the frequency with which one type of nucleotide was found next
to another, the number of chemically modified nucleotides, and so forth.
Very many such papers have been published over the years in the Journalof Molecular Evolution, including «Examination of Protein Sequence
Homologies: IV Twenty-Seven Bacterial Ferredoxins,»14 «Evolution ofα- and β-Tubulin Genes as Inferred by the Nucleotide Sequences of Sea
Urchin cDNA Clones,»15 «Phylogeny of Protozoa Deduced from 5S rRNA
Sequences,»16 and «Tail-to-Tail Orientation of the Adantic Salmon Alphaand Beta-Globin Genes.»17
Although useful for determining possible lines of descent, which is aninteresting question in its own right, comparing sequences cannot show
how a complex biochemical system achieved its function—the question thatmost concerns us in this book.18 By way of analogy, the instruction manuals
for two different models of computer put out by the same company might
have many identical words, sentences, and even paragraphs, suggesting
a common ancestry (perhaps the same author wrote both manuals),but comparing the sequences of letters in the instruction manuals will
never tell us if a computer can be produced step-by-step starting from a
typewriter.
The three general topics of papers published in JME—the origin of life,
mathematical models of evolution, and sequence analyses—have included
many intricate, difficult, and erudite studies. Does such valuable andinteresting work contradict this book's message? Not at all.
To say that Darwinian evolution cannot explain everything in nature
is not say that evolution, random mutation, and natural selection do notoccur; they have been observed (at least in cases of microevolution)

176 WHAT DOES THE BOX TELL US?
many different times. Like the sequence analysts, I believe the evidence
strongly supports common descent. But the root question remains
unanswered: What has caused complex systems to form? No one hasever explained in detailed, scientific fashion how mutation and natural
selection could build the complex, intricate structures discussed in thisbook.
In fact, none of the papers published in JME over the entire course of
its life as a journal has ever proposed a detailed model by which a complex
biochemical system might have been produced in a gradual, step-bystep Darwinian fashion. Although many scientists ask how sequences
can change or how chemicals necessary for life might be producedin the absence of cells, no one has ever asked in the pages of JME suchquestions as the following: How did the photosynthetic reaction center
develop? How did intramolecular transport start? How did cholesterol
biosynthesis begin? How did retinal become involved in vision? How
did phosphoprotein signaling pathways develop? The very fact that noneof these problems is even addressed, let alone solved, is a very strong
indication that Darwinism is an inadequate framework for understanding
the origin of complex biochemical systems.
To take up the questions raised in this book, one would need to findpapers with titles such as «Twelve Intermediate Steps Leading to theBacterial Photosynthetic Reaction Center,» «A Proto-Cilium Could
Generate a Power Stroke Sufficient to Turn a Cell by Ten Degrees,»«Intermediates in Adenosine Biosynthesis Effectively Mimic Adenosine
Itself in RNA Function,» and «A Primitive Clot Made of Randomly Aligned
Fibers Would Block Circulation in Veins Smaller Than 0.3 Millimeters.»
But the papers are missing. Nothing remotely like this has been published.
Perhaps we can understand why detailed models are missing from JME
by asking what a real scientific investigation of mousetrap evolution by anenthusiastic young scientist would look like. He would first have to thinkof a precursor to the modern mousetrap, one that was simpler. Suppose hestarted with just a wooden platform? No, that won't catch mice. Suppose
he started with a modern mousetrap that has a shortened holding bar? No,
if the bar is too short it wouldn't reach the catch, and the trap would springuselessly while he was holding it. Suppose he started with a smaller trap?
No, that wouldn't explain the complexity. Suppose the parts developedPUBLISH OR PERISH 177
individually for other functions—such as a Popsicle stick for the platform,a clock spring for the trap spring, and so on—and then accidentally got
together? No, their previous functions would leave them unfit for crapping
mice, and he'd still have to explain how they gradually developed into amousetrap. With his tenure evaluation coming up, a smart young scientist
would switch his interests to more tractable topics.
Attempts to explain the evolution of highly specified, irreduciblycomplex systems—either mousetraps or cilia or blood clotting—by agradualism: route have so far been incoherent as we have seen in previous
chapters. No scientific journal will publish patently incoherent papers, so
no studies asking detailed questions of molecular evolution are to be found.
Calvin and Hobbes stories can sometimes be spun by ignoring criticaldetails, as Russell Doolittle did when imagining the evolution of bloodclotting, but even such superficial attempts are rare. In fact, evolutionary
explanations even of systems that do not appear to be irreducibly complex,
such as specific metabolic pathways, are missing from the literature. The
reason for this appears to be similar to the reason for the failure to explain
the origin of life: a choking complexity strangles all such attempts.

SEARCHING HIGH AND LOW

There are scores of journals devoted to biochemical research. Although
JME carries articles concerning molecular evolution exclusively, otherjournals carry such articles also, mixed in with research on other topics.
Perhaps, then, it is a mistake to conclude too much based just on a surveyof JME. Perhaps other; nonspecialized journals publish research on theorigins of complex biochemical systems. To see if JME is simply the wrong
place to look, let's take a quick look at a prestigious journal that covers abroad range of biochemical topics: thе Proceedings of the National Academyof Sciences.
Between 1984 and 1994 PNAS published about twenty thousand Papers,
the large majority of which were in the life sciences. Every year the journal
compiles an index in which it lists the year's papers by category. The index
shows that in those ten years, about 400 papers were concerned withmolecular evolution.19 This is approximately one-third as many papers as
the Journal of Molecular Evolution published over the178 WHAT DOES THE BOX TELL US?
same time period. The number of papers on the topic published yearlyby PNAS has increased significantly, going from about 15 in 1984 to about
100 in 1994; clearly this is a growth area. But the great majority (about 85
percent) are concerned with sequence analysis, just as most papers in JME
were, passing over the fundamental question of how. About 10 percentof the molecular evolution papers are mathematical studies—either new
methods to improve sequence comparisons or highly abstract models. No
papers were published in PNAS that proposed detailed routes by which
complex biochemical structures might have developed. Surveys of otherbiochemistry journals show the same result: sequences upon sequences,
but no explanations.
Perhaps if there are no answers in journals then we should look in books.
Darwin proposed his revolutionary theory in a book, and so did Newton.
The advantage of a book is that it gives the author a lot of room to develop
his or her ideas. Setting a new idea in context, bringing in appropriate
examples, explaining a lot of detailed steps, meeting many anticipatedobjections—all of this can take a fair amount of space. A good example
in the modern evolution literature is a book called The Neutral Theory of
Molecular Evolution by Motoo Kimura.20 In the book he had the room
to explain his idea that most sequence changes that occur in DNA andproteins do not affect the way they do their jobs; the mutations are neutral.
A second example is The Origins of Order by Stuart Kauffman, who argues
that the origins of life, metabolism, genetic programs, and body plans are all
beyond Darwinian explanation but may arise spontaneously through selforganization.21 Neither book explains biochemical structures: Kimura's
work has to do simply with sequences, and Kauffman's is a mathematicalanalysis. But perhaps in one of the libraries of the world there is a bookthat tells us how specific biochemical structures came to be.
Unfortunately, a computer search of library catalogs shows there is nosuch book. That isn't too surprising in this day and age; even books like
Kimura's and Kauffman's that propose new theories are usually precededby papers on the topic that are first published in scientific journals. The
absence of papers on the evolution of biochemical structures in the journals
just about kills any chance of there being a book published on the matter.
During a computer search for books on biochemical evolution, youcome across a number of juicy titles. For example, a book by John

PUBLISH OR PERISH 179
Gillespie was published in 1991 with the enticing name The Causes of
Molecular Evolution. But it does not concern specific biochemical systems.
It is, like Kauffmans, a mathematical analysis that leaves out all of thespecific features of organisms, reducing them to mathematical symbols
and then manipulating the symbols. Nature is blanched. (I should add
that, of course, mathematics is an extremely powerful tool. But math isuseful to science only when the assumptions the mathematical analysis
starts with are true.)
Another book, published the same year, is Evolution at the Molecular
Level.22 Although it sounds promising, it is not a book by someone
proposing a new idea. It's one of the many academic books that arecollections of articles by different authors, each treating a particular area
in not much more depth than a journal article. Inevitably the contentsof the book pretty closely resemble the contents of the journals: a lot of
sequences, some math, and no answers.
A somewhat different type of book is one that reports the results froma scientific meeting. Cold Spring Harbor Laboratories on Long Island hassponsored a number of meetings on various topics throughout the years.
A meeting was held there in 1987 on the topic of «Evolution of Catalytic
Function,» and about one hundred papers by the participants were
published as a book.23 As is typical of meeting books, about two-thirdsof the papers are simply overviews of what was going on in the author's
lab at the time, with little or no attempt to tie it into the theme of thebook. Of the remaining papers, most are sequence analyses, and some areconcerned with prebiotic chemistry or simple catalysts (not the complex
machinery of known organisms).
The search can be extended, but the results are the same. There has
never been a meeting, or a book, or a paper on details of the evolution ofcomplex biochemical systems.

ACCULTURATION

Many scientists are skeptical that Darwinian mechanisms can explain
all of life, but a large number do believe it. Since we have just seen thatthe professional biochemical literature contains no papers or books
that explain in detail how complex systems might have arisen, why is
Darwinism nonetheless credible with many biochemists? A large part of
the answer is that they have been taught as part of their biochemical

180 WHAT DOES THE BOX TELL US?
training that Darwinism is true. To understand both the success of
Darwinism as orthodoxy and its failure as science at the molecular level,
we have to examine the textbooks that are used to teach aspiring scientists.
One of the most successful texts of biochemistry over the past several
decades was first written in 1970 by Albert Lehninger, a professor ofbiophysics at Johns Hopkins University, and has been updated several times
over the years. On the first page of the first chapter of his first textbook,Lehninger mentions evolution. He asks why the biomolecules that occur
in virtually all cells appear to be extraordinarily well fitted to their tasks:
In this chapter, the first in a series of 12 devoted to the structures andproperties of the major classes of biomolecules, we shall develop the ideathat biomolecules should be studied from two points of view. We mustof course examine their structure and properties as we would those ofnonbiological molecules, by the principles and approaches used in classicalchemistry. But we must also examine them in the light of the hypothesisthat biomolecules are the products of evolutionary selection, that they may
be the fittest possible molecules for their biological function.24

Lehninger, a fine teacher, was passing on to his students the worldview of biochemical professionals—that evolution is important forunderstanding biochemistry, that it is one of just two «points of view» bywhich they must study the molecules of life. Although a callow student
might take Lehninger's word for it, a dispassionate observer would lookfor evidence of evolution's importance to the study of biochemistry. An
excellent place to start is the book's index.
Lehninger provided a very detailed index in his book to help students
readily find information. Many topics in the index have multiple entries,
because they must be considered in various contexts. For example,
ribosomes have 21 entries in the index of Lehninger's first edition;
photosynthesis has 26 entries; the bacterium E. coli has 42 entries; andunder «proteins» are entered 70 references. In all, there are nearly 6,000
entries in the index, but only 2 under the heading of «evolution.» The firstcitation is in a discussion of the sequences of proteins; as discussed earlier,
however, although sequence data can be used to infer relationships, theycannot be used to determine how a complex biochemical structure

PUBLISH OR PERISH 181
originated. Lehninger's second reference is to a chapter on the origin oflife in which he discusses proteinoids and other topics that have not stood
the test of time.
With just 2 citations out of 6,000, Lehninger's teacherly advice to his
students concerning the importance of evolution to their studies is beliedby his index. In it Lehninger included virtually everything of relevance tobiochemistry. Apparently, though, evolution is rarely a relevant topic.
Lehninger published a new edition of his text in 1982; its index contains
just 2 references to evolution out of 7,000 entries. After Lehninger diedin 1986, Michael Cox and David Nelson of the University of Wisconsin
updated and rewrote the 1982 text. In the preface the new authors include
the following under a list of goals:
To project a clear and repeated emphasis on major themes, especially thoserelating to evolution, thermodynamics, regulation, and the relationshipbetween structure and function.25

Indeed, in the index of the new edition there are 22 references toevolution out of a total of 8,000, an increase of more than tenfold from thelast edition. But when we get past origin-of-life chemistry and sequencecomparisons (the two references in Lehninger's earlier text), we find thatthe new edition uses the word evolution as a wand to wave over mysteries.
For example, one citation is to «evolution, adaptation of sperm whale.»
When we flip to the indicated page, we learn that sperm whales haveseveral tons of oil in their heads which becomes more dense at colder
temperatures. This allows the whale to match the density of the waterat the great depths where it often dives and so swim more easily. After
describing the whale the textbook remarks, «Thus we see in the sperm
whale a remarkable anatomical and biochemical adaptation, perfected byevolution.»26 But that single line is all that's said! The whale is stamped«perfected by evolution,» and everybody goes home. The authors make noattempt to explain how the sperm whale came to have the structure it has.
The extra references to evolution in the newest edition of the Lehninger
text can all be fit into three categories: sequence similarity, comments on
the ancestry of cells, and pious but unsupported attributions of a feature to
evolution. But none of these, even in principle, can tell us how molecularmachinery arose step by step. In no instance is a detailed route given

182 WHAT DOES THE BOX TELL US?
by which any complex biochemical system might have arisen in a
Darwinian manner.
A survey of thirty biochemistry textbooks (summarized in Table 8—1)
used in major universities over the past generation shows that many
textbooks ignore evolution completely. For example, Thomas Devlin ofJefferson University in Philadelphia wrote a biochemistry textbook
TABLE 8-1
Reference to Evolution in the Indexes of Biochemistry
Textbooks

PUBLISH OR PERISH 183
that was first published by John Wiley & Sons in 1982; new editions
followed in 1986 and 1992. The first edition has about 2,500 entries in
its index; the second also has 2,500; and the third has 5,000. Of these,
the number referring to evolution are zero, zero, and zero, respectively. A
textbook by Frank Armstrong of North Carolina State University, publishedby Oxford University Press, is the only recent book to include an historicalchapter reviewing important developments in biochemistry, beginningwith the synthesis of urea by Friedrich Wohler in 1828. The chapter does
not mention Darwin or evolution. In three editions Armstrong's book has
found it unnecessary to mention evolution in its index. Another textbook
published by John Wiley & Sons has one citation to evolution in its index
out of a total of about 2,500. It refers to a sentence on page 4: «Organisms
have evolved and adapted to changing conditions on a geological timescale and continue to do so.»27 Nothing else is said.
Some textbooks make a concerted effort to inculcate in students anevolutionary view of the world. For example, a textbook by Voet and Voetcontains a marvelous, full-color drawing nicely capturing the orthodox
position.28 The top third of the drawing shows a volcano, lightning, an
ocean, and little rays of sunlight, to suggest how life started. The middle ofthe picture has a stylized drawing of a DNA molecule leading out from theorigin of life ocean and into a bacterial cell, to show how life developed.
The bottom third of the picture—no kidding—is like the Garden of Eden,
depicting a number of animals that have been produced by evolution
milling about. Included in the throng are a man and a woman (the woman
is offering the man an apple), both especially attractive and in the buff.
This undoubtedly adds to the interest for students, but the drawing is atease. The implicit promise that the secrets of evolution will be uncoveredis never consummated.29
Many students learn from their textbooks how to view the world
through an evolutionary lens. However, they do not learn how Darwinianevolution might have produced any of the remarkably intricate biochemicalsystems that those texts describe.

HOW DO YOU KNOW?

How do we know what we say we know-not in some deep philosophicalsense, but on a practical, everyday level? On any particular day you

184 WHAT DOES THE BOX TELL US?
might tell someone that you know your living room is painted green,that you know the Philadelphia Eagles are going to win the Super Bowl,
that you know the earth goes around the sun, that you know democracy isthe best form of government, that you know the way to San Jose. Clearlythese different assertions are based on different ways of knowing. What
are they?
The first way to know something is, of course, through personal
experience. You know that your living room is painted green because
you've been in your living room and saw that it was green. (I won't worry
here about things like how you know you aren't dreaming or insane or
such.) Similarly you know what a bird is, how gravity works (again, in an
everyday sense), and how to get to the nearest shopping mall, all by direct
experience.
The second way to know things is by authority. That is, you rely onsome source of information, believing it to be reliable, when you have noexperience of your own. So almost every person who has gone to school
believes that the earth goes around the sun, even though very few people
would be able to tell you how anybody could even detect that motion. You
are relying on authority if, when asked if you know the way to San Jose,
you answer yes and pull out a map. You might be able to personally test the
map's reliability by using it to navigate to San Jose, but until you do you are
relying on authority. Many people believe democracy is superior to otherforms of government even though they haven't lived under any other type.
They rely on the authority of textbooks and politicians, and perhaps on
verbal or pictorial descriptions of what it's like in other societies. Of course
other societies do the same, and most of their defenders rely on authority.
But how about those Eagles? How do you know they are going to win it
all this year? If pressed you might admit that no sports commentator has
picked them to win, so you aren't relying on authority. Furthermore, youhave no firsthand information that, say, some of the players are training
secretly under a Zen master, who promises to greatly increase their agility.
You are not basing it on their performance in the recent past, which has
been mediocre to abysmal. If really pressed you might point to successes
in the distant past (like their championships in 1948, 1949, and 1960, or
their Super Bowl appearance in 1981) and say that you just know thatthey're due for success this year. So in fact you do not know that the Eagles
are going to win this year; it was just a figure of speech. Your assertion isPUBLISH OR PERISH 185
based on neither experience nor authority. It is bluster.
Scientists are people, too, so we can ask how scientists know what they
say they know. Like everybody else, scientists know things either throughtheir own experience or through authority. In the 1950s, Watson andCrick saw a diffraction pattern produced by shining X-rays on fibers of
DNA and, using their mathematical abilities, determined that DNA wasa double helix. They knew by doing, from their own experience. As anundergraduate I learned DNA is a double helix, but I have never done anexperiment to show it; I rely on authority. All scientists rely on authority
for almost all of their scientific knowledge. If you ask a scientist how she
knows about the structure of cholesterol, or the behavior of hemoglobin,or the role of vitamins, she will almost always point you to the scientific
literature rather than to her own records of what she has done in her
laboratory.
The nice thing about science is that authority is easy to locate: it's in
the library. Watson and Crick's work on DNA structure can be tracked
down and read in Nature. The structure of cholesterol and other things
can be found there as well. So we can say we know the structure of DNA
or cholesterol based on scientific authority if papers on those topics arein the literature. If James Watson or a Presidential Science Commission
decreed that DNA was made of green cheese, however, but didn't publish
supporting evidence in the literature, then we could not say that a beliefin cheesy DNA was based on scientific authority. Scientific authority restson published work, not on the musings of individuals. Moreover, thepublished work must also contain pertinent evidence. If Watson publisheda bare statement about the curdled composition of DNA in a paper largely
devoted to something else, but provided no relevant support, then we still
have no scientific authority to back up the claim.
Molecular evolution is not based on scientific authority. There is no
publication in the scientific literature—in prestigious journals, specialty
journals, or books—that describes how molecular evolution of any real,complex, biochemical system either did occur or even might have occurred.
There are assertions that such evolution occurred, but absolutely none aresupported by pertinent experiments or calculations. Since no one knows
molecular evolution by direct experience, since there is no authority on
which to base claims of knowledge, it can truly be said that—like the186 WHAT DOES THE BOX TELL US?
contention that the Eagles will win the Super Bowl this year—theassertion of Darwinian molecular evolution is merely bluster.
«Publish or perish» is a proverb that academicians take seriously. If you
do not publish your work for the rest of the community to evaluate, thenyou have no business in academia (and if you don't already have tenure,
you will be banished). But the saying can be applied to theories as well.
If a theory claims to be able to explain some phenomenon but does not
generate even an attempt at an explanation, then it should be banished.
Despite comparing sequences and mathematical modeling, molecular
evolution has never addressed the question of how complex structures
came to be. In effect, the theory of Darwinian molecular evolution has not
published, and so it should perish.

CHAPTER 9INTELLIGENT DESIGN

WHAT'S GOING ON?

The impotence of Darwinian theory in accounting for the molecularbasis of life is evident not only from the analyses in this book, but also
from the complete absence in the professional scientific literature of any
detailed models by which complex biochemical systems could have been
produced, as shown in Chapter 8. In the face of the enormous complexitythat modern biochemistry has uncovered in the cell, the scientificcommunity is paralyzed. No one at Harvard University, no one at the
National Institutes of Health, no member of the National Academy of
Sciences, no Nobel prize winner—no one at all can give a detailed accountof how the cilium, or vision, or blood clotting, or any complex biochemical
process might have developed in a Darwinian fashion. But we are here.
Plants and animals are here. The complex systems are here. All thesethings got here somehow: if not in a Darwinian fashion, then how?
Clearly, if something was not put together gradually, then it must havebeen put together quickly or even suddenly. If adding individual pieces
does not continuously improve the function of a system, then multiple
pieces have to be added together. Two ways to rapidly assemble complex

187

188 WHAT DOES THE BOX TELL US?
systems have been proposed by scientists in recent years. Let's briefly
consider those proposals, and then look in depth at a third alternative.
The first alternative to gradualism has been championed by Lynn
Margulis. In place of a Darwinian view of progress by competition andstrife, she proposes advancement by cooperation and symbiosis. Organisms
in her view aid one another, join forces, and accomplish together what
they could not accomplish separately. While still a graduate student she
brought this idea to bear on problems of cell structure. Although initiallypatronized and ridiculed, Margulis eventually won grudging acceptance—
and then acclaim (she was elected to the National Academy of Sciences)—for her idea that parts of the cell were once free-living organisms.
The eukaryotic cell, as we have seen, is chock full of complex molecularmachines tidily separated into many discrete compartments. The biggest
compartment is the nucleus, which could be seen even with the crude
microscopes of the seventeenth century. Smaller compartments were
not discovered until improved microscopes became available in the later
nineteenth and twentieth centuries. One of the smaller compartments isthe mitochondrion.
Perhaps I should say that many of the smaller compartments are
mitochondria: the typical cell contains about two thousand of them, andthey occupy a total of about 20 percent of the cell's volume. Each of thelittle compartments contains machinery necessary to capture the energy
of foodstuffs and store it in a chemically stable, yet readily available, form.
The mitochondrial mechanisms that do this are quite complex. The system
uses a flow of acid to power its machines, which shuttles electrons amonga half-dozen carriers, requiring an exquisitely delicate interaction between
many components.
Mitochondria are roughly the same size and shape as some free-living
bacterial cells. Lynn Margulis proposed that at one time on the ancientearth a larger cell «swallowed» a bacterial cell, but did not digest it. Rather,
the two cells—one now living inside the other—adapted to the situation.
The smaller cell received nutrients from the larger one and, in return, passedon some of the stored chemical energy it made to the larger cell. Whenthe larger cell reproduced, the smaller one did too, and its descendants
continued to reside inside the host. Over time the symbiotic cell lost manyof the systems that free-living cells need, and specialized more

INTELLIGENT DESIGN 189
and more in providing energy for its host. Eventually it became amitochondrion.
The stifled laughs and smirks that greeted Margulis's proposal slowly
faded when new sequencing techniques, developed after she proposed
the theory, showed that mitochondrial proteins more closely resemble
bacterial proteins than host cell proteins. Other resemblances between
mitochondria and bacteria were then noticed. Furthermore, proponentsof the symbiotic origin of mitochondria pointed to symbiotic cells incontemporary organisms to support their theory. For example, a speciesof flatworm has no mouth because it never has to eat—it contains
photosynthetic algae that supply its energy! Such pieces of evidence havecarried the day. Margulis's theory concerning mitochondria has now
become textbook orthodoxy.
Periodically over the last two decades Margulis and other scientists haveproposed that other cellular compartments are the result of symbiosis.
These proposals are not so widely accepted. For purposes of argument,
however, let's suppose that the symbiosis Margulis envisions was in fact
a common occurrence throughout the history of life. The importantquestion for us biochemists is, can symbiosis explain the origin of complex
biochemical systems?
Clearly it cannot. The essence of symbiosis is the joining of two separate
cells, or two separate systems, both of which are already functioning. In the
mitochondrion scenario, one preexisting viable cell entered a symbiotic
relationship with another such cell. Neither Margulis nor anyone else
has offered a detailed explanation of how the preexisting cells originated.
Proponents of the symbiotic theory of mitochondria explicitly assume
that the invading cells could already produce energy from foodstuffs; they
explicitly assume that the host cell already was able to maintain a stableinternal environment that would benefit the symbiont.
Because symbiosis starts with complex, already-functioning systems,
it cannot account for the fundamental biochemical systems we havediscussed in this book. Symbiosis theory may have important points tomake about the development of life on earth, but it cannot explain theultimate origins of complex systems.
The second alternative to Darwinian gradualism proposed in recent
years is known as «complexity theory» and has been championed by Stuart
Kauffman. In brief, complexity theory states that systems with a large
number of interacting components spontaneously organize themselves

190 WHAT DOES THE BOX TELL US?
into ordered patterns. Sometimes there are several patterns available to thecomplex system, and «perturbations» of the system can cause it to switchfrom one pattern to the other. Kauffman proposes that chemicals in theprebiotic soup organized themselves into complex metabolic pathways. He
further proposes that the switch between different cell «types» (like whena developing organism starts with just a fertilized egg but then goes on to
make liver cells, skin cells, etc.) is a perturbation of a complex system andresults from the self-organization he envisions.
The above explanation may sound a bit fuzzy. Some of the fuzz is no
doubt due to my modest powers of description. But a good deal is dueto the fact that complexity theory began as a mathematical concept todescribe the behavior of some computer programs, and its proponents
have not yet succeeded in connecting it to real life. Rather, the chief modeof argumentation so far has been for proponents to point to the behaviorof a computer program and assert that the computer behavior resembles
the behavior of a biological system. For example, Kauffman writes aboutchanges (which he calls mutations) in some computer programs he has
written:Most mutations have small consequences because of the system's [changeresisting] nature. A few mutations, however, cause larger cascades ofchange. Poised systems will therefore typically adapt to a changing
environment gradually, but if necessary, they can occasionally change
rapidly. These properties are observed in organisms.1

In other words, some small changes in a computer program cause largechanges in the program's output (typically a pattern of dots on a computer
screen), so perhaps small changes in DNA can produce large, coordinatedbiological changes. The argument never goes further than that. No
proponent of complexity theory has yet gone into a laboratory, mixed alarge variety of chemicals in a test tube, and looked to see if self-sustaining
metabolic pathways spontaneously organize themselves. If they ever dotry such an experiment, they will merely be repeating the frustrating workof origin-of-life scientists who have gone before them—and who have seenthat complex mixtures yield a lot of muck on the sides of a flask, and notmuch else.
In his book on the subject Kauffman muses that complexity theory

INTELLIGENT DESIGN 191
might explain not only the origin of life and metabolism, but also
body shapes, ecological relationships, psychology, cultural patterns, andeconomics.2 The vagueness of complexity, though, has started to turnoff early boosters of the theory. Scientific American ran favorable articles
over a number of years (one authored by Kauffman himself). On its cover,
however, the June 1995 issue asked, «Is Complexity a Sham?» Inside was anarticle entitled «From Complexity to Perplexity» that noted the following:
Artificial life, a major subfield of complexity studies, is «fact-free science,»
according to one critic. But it excels at generating computer graphics.

Indeed, some proponents see great significance in the fact that they
can write short computer programs which display images on the screenthat resemble biological objects such as a clam shell. The implication isthat it doesn't take much to make a clam. But a biologist or biochemist
would want to know, if you opened the computer clam, would you see apearl inside? If you enlarged the image sufficiently, would you see cilia andribosomes and mitochondria and intracellular transport systems and all
the other systems that real, live organisms need? To ask the question is toanswer it. In the article, Kauffman observes that «At some point artificial
life drifts off into someplace where I cannot tell where the boundary is
between talking about the world—I mean, everything out there—andreally neat computer games and art forms and toys.» More people are
beginning to think that the drifting point occurs very early.
For the sake of argument, however, let us suppose that complexity
theory is true—that complex mixtures somehow organized themselves,
and that had something to do with the origin of life. Granted its premises,
can complexity theory explain the complex biochemical systems we havediscussed in this book? I don't believe so. The complex, interacting mixtureof chemicals it envisions might have occurred before life developed (again,
though, there is virtually no evidence to support even this), but it would
not have mattered once cellular life began. The essence of cellular life isregulation: The cell controls how much and what kinds of chemicals it
makes; when it loses control, it dies. A controlled cellular environment
does not permit the serendipitous interactions between chemicals (always
unspecified) that Kauffman needs. Because a viable cell keeps its chemicals
on a short leash,

192 WHAT DOES THE BOX TELL US?
it would tend to prevent new, complex metabolic pathways fromorganizing by chance.
Let's further suppose that the pattern of genes that are turned on and
off in a cell, corresponding to different cell types, can switch according to
the theories of Stuart Kauffman. (Different cell types form when different
genes are turned on or off. For example, the genes for hemoglobin—theprotein that carries oxygen to tissues—are turned on in cells that makered blood cells, but are turned off in other cells.) Although there is noevidence for it, let us say that complexity theory has something to do withthe switch that turns one cell into a red blood cell and another into a nerve
cell. Can this explain the origin of complex biochemical systems? No. Like
symbiosis theory, this aspect of complexity theory requires preexisting,already functional systems. So if a cell turns off almost all genes except theones to make hemoglobin, it might turn into a red blood cell; if anothercell turns on another set of genes, it might make the proteins characteristicof a nerve cell. But no eukaryotic cell can turn on preexisting genes andsuddenly make a bacterial flagellum, because no preexisting proteins in
the cell interact in that way. The only way a cell could make a flagellum is
if the structure were already coded for in its DNA. In fact, Kauffman neverclaims that such new and complex structures can be produced suddenly
according to complexity theory.
Complexity theory may yet make important contributions tomathematics, and it may still make modest contributions to biochemistry.
But it cannot explain the origin of the complex biochemical structuresthat undergird life. It doesn't even try.

DETECTION OF DESIGN

Imagine a room in which a body lies crushed, flat as a pancake. A dozen
detectives crawl around, examining the floor with magnifying glasses forany clue to the identity of the perpetrator. In the middle of the room, next
to the body, stands a large, gray elephant. The detectives carefully avoid
bumping into the pachyderm's legs as they crawl, and never even glance
at it. Over time the detectives get frustrated with their lack of progress
but resolutely press on, looking even more closely at the floor. You see,textbooks say detectives must «get their man,» so they never consider
elephants. There is an elephant in the roomful of scientists who are

INTELLIGENT DESIGN 193
trying to explain the development of life. The elephant is labeled«intelligent design.» To a person who does not feel obliged to restrict
his search to unintelligent causes, the straightforward conclusion is thatmany biochemical systems were designed. They were designed not by thelaws of nature, not by chance and necessity; rather, they were planned.
The designer knew what the systems would look like when they werecompleted, then took steps to bring the systems about. Life on earth at its
most fundamental level, in its most critical components, is the product ofintelligent activity.
The conclusion of intelligent design flows naturally from the data itself—
not from sacred books or sectarian beliefs. Inferring that biochemicalsystems were designed by an intelligent agent is a humdrum process that
requires no new principles of logic or science. It comes simply from thehard work that biochemistry has done over the past forty years, combinedwith consideration of the way in which we reach conclusions of design
every day. Nonetheless, saying that biochemical systems were designed
will certainly strike many people as strange, so let me try to make it soundless strange.
What is «design»? Design is simply the purposeful arrangement ofparts. With such a broad definition we can see that anything might havebeen designed. Suppose that as you drive to work one bright morning,
you observe a burning car by the side of the road—its front end pushed
in, broken glass all around. About twenty feet from the car you see a
motionless body lying in a heap. Stamping on the brakes, you pull overto the side of the road. You rush up to the body, grab a wrist to feel fora pulse, and then notice that a young man with a mini-cam is standing
behind a nearby tree. You yell to him to call an ambulance, but he keeps on
filming. Turning back to the body, you notice that it is smiling at you. The
uninjured actor explains that he is a graduate student in the department ofsocial work and is doing research on the willingness of motorists to cometo the aid of injured strangers. You glare at the grinning charlatan as hestands and wipes the fake blood off his face. You then help him to achievea more realistic look and walk away contentedly as the cameraman runs
off to call an ambulance.
The apparent accident was designed; a number of parts were purposely
arranged to look like a mishap. Other, less noticeable events could be194 WHAT DOES THE BOX TELL US?
designed also: The coats on a rack in a restaurant may have beenarranged by the owner before you came in. The trash and tin cans along
the edge of a highway may have been placed by an artist trying to makesome obscure environmental statement. Apparently chance meetings
between people might be the result of a grand design (conspiracy theorists
thrive on postulating such designs). On the campus of my university there
are sculptures that, if I saw them lying beside the road, I would guess were
the result of chance blows to a piece of scrap metal, but they were designed.
The upshot of this conclusion—that anything could have been purposely
arranged—is that we cannot know that something has not been designed.
The scientific problem then becomes, how do we confidently detect design?
When is it reasonable to conclude, in the absence of firsthand knowledge
or eyewitness accounts, that something has been designed? For discrete
physical systems—if there is not a gradual route to their production—
design is evident when a number of separate, interacting components areordered in such a way as to accomplish a function beyond the individualcomponents.3 The greater the specificity of the interacting components
required to produce the function, the greater is our confidence in the
conclusion of design.
This can be seen clearly in examples from diverse systems. Suppose thatyou and your spouse are hosting another couple one Sunday afternoon fora game of Scrabble. When the game ends, you leave the room for a break.
You come back to find the Scrabble letters lying in the box, some face up
and some face down. You think nothing of it until you notice that theletters facing up read, «TAKE US OUT TO DINNER CHEAPSKATES.» In
this instance you immediately infer design, not even bothering to consider
that the wind or an earthquake or your pet cat might have fortuitously
turned over the right letters. You infer design because a number of
separate components (the letters) are ordered to accomplish a purpose (themessage) that none of the components could do by itself. Furthermore, themessage is highly specific; changing several of the letters would make it
unreadable. For the same reason, there is no gradual route to the message:
one letter does not give you part of the message, a few more letters does notgive a little more of the message, and so on.
Despite my inability to recognize design in the sculptures aroundcampus, it is often easy to recognize design in other pieces of artwork

INTELLIGENT DESIGN 195
here. For example, the gardeners arrange flowers near the student
center to spell out the name of the university. Even if you had not seen
them working, you could easily tell that the flowers had been purposely
arranged. For that matter, if you came across flowers deep in the woods
that clearly spelled out the name «LEHIGH,» you would have no doubtthat the pattern was the result of intelligent design.
Design can most easily be inferred for mechanical objects. While
walking through a junkyard you might observe separated bolts and screws
and bits of plastic and glass—most scattered, some piled on top of eachother, some wedged together. Suppose your eye alighted on a pile that
seemed particularly compact, and when you picked up a bar sticking outof the pile, the whole pile came along with it. When you pushed on the bar
it slid smoothly to one side of the pile and pulled an attached chain alongwith it. The chain in turn yanked a gear which turned three other gears
which turned a rod, spinning it smoothly. You quickly conclude that thepile was not a chance accumulation of junk but was designed (that is, wasput together in that order by an intelligent agent), because you see that thecomponents of the system interact with great specificity to do something.
Systems made entirely from natural components can also evince
design. For example, suppose you are walking with a friend in the woods.
All of a sudden your friend is pulled high in the air and left dangling by
his foot from a vine attached to a tree branch. After cutting him down you
reconstruct the trap. You see that the vine was wrapped around the tree
branch, and the end pulled tightly down to the ground. It was securely
anchored to the ground by a forked branch. The branch was attached
to another vine—hidden by leaves—so that, when the trigger-vine wasdisturbed, it would pull down the forked stick, releasing the spring-vine.
The end of the vine formed a loop with a slipknot to grab an appendage
and snap it up into the air. Even though the trap was made completely ofnatural materials you would quickly conclude that it was the product ofintelligent design.
For a simple-artificial object such as a steel rod, the context is often
important in concluding design. If you saw the rod outside a steel plant,
you would infer design. Suppose however, that you traveled in a rocket ship
to a barren alien planet that had never been explored. If you saw dozens ofcylindrical steel rods lying on the side of a volcano, you would need more
information before you could be sure that alien geological196 WHAT DOES THE BOX TELL US?
processes—natural for that planet—had not produced the rods. In
contrast, if you found dozens of mousetraps near the volcano you would
apprehensively look over your shoulder for signs of the designer.
In order to reach a conclusion of design for something that is not an
artificial object (for example, an arrangement of vines and sticks in thewoods to make a trap), or to reach a conclusion of design for a systemcomposed of a number of artificial objects, there must be an identifiable
function of the system. One has to be careful, though, in defining thefunction. A sophisticated computer can be used as a paper weight; is thatits function? A complex automobile can be used to help dam a stream; isthat what we should consider? No. In considering design, the function of
the system we must look at is the one that requires the greatest amount of
the system's internal complexity. We can then judge how well the parts fit
the function.4
The function of a system is determined from the system's internal logic:
the function is not necessarily the same thing as the purpose to which thedesigner wished to apply the system. A person who sees a mousetrap for
the first time might not know that the manufacturer expected it to be used
for catching mice. He might use it instead for a defense against burglars
or as a warning system for earthquakes (if the vibrations would set off thetrap), but he still knows from observing how the parts interact that it was
designed. Similarly, someone might try to use a lawnmower as a fan or as
an outboard motor. But the function of the equipment—to rotate a blade—is best defined by its intenal logic.

WHO'S THERE?

Inferences to design do not require that we have a candidal role ofdesigner. We can determine that a system was designed by examining
the system itself, and we can hold the conviction of design much morestrongly than a conviction about the identity of the designer. In several of
the examples above, the identity of the designer is not obvious. We have noidea who made the contraption in the junkyard, or the vine trap, or why.
Nonetheless, we know that all of these things were designed because of theordering of independent components to achieve some end.

INTELLIGENT DESIGN 197
The inference to design can be made with a high degree of confidence
even when the designer is very remote. Archeologists digging for a lost city
might come across square stones, buried dozens of feet under the earth,with pictures of camels and cats, griffins and dragons. Even if that were
all they found, they would conclude that the stones had been designed.
But we can go even further than that. I was a teenager when I saw 2001:
A Space Odyssey. To tell the truth I really didn't care for the movie; I justdidn't get it. It started out with monkeys beating each other with sticks,
then shifted to a space flight with a homicidal computer, and ended up
with an old man spilling a drink and an unborn child floating in space.
I'm sure it had some profound meaning, but we scientific types don't catchon quickly to artsy stuff.
There was one scene, however, that I did get quite easily. The firstspace flight had landed on the moon, and an astronaut was going out toexplore. In his meanderings he came across a smoothly shaped obeliskthat towered against the moonscape. I, the astronaut, and the rest of theaudience immediately understood, with no words necessary, that theobject was designed—that some intelligent agent had been to the moonand formed the obelisk. Later the movie showed us that there were alienson the planet Jupiter, but we couldn't tell that from the obelisk. For all weknew by looking at the object itself it might have been designed by space
aliens, angels, humans from the past (whether Russians or inhabitants of
the lost civilization of Atlantis) who could fly through space, or even by
one of the other astronauts on the flight (who, as a practical joke, might
have stowed it away and put it on the moon ahead of the astronaut wholater discovered it). If the plot had actually developed along any of theselines, the audience would not be able to say the plot was contradicted by
the appearance of the obelisk. If the movie had contrived to assert that theobelisk was not designed, however, the audience would have hooted till the
projectionist turned the film off.
The conclusion that something was designed can be made quite
independently of knowledge of the designer. As a matter of procedure,thе design must first be apprehended before there can be any further
question about the designer. The inference to design can be held with thefirmness that is possible in this world, without knowing anything about
the designer.

198 WHAT DOES THE BOX TELL US?

ON THE EDGE

Anyone can tell that Mt. Rushmore was designed—but, as the king ofSiam often said, this too shall pass. As time marches and rains fall andwinds gust, Mt. Rushmore will change its shape. Millennia in the future,people may pass the mountain and see just the barest hint of faces in therocks. Could a person conclude that an eroded Mt. Rushmore had been
designed? It depends. The inference to design requires the identification of
separate components that have been ordered to accomplish a purpose, andthe strength of the inference is not an easy matter to quantify. An eroded
Mt. Rushmore might give future archeologists fits if they could only see
what looked like an ear, a nose, a bottom lip, and maybe a chin, each froma different presidential image. The parts really aren't ordered to each otherand might be simply an unusual rock formation.
There appears to be the face of a man on the surface of the moon. One
can point to darkened areas that look like eyes and a mouth. This might
have been designed, perhaps by aliens, but the number and specificity of
the components is not sufficient to determine if the purpose that is ascribedto the pattern was actually intended. Italy may have been intentionallydesigned to look like a boot, but maybe not. There is not enough data
to reach a confident conclusion. The National Enquirer once ran a story
purporting to show a human face on the surface of Mars; however, theresemblance was only slight. In such cases we can just say that, likeanything, it could have been designed, but we cannot tell for sure.
As the number and quality of the components that fit together to form
the system increases, we can be more and more confident of the conclusionof design. A few years ago it was reported that an image of Elvis was formedby mold growing on the refrigerator of a lady from Tennessee. Again, theresemblance could be seen, but it was slight. Suppose, however, that theresemblance was actually very good. Suppose that the image was made up
not only of black mold. Suppose that there was also Serratia marcescens—abacterium that grows in red sheets. And suppose there were colonies ofthe yeast Saccharomyces cerevisiae, which are shiny white. And there wasalso Pseuodomonas aeruginosa, which is green, and Chromobacterium
violaceum, which is purple, and Staphylococcus aureus, which is yellow.
And suppose the green microorganisms were growing in the shapeINTELLIGENT DESIGN 199
of Elvis's pants, and the purple bacteria formed his shirt. And very small
dots of alternating red and white bacteria gave his face a flesh-colored look.
In fact, suppose the bacteria and mold on the refrigerator formed animage of Elvis that was well nigh identical to one of those velvet posters of
him that you see in variety stores. Can we then conclude that the image
was designed? Yes we can—with the same confidence that we conclude thedimestore posters were designed.
If the «man in the moon» had a beard and ears and eyeglasses andeyebrows we would conclude that it was designed. If Italy had buttonholes
and shoelaces and if Sicily closely resembled a soccer ball, with colored
stripes and a logo, we would think that they were designed. As the numberor quality of the parts of an interacting system increase, our judgmentof design increases also and can reach certitude. It is hard to quantify
these things.5 But it is easy to conclude that a system of such detail as thecompleted bacterial Elvis was designed.

BIOCHEMICAL DESIGN

It is easy to see design in Elvis posters, mousetraps, and Scrabble
messages. But biochemical systems aren't inanimate objects; they're partof living organisms. Can living biochemical systems be intelligently
designed? It wasn't too long ago that life was thought to be made of a special
substance, different from the stuff that comprised nonliving objects.
Friedrich WÖhler debunked that idea. For a long while afterward, thecomplexity of life defeated most attempts to understand and manipulate
it. In recent decades, however, biochemistry has made such great strides
that basic changes in living organisms are being designed by scientists.
Let's take a look at a few examples of biochemical design.
When the blood-clotting system misfires, a wayward clot can block
blood flow through the heart, endangering life. In current treatmenta naturally occurring protein is injected into the patient to help breakup the clot. But the natural protein has some drawbacks, so innovative
researchers are trying to make a new protein in the laboratory that can doa better job.6 Briefly, the strategy is the following (Figure 9-1). Many of theproteins of the blood-clotting system are activated by other factors

200 WHAT DOES THE BOX TELL US?
that clip a piece of the target protein, activating it. The piece that is clipped,
however, is targeted by just its activator and no other. Plasminogen—theprecursor of plasmin, the protein that breaks up blood clots—contains atarget that is clipped only very slowly, after the clot has formed and healing
begins. To treat a heart attack, though, plasmin is needed immediately at
the site of the blood clot that is inhibiting circulation.
In order to make plasmin available immediately at the right place, thegene for plasminogen has been isolated by researchers and altered. The partof the gene coding for the site in plasminogen that is cleaved to activate theprotein is replaced. It is replaced by the part of a gene
FIGURE 9-1(1)
The gene for plasminogen is isolated. (In the figure
the amino acids, not the DNA, that the gene codes for are
shown. (2) The section of the gene that codes for thearea of the protein that is cut slowly during activation is
taiken out. (3) The section of another gene that codes fora protein region that is cut rapidly by thrombin is put into
the plasminogen gene. (4) A designed, hybrid gene now existsthat will, when placed in a cell, produce a plasminogen thatis rapidly activated by thrombin.

INTELLIGENT DESIGN 201
for another component of the blood-clotting pathway (such as plasma
thromboplastin antecedent, or РТА) that is cleaved rapidly by thrombin.
Now the idea is this: the engineered plasminogen, carrying the thrombincleavable piece, will quickly be cut and activated in the close vicinity ofa clot, because thrombin is present at the clot site. But the activity that isquickly released is not that of РТА; rather, it is plasmin. If such a protein
were quickly injected into a heart attack victim, the hope is that the plasminwould help him or her recover with minimum permanent damage.
The new protein is the product of intelligent design. Someone withknowledge of the blood-clotting system sat down at his desk and sketchedout a route to produce a protein that would combine the clot-dissolving
properties of plasmin with the rapid-activation property of proteins thatare cleaved by thrombin. The designer knew what the end product of
his work was going to do, and he worked to achieve that goal. After theplan was drawn up, the designer (or his graduate student) went into thelaboratory and took steps to carry out the plan. The result is a protein thatno one in the world has ever seen before— a protein that will carry out theplan of the designer. Biochemical systems can indeed be designed.
Intelligent design of biochemical systems is really quite common-placethese days. In order to supply diabetics with hard-to-get human insulin,
researchers a decade ago isolated the human insulin gene. They placed it
into a piece of DNA that could survive in a bacterial cell and grew up themodified bacteria. The bacteria's cellular machinery then produced humaninsulin, which was isolated and used to treat patients. Some laboratories
are now modifying higher organisms by incorporating altered DNA
directly into their cells. Designed plants that resist frost or insect pests
have been around for a while now; somewhat newer is the engineeringof cows that give milk containing large amounts of useful proteins. (Thepeople who do this by injecting extraneous genes into cow embryos like tocall themselves «pharmers,» short for pharmaceutical farmers.)
It might be observed that although the systems described above areexamples of biochemical design, in each case the designer did no morethan rearrange pieces of nature; he or she did not produce a new systemfrom scratch. That is true, but it probably won't be true for very long.
Scientists today are actively working on uncovering the secrets of202 WHAT DOES THE BOX TELL US?
what gives proteins their special activity. Progress has been slow but
steady. It won't be long before proteins are made from scratch, designed forspecific, novel purposes. Even more impressively, new chemical systems
are being developed by organic chemists to mimic the activities of life.
This has been played up in the popular media as «synthetic life.» Althoughthat is a gross exaggeration designed to sell magazines, the work does
show that an intelligent agent can design a system exhibiting biochemicallike properties without using the bio-chemicals known to occur in living
systems.
In recent years some scientists have even begun to design new biochemicals using the principles of microevolution—mutation and selection.7
The idea is simple: chemically make a large number of different pieces of
DNA or RNA, then pull out of the mix the few pieces that have a property
that the designer wants, such as the ability to bind to a vitamin or protein.
This is done by mixing solid particles to which the vitamin or protein has
been attached with a solution containing the mix of DNA or RNA pieces,and then washing away the solution. Pieces of DNA or RNA that bind thevitamin or protein remain stuck to the solid; all the pieces which don'tbind are washed away. After selecting the right pieces the experimenter
uses enzymes to make many copies of them. Gerald Joyce, a leader in thefield, likens the process to selective breeding: «If one wants a redder rose ora fluffier Persian, one chooses as breeding stock those individuals that best
exemplify the desired trait. So, too, if one wants a molecule that exhibita particular chemical trait, then one selects from a large population ofmolecules those individuals that best manifest the property.»8 Like
selective breeding, the method has the advantages of microevolution, butalso has its limitations. Simple biochemical activities can be produced, but
not the complicated systems we have discussed in this book.
In many ways this technique is like the clonal selection of antibodies,
discussed in Chapter 7. Indeed, other scientists are taking advantage of theability of the immune system to generate antibodies against almost any
molecule. The scientists inject an animal with a molecule of interest (forexample, a drug) and isolate the antibodies that are made against it. The
antibodies can then be used as clinical or commercial reagents to detect
the molecule. In some cases antibodies can be produced which behave like
simple enzymes9 (they are called «abzymes»). Both of these approaches—
DNA/RNA or antibodies— promise to find a host of industrial andINTELLIGENT DESIGN 203
medical applications in the coming years.
The fact that biochemical systems can be designed by intelligent agentsfor their own purposes is conceded by all scientists, even Richard Dawkins.
In his newest book Dawkins envisions a hypothetical scenario where aleading scientist is kidnaped and forced to work on biological weapons
for an evil, militaristic country.10 The scientist gets help by encoding amessage in the DNA sequence of an influenza virus: he infects himself
with the altered virus, sneezes on a crowd of people, and patiently waits
for the flu to spread around the world, confident that other scientists will
isolate the virus, sequence its DNA, and decipher his code. Since Dawkins
agrees that biochemical systems can be designed, and that people who did
not see or hear about the designing can nonetheless detect it, then thequestion of whether a given biochemical system was designed boils down
simply to adducing evidence to support design.
We must also consider the role of the laws of nature. The laws of nature
can organize matter—for example, water flow can build up silt sufficiently
to dam a portion of a river, forcing it to change course. The most relevantlaws are those of biological reproduction, mutation, and natural selection. If
a biological structure can be explained in terms of those natural laws, thenwe cannot conclude that it was designed. Throughout this book, however, I
have shown why many biochemical systems cannot be built up by natural
selection working on mutations: no direct, gradual route exists to these
irreducibly complex systems, and the laws of chemistry work strongly
against the undirected development of the biochemical systems that makemolecules such as AMP. Alternatives to gradualism that work throughunintelligent causes, such as symbiosis and complexity theory, cannot (anddo not even try to) explain the fundamental biochemical machines of life.
If natural laws peculiar to life cannot explain a biological system, then thecriteria for concluding design become the same as for inanimate systems.
There is no magic point of irreducible complexity at which Darwinism islogically impossible. But the hurdles for gradualism become higher andhigher as structures are more complex, more interdependent.
Might there be an as-yet-undiscovered natural process that would
explain biochemical complexity? No one would be foolish enough tocategorically deny the possibility. Nonetheless, we can say that if there204 WHAT DOES THE BOX TELL US?
is such a process, no one has a clue how it would work. Further, it would
go against all human experience, like postulating that a natural process
might explain computers. Concluding that no such process exists is as
scientifically sound as concluding that mental telepathy is not possible,or that the Loch Ness monster doesn't exist. In the face of the massive
evidence we do have for biochemical design, ignoring that evidence in thename of a phantom process would be to play the role of the detectives who
ignore an elephant.
With these preliminary questions cleared out of the way, we canconclude that the biochemical systems discussed in Chapters 3 through6 were designed by an intelligent agent. We can be as confident of ourconclusion for these cases as we are of the conclusion that a mousetrap
was designed, or that Mt. Rushmore or an Elvis poster were designed.
There is no question of degree for those systems, such as for the man in
the moon or the shape of Italy. Our ability to be confident of the designof the cilium or intracellular transport rests on the same principles as ourability to be confident of the design of anything: the ordering of separate
components to achieve an identifiable function that depends sharply on
the components.
The function of the cilium is to be a motorized paddle. In order toachieve this function microtubules, nexin linkers, and motor proteins all
have to be ordered in a precise fashion. They have to recognize each otherintimately, and interact exactly. The function is not present if any of thecomponents is missing. Furthermore, many more factors besides thoselisted are required to make the system useful for a living cell: the cilium
has to be positioned in the right place, oriented correctly, and turned on or
off according to the needs of the cell.
The function of the blood-clotting system is as a strong, but transientbarrier. The components of the system are ordered to that end. Fibrinogen,plasminogen, thrombin, protein C, Christmas factor, and the othercomponents of the pathway together do something that none of thecomponents can do alone. When vitamin К is unavailable or antihemophilic
factor is missing, the system crashes just as surely as a Rube Goldberg
machine fails if a component is missing. The components cut each otherin precise places, align with each other in exact ways. They act to form an
elegant structure that accomplishes a specific task.
The function of the intracellular transport systems is to carry cargo

INTELLIGENT DESIGN 205
from one place to another. To do this packages must be labeled,destinations recognized, and vehicles equipped. Mechanisms must be inplace to leave one enclosed area of the cell and enter a different enclosed
area. The failure of the system leaves a deficit of critical supplies here, achoking surplus there. Enzymes that are useful in a confined area wreak
havoc in another area.
The functions of the other biochemical systems I have discussed arereadily identifiable, and their interacting parts can be enumerated. Because
the functions depend critically on the intricate interactions of the parts wemust conclude that they, like a mousetrap, were designed.
The designing that is currently going on in biochemistry laboratories
throughout the world—the activity that is required to plan a new
plasminogen that can be cleaved by thrombin, or a cow that gives growth
hormone in its milk, or a bacteria that secretes human insulin—isanalogous to the designing that preceded the blood-clotting system. The
laboratory work of graduate students piecing together bits of genes in adeliberate effort to make something new is analogous to the work that wasdone to cause the first cilium.

MAKING DISTINCTIONS

Just because we can infer that some biochemical systems were designed
does not mean that all subcellular systems were explicitly designed.
Further, some systems may have been designed, but proving their design
may be difficult. The face of Elvis might be clear and distinct while his(assumed) guitar is an impressionistic blur. Detecting design in the cilium
might be a piece of cake, but design in another system might be borderline
or undetectable. It turns out that the cell contains systems that span therange from obviously designed to no apparent design. Keeping in mind
that anything might have been designed, let's take a brief look at a coupleof systems where design is hard to see.
The basis of life is the cell, in which the biochemical processes that
undergird the cell's existence are cordoned off from the rest of theenvironment. The structure that encapsulates the cell is called the cell
membrane. It is made up mostly of molecules that are chemically similar
to the detergents with which we wash our dishes and clothes. The

206 WHAT DOES THE BOX TELL US?
exact type of detergent-like molecules that are used in membranes
varies widely from one kind of cell to another: some are longer, some areshorter; some are looser, some are stiffer; some have positive charges, somehave negative charges, and some are neutral. Most cells contain a mixtureof different types of molecules in their membranes, and the blend can bedifferent for different types of cells.
When detergent molecules find themselves in water, they tend toassociate with each other. A good example of this association is seen in
the bubbles that slosh around in the washing machine while you're doing
laundry. The bubbles consist of very thin layers of detergent (plus somewater) in which the molecules are packed side by side. The spherical shapeof the bubbles is due to a physical force called surface tension, which acts
to reduce the area of the bubble to the smallest area able to accommodate
the detergent. If you take the molecules from a cell membrane, purify
them away from all the other components of a cell, and dissolve them inwater, they will often pack together into a spherical, enclosed shape.
Because these molecules form bubbles on their оwn, because theassociation of molecules is indiscriminate, and because a particular
individual molecule is not necessary to form а membrane, it is difficult
to infer intelligent design from cell membranes. Like the stones in a stonewall, each of the components is easily replaced by a different component.
Like the mold on my refrigerator, design is not detectable.
Or consider hemoglobin—the protein in our red blood cells that carries
oxygen from the lungs to the peripheral tissue. Hemoglobin is made up offour individual proteins stuck together, and each of the four proteins canbind oxygen. Two of the four proteins are identical to each other; as are
the other two to each other. It turns out that, because of the way the four
component proteins of hemoglobin stick to each other, the first oxygenthat hops on binds less strongly than the last three. The difference in thestrength of binding oxygen results in a behavior called «cooperativity.»
Simply put, this means that the amount of oxygen bound by a large numberof hemoglobins (as occurs in the blood) does not increase directly with theamount of oxygen in the air. Rather, when the amount of oxygen in thesurroundings is low, practically no oxygen binds to hemoglobin—muchless than would bind if there were no cooperativity. On the other hand,when the oxygen in the surroundings increases, the amount of oxygen

INTELLIGENT DESIGN 207
bound to hemoglobin in the blood increases at a very fast rate. This canbe thought of as something like a domino effect; it takes some effort toknock over the first domino (bind the first oxygen), but the other dominos
then fall down automatically. Cooperativity has important physiologicalconsequences: it allows hemoglobin to become fully saturated where there
is a lot of oxygen (such as in the lungs) and to easily dump off the oxygen
where it is needed (such as peripheral tissues).
There is also another protein, called myoglobin, that is very similar
to hemoglobin except that it has only one protein chain, not four, andtherefore binds only one oxygen. The binding of oxygen to myoglobin is notcooperative. The question is, if we assume that we already have an oxygenbinding protein like myoglobin, can we infer intelligent design from thefunction of hemoglobin? The case for design is weak. The starting point,
myoglobin, already can bind oxygen. The behavior of hemoglobin can beachieved by a rather simple modification of the behavior of myoglobin, andthe individual proteins of hemoglobin strongly resemble myoglobin. So
although hemoglobin can be thought of as a system with interacting parts,
the interaction does nothing much that is clearly beyond the individualcomponents of the system. Given the starting point of myoglobin, I would
say that hemoglobin shows the same evidence for design as does the manin the moon: intriguing, but far from convincing.
The final biochemical system is one I already talked about in Chapter
7—the system that makes AMP. Concluding design here is like concludingthat a painting attributed to a famous-but-dead artist is actually a forgery
by another person from the same era. Perhaps you see that the painting
has the famous artist's name printed on the lower left corner, but the brushstrokes, the color combination, the subject matter, the canvas material,
and the paint itself are all different.
Because so many successive steps are needed to make AMP, because
the intermediates are not used, and because our best chemical knowledge
argues strongly against the undirected production of the pathway, the casefor the design of the AMP pathway appears to be very strong. In theory
the conclusion for design here is vulnerable to a Stuart Kauffman-type
scenario; however, complexity theory is currently not much more than aphantom, and the known chemical behavior of molecules strongly

208 WHAT DOES THE BOX TELL US?
dictates against the scenario. Furthermore, the conclusion of intelligent
design for other biochemical systems bolsters the credibility of invoking
design for this system as well.
Since anything could have been designed, and since we need to adduce
evidence to show design, it is not surprising that we can be more successful
in demonstrating design with one biochemical system and less successful
with another. Some features of the cell appear to be the result of simple
natural processes, others probably so. Still other features were almost
certainly designed. And with some features, we can be as confident thatthey were designed as that anything was.

CHAPTER 10

QUESTIONS ABOUT DESIGNSIMPLE IDEAS

A simple idea can take a surprising length of time to be properly
developed, even though the idea is very powerful. Perhaps the most
famous example of this is the invention of the wheel. Before the wheel
people slogged around in horse-drawn carts that slid on poles, scraping
across the ground and generating a lot of friction. Any schoolboy of ourtime could have advised them to build wagons with wheels, because theschoolboy has learned about wheels. The idea of a wheel is both extremely
powerful and, looking back, stunningly simple, and it leads to all sorts ofpractical advantages in life. Yet the idea was formed and developed onlywith difficulty.
Another powerful idea is the phonetic alphabet. Phonetic alphabets arecomprised of symbols that stand for sounds; by putting together severalof these symbols, one gets a symbol string that stands for the sound of areal word. Phonetic alphabets contrast with hieroglyphic writing systems,
in which pictorial characters stand for words. In many ways hieroglyphics
are a much more natural way to write, especially for someone who is justbeginning. Someone who has no knowledge of written communication

209

210 WHAT DOES THE BOX TELL US?
is much more likely to draw a picture of a dog eating a bone than towrite marks on paper in the form of «DOG EAT BONE» and then tell all
his friends that the mark resembling a half circle with a line down one
side (D) stands for the sound «duh,» the circle (O) stands for the sound«ahh,» and so on. If it were already in place, the more natural hieroglyphic
system would tend to prevent a phonetic alphabet from being adopted,
even though a phonetic system is actually simpler and much more versatile
as language becomes more complex.
In grammar school we learn that in the number 561 the digit 1 stands
for 1, but the digit 6 stands for 60, and the digit 5 stands for 500. Because ofthis little place-value trick, working with numbers becomes so simple thata child can do it. Any ten-year-old who has been properly instructed can
add 561 to 427 to get 988, and any twelve-year-old can multiply 41 by 17 toget 697. But try to add or multiply those numbers using Roman numerals!
Try to add XXIV to LXXVI to get С (without first converting the Roman
numerals to Arabic numerals). Roman numerals were used in Europe
until the Middle Ages; consequently, the vast majority of the populace
could not do the simple calculations that a modem teller or cashier can do.
Simple sums required the talents of specially trained people who earned
their living by counting.

SLOUCHING TOWARD DESIGN

The idea of intelligent design is also a simple, powerful, obvious ideathat has been sidetracked by competition from, and contamination with,extraneous ideas. From the beginning the chief competitor to a rigorous
design hypothesis has been the fuzzy feeling that if something fit our ideaof the way things ought to be, then that was evidence of design. The early
Greek philosopher Diogenes saw design in the regularity of the seasons:Such a distribution would not have been possible without Intelligence,that all things should have their measure: winter and summer and nightand day and rain and winds and periods of fine weather; other things
also, if one will study them closely, will be found to have the best possible
arrangement.1

QUESTIONS ABOUT DESIGN 211
Socrates is said to have observed:
Is it not to be admired ... that the mouth through which the food is conveyedshould be placed so near the nose and eyes as to prevent the passage
unnoticed of whatever is unfit for nourishment? And cans't thou still doubt,
Aristodemus, whether a disposition of parts like this should be the work ofchance, or of wisdom and contrivance.2

Such sentiments, although humanly understandable, are based simply
on the feeling that the world is a jolly place, and not much eke. It is not
hard to imagine that if Diogenes lived in Hawaii, where winter weather
does not come, he might easily think that the lack of seasons was «thebest possible arrangement.» If Socrates's mouth was next to his hand
we could imagine him saying that was convenient for transferring foodto the mouth. Arguments to design based on the bare assertion of their«rightness» evaporate like the morning dew when faced with the least
skepticism.
Over the course of human history, most learned folks (and even moreunlearned folks) have thought that design was evident in nature. Up until
the time of Darwin, in fact, the argument that the world was designed
was commonplace in both philosophy and science. But the intellectual
soundness of the argument was poor, probably due to lack of competition
from other ideas. The pre-Darwinian strength of the design argument
reached its zenith in the writings of the nineteenth-century Anglicanclergyman William Paley. An enthusiastic servant of his God, Paley
brought a wide scientific scholarship to bear in his writings but, ironically,
set himself up for refutation by overreaching.
The famous opening paragraph of Paley's Natural Theology shows thepower of the argument and also contains some of the flaws that led to its
later rejection:
In crossing a heath, suppose I pitched my foot against a stone, and wereasked how the stone came to be there, I might possibly answer, that forany thing I knew to the contrary it had lain there for ever; nor would it,
perhaps, be very easy to show the absurdity of this answer. But suppose
I had found a watch upon the ground, and it should be inquired how the
watch happened to be in that place, I should hardly think of the answer
which I had before given, that for any thing I knew the watch might havealways been there. Yet why should this answer not serve for the watch as

212 WHAT DOES THE BOX TELL US?
well as for the stone; why is it not as admissible in the second case as in
the first? For this reason, and for no other, namely, that when we come toinspect the watch, we perceive—what we could not discover in the stone—that its several parts are framed and put together for a purpose, e.g. thatthey are so formed and adjusted as to produce motion, and that motion
so regulated as to point out the hour of the day; that if the different parts
had been differently shaped from what they are, or placed after any othermanner or in any other order than that in which they are placed, either nomotion at all would have been carried on in the machine, or none which
would have answered the use that is now served by it. To reckon up a few
of the plainest of these parts and of their offices, all tending to one result:
We see a cylindrical box containing a coiled elastic spring, which, by its
endeavor to relax itself, turns round the box. We next observe a flexible
chain.... We then find a series of wheels.... We take notice that the wheels
are made of brass, in order to keep them from rust;... that over the face of
the watch there is placed a glass, a material employed in no other partof the work, but in the room of which, if there had been any other thana transparent substance, the hour could not be seen without opening thecase. This mechanism being observed—it requires indeed an examinationof the instrument, and perhaps some previous knowledge of the subject,
to perceive and understand it; but being once, as we have said, observed
and understood, the inference we think is inevitable, that the watch musthave had a maker—that there must have existed, at some time and at someplace or other, an artificer or artificers who formed it for the purpose which
we find it actually to answer, who comprehended its construction anddesigned its use.3

Compared with that of the Greeks, Paley's argument is improved.
Although in Natural Theology he gives many poor examples of design(akin to Diogenes and Socrates), he also frequently hits the nail on thehead. Among other things, Paley writes about discrete systems, such asmuscles, bones, and mammary glands, that he believes would cease tofunction if one of several components were missing. This is the essenceof the design argument. However, it must be emphasized for the modern
reader that, even at his best, Paley was talking about biological blackboxes: systems larger than a cell. Paley's example of a watch, in contrast, is
excellent because the watch was not a black box; its components and theirroles were known.

QUESTIONS ABOUT DESIGN 213

SIDETRACKED

Paley expresses the design argument so well that he even earns therespect of dedicated evolutionists. Richard Dawkins's The Blind Watchmaker takes its title from Paley's watch analogy but claims that evolution,rather than an intelligent agent, plays the role of the watchmaker:
Paley drives his point home with beautiful and reverent descriptions of
the dissected machinery of life, beginning with the human eye... Paley's
argument is made with passionate sincerity and is informed by the best
biological scholarship of his day, but it is wrong, gloriously and utterly
wrong...If [natural selection] can be said to play the role of watchmaker innature, it is the blind watchmaker. . . . But one thing I shall not do is belittle
the wonder of the living «watches» that so inspired Paley. On the contrary,
I shall try to illustrate my feeling that here Paley could have gone evenfurther.4

Dawkins's feeling toward Paley is that of a conqueror toward a worthy
but defeated enemy. Magnanimous in victory, the Oxford scientist canafford to pay tribute to the cleric who shared Dawkins's own concern forcomplexity in nature. Certainly Dawkins is justified in considering Paley
to be defeated; very few philosophers or scientists refer to him anymore.
Those that do, like Dawkins, do so only to dismiss rather than engage hisargument. Paley has been lumped in with earth-centered astronomy andthe phlogiston theory of burning—another loser in science's struggle toexplain the world.
But exactly where, we may ask, was Paley refuted? Who has answered hisargument? How was the watch produced without an intelligent designer?
It is surprising but true that the main argument of the discredited Paley
has actually never been refuted. Neither Darwin nor Dawkins, neither
science nor philosophy, has explained how an irreducibly complex systemsuch as a watch might be produced without a designer. Instead Paley's
argument has been sidetracked by attacks on its injudicious examples andoff-the-point theological discussions. Paley, of course, is to blame for not
framing his argument more tightly. But many of Paley's detractors are also
to blame for refusing to engage his main point, playing dumb in order toreach a more palatable conclusion.

214 WHAT DOES THE BOX TELL US?

A MIXED BAG

In Natural Theology Paley points to biological examples that, he argues,
are systems of interacting components like a watch and therefore indicate
a designer. Paley's examples are a mixed bag, ranging from the truly
astonishing to the mildly interesting to the rather silly, from mechanicalsystems to instincts to mere shapes. Almost none of his examples has been
specifically refuted by demonstrating that the features could arise without
a designer, but because for many examples Paley appeals to no principlethat would prevent incremental development, people have assumed sinceDarwin that such gradual development is possible.
Paley is at his best when writing about mechanical systems. Concerning
the heart, he observes as follows:
It is evident that it must require the interposition of valves—that thesuccess indeed of its action must depend upon these; for when any one ofits cavities contracts, the necessary tendency of the force will be to drive
the enclosed blood not only into the mouth of the artery where it ought togo, but also back again into the mouth of the vein from which it flowed...
The heart, constituted as it is, can no more work without valves that a pumpcan.5

Here he identifies a function of the system and tells the reader why
the heart requires several parts—not just a pump, but also valves. Paley is
mediocre, though, when describing instincts:
What should induce the female bird to prepare a nest before she lays her
eggs? . .. The fulness or distension which she might feel in a particular partof the body, from the growth and solidity of the egg within her, could not
possibly inform her that she was about to produce something which, when
produced, was to be preserved and taken care of... How should birds knowthat their eggs contain their young?6

The example may be interesting, but it is hard to put your finger on an
exact function in this example. Also, many of the component parts of thesystem (perhaps residing in the bird's brain) are unknown, and so it is a
black box.
Paley was probably overtired when writing about fetal development:

QUESTIONS ABOUT DESIGN 215
The eye is of no use at the time when it is formed. It is an optical instrument
made in a dungeon; constructed for the refraction of light to a focus,
and perfect for its purpose before a ray of light has had access to it... It isproviding for the future.7

In this example Paley invites us to admire simply the timing of anevent, not any feature of a particular, identified system.
Paley seems actively to invite ridicule when writing of what he calls
compensation:
The short unbending neck of the elephant is compensated by the lengthand flexibility of his proboscis...
The crane kind are to live and seek their food among the waters; yethaving no web-foot, are incapable of swimming. To make up for thisdeficiency, they are furnished with long legs for wading, or long bilk forgroping, or usually with both. This is compensation.8

Reasoning such as this can provide a rich source of comedy material(he's tall to compensate for being so ugly; she's rich to compensate for being
so dumb; and so on), but it does precious little to demonstrate design. To
be charitable, Paley may have thought that his strong examples madedesign inevitable, and he used the weak examples as icing on the cake. He
likely didn't anticipate that later opponents would refute his argument byattacking the icing.

REFUTING PALEY

Despite many of his misguided examples, Paley's famous first paragraphconcerning the watch is exactly correct—no one would deny that if you
found a watch you would immediately, and with certainty, conclude that it
had been designed. The reason for the conclusion is just as Paley implied:the ordering of separate components to accomplish a function beyond
that of the individual components. The function of the watch is to act as atimekeeping device. Its components are the various gears, springs, chains,
and the like that Paley lists.
So far, so good. But if Paley knows what to look for in his mechanicalparadigm, why did he go downhill so quickly? Because he got carried away
and started to look at the wrong features of the watch.

216 WHAT DOES THE BOX TELL US?
The problems start when Paley digresses from systems of necessarily
interacting components to talk about arrangements that simply fit his ideaof the way things ought to be. The first hint of trouble comes in Paley's
opening paragraph, when he mentions that the watch's wheels are madeof brass to prevent rust. The problem is that the exact material, brass, is
not required for the watch to function. It might help, but a watch canfunction with wheels made of almost any hard material—probably evenwood or bone. Things only get worse when Paley mentions the glass coverof the watch. Not only is the exact material not required, but the whole
component is dispensable: a cover is not| necessary for the function of thewatch. A watch cover is simply a convenience that has been attached to an
irreducibly complex system, not part of the system itself.
Throughout his book Paley strays from the feature of the watch-a system
of interacting components—that caused him to select it as an example in
the first place. As is often the case for the rest of us, too, his argument
would have been greatly improved if he had said less.
Because of his indiscretion, Paley's argument over the years has been
turned into a straw man to knock down. Instead of dealing with the realcomplexity of a system (such as a retina or a watch), some defenders of
Darwinism are satisfied with offering a story to account for peripheralfeatures. As an analogy, a Darwinian «explanation» for a watch with acover would start by assuming that a factory already was making a watch
without a cover! And then the explanation would go on to show what an
improvement a cover would be.
Poor Paley. His modern opponents feel justified in assuming enormously
complex starting points (such as a watch or a retina) if they think they canthen explain a simple improvement (such as a watch cover or curvatureof the eye). No further arguments are made; no explanation is given for
the real complexity, the irreducible complexity. The refutation of Paley's
overreaching is asserted to be a refutation of Paley's main point, even by
those who know better.

THE ARGUMENT AGAINST DESIGN

Just as the argument for intelligent design has been around a long time,arguments against design have, too. The best arguments are made byDarwin and his successors, but some arguments are older

QUESTIONS ABOUT DESIGN 217
than Darwin's theory. The philosopher David Hume argued against
design in Dialogues Concerning Natural Religion, published in 1779. In
The Blind Watchmaker Richard Dawkins recalls a dinner conversation
with «a well-known atheist» that touched on the subject:
I said that I could not imagine being an atheist at any time before 1859,
when Darwin's Origin of Species was published. 'What about Hume?',
replied the philosopher. «How did Hume explain the organized complexityof the living world?» I asked. «He didn't,» said the philosopher. «Why doesit need any special explanation?»9

Dawkins goes on to explain:
As for David Hume himself, it is sometimes said that that great Scottish
philosopher disposed of the Argument from Design a century before
Darwin. But what Hume did was criticize the logic of using apparent designin nature as positive evidence for the existence of a God. He did not offer
an alternative explanation for complex biological design.10

A modern philosopher, Elliott Sober of the University of Wisconsin, in
his book Philosophy of Biology, explains Hume's reasoning for us in moredetail:Hume believes ... we must ask how similar watches and organisms reallyare. A moment's reflection shows that they are very dissimilar. Watches
are made of glass and metal; they do not breathe, excrete, metabolize,
or reproduce... The immediate consequence, of course, is that the design
argument is a very weak analogy argument. It is preposterous to infer thatorganisms have a given property simply because watches happen to have
it.11

But Sober does not agree with Hume:
Although Hume's criticism is devastating if the design argument is anargument from analogy, I see no reason why the design argument must be
construed in this way. Paley's argument about organisms stands on its own,
regardless of whether watches and organisms happen to be similar. The
point of talking about watches is to help the reader see that the argument
about organisms is compelling.12

In other words, David Hume thought that the design argument
depended on a close similarity in accidental details of biological organisms
to other designed objects. But this line of thinking would destroy

218 WHAT DOES THE BOX TELL US?
all analogies, since any two nonidentical objects will differ in more ways
than they are similar. For example, by Hume's thinking you could not
liken a car to an airplane, even though both are transportation devices,because an airplane has wings and a car does not, and so forth. Soberrejects Hume's thinking because he says the intelligent-design argument
is really something called an inference to the best explanation. This
simply means that, given a choice between the competing explanations ofintelligent design versus unguided natural forces, Paley's argument would
seem more likely (at least, says Sober, before Darwin came along).
Sober's conclusion is fine as far as it goes, but he could also have notedthat the argument from analogy is still valid; it was just twisted out of
shape by Hume. Analogies always are set up so that they either explicitly or(more frequently) implicitly propose that A is like В in a restricted subset
of properties. Rust is like tooth decay in that they both start from small
spots and work outward, even though tooth decay takes place in living
materials, is caused by bacteria, can be inhibited by fluoride, and so on.
A Rube Goldberg machine is like the blood-clotting system in that they
are both irreducibly complex, even though they have many differences. In
order to reach a conclusion based on an analogy, it is only necessary that the
deduction flow out of the shared properties: The irreducibly complex Rube
Goldberg machine required an intelligent designer to produce it; therefore
the irreducibly complex blood-clotting system required a designer also.
Incidentally, even by Hume's criteria, the analogy between а watch
and a living organism could be made very strong. Modern biochemistry
probably could make a watch, or a time-keeping device, out of biologicalmaterials—if not now, then certainly in the near future. Many biochemicalsystems keep time, including the cells that pace the heart, the systemthat initiates puberty, and the proteins that tell the cell when to divide.
Moreover, biochemical components are known that can act as gears andflexible chains, and feedback mechanisms (which are necessary to regulate
a watch) are common in biochemistry. Hume's criticism of the design
argument that asserts a fundamental difference between mechanicalsystems and living systems is out of date, destroyed by the advance of
science which has discovered the machinery of life.
Sober continues his analysis of Hume:QUESTIONS ABOUT DESIGN 219
I now turn to Hume's second criticism of the design argument, which is no
more successful than the first. . . . [Hume] contends that if we are to havegood reason to think that the organisms in our world are the products ofintelligent design, then we must have looked at lots of other worlds andobserved intelligent designers producing organisms there.13

Hume is criticizing design as an inductive argument. An example of an
induction is the argument that because no pigs have ever been observed
to fly, pigs in all probability cannot fly. A conclusion of design based on
induction would require that we have experience of living things being
designed. Hume thinks that since we have not observed such designing in
our world, we must look to other worlds for such an experience. Since wehave no knowledge of other worlds, however, then we have no experience
to make an induction. Sober believes that Hume's argument is invalid
because, again, Sober thinks that intelligent design is actually an inference
to the best explanation, not an inductive argument.
And again Sober is right as far as he goes, but he could have gone
further. Although Hume's objection to the inductive argument might
have been valid in his day, it has been destroyed by the advance of science.
Modern biochemistry routinely designs biochemical systems, which are
now known to be the basis of life. Therefore we do have experience inobserving the intelligent design of components of life. There have probably
been tens of thousands of experiments in which new biochemical systems
were put together, and in the future there will be many, many more.
The failure of David Hume's arguments has required modern opponents
of design to advance other rationales for their views. In the remainderof the chapter I will consider the most frequently heard of the modern
arguments against design.

THE OUIJA ANALOGY

Thе philosopher friend of Richard Dawkins who thought that David
Hume refuted the argument from design was mistaken in his philosophy aswell as in his science. Elliott Sober is more successful with his philosophy,
but apparently he is unaware of relevant developments in science. Although
he thinks Hume was incorrect, Sober is unsympathetic to claims

220 WHAT DOES THE BOX TELL US?
of intelligent design because he thinks that Darwinian evolution
provides a mechanism for the production of life. He does not base his
conclusion on published models for the gradual production of irreduciblycomplex biochemical systems; he does not even consider the molecularbasis of life. Rather, he rejects design and еmbraces Darwinism based
primarily (and ironically) on an analogy. He explains in Philosophy ofBiology:
The fact that the mutation-selection process has two parts ... is brought
vividly by Richard Dawkins in his book The Blind Watchmaker. Imagine a
device that is something like a combination lock. It is composed of a seriesof disks placed side by side. On the edge of each disk, the twenty-six lettersof the alphabet appear. The disks can be spun separately so that different
sequences of letters may appear in the viewing window.
How many different combinations of letters may appear in the window?
There are 26 possibilities on each disk and 19 disks in all. So there are 2619
different possible sequences. One of these is METHINKSITISAWEASEL...
The probability that METHINKSITISAWEASEL will appear after all thedisks are spun is 1/2619, which is a very small number indeed...
But now imagine that a disk is frozen if it happens to put a letter in theviewing window that matches the one in the target message. The remaining
disks that do not match the target then are spun at random, and the process
is repeated. What is the chance now that the disks will display the message
METHINKSITISAWEASEL after, say, fifty repetitions?
The answer is that the message can be expected to appear after asurprisingly small number of generations of the process...
Variation is generated at random, but selection among variants isnonrandom.14

This analogy is intended to illuminate how complex biological systems
might have been produced. So we are asked to conclude, based on thespinning-disk analogy, that the cilium evolved step-by-step, that the initialsteps in vision could be produced gradually, and so forth. The analogy
is offered in lieu of actual evidence that these or other complex systems
could have evolved in a Darwinian fashion. And Sober thinks the analogy
is so compelling that, based on it, Darwinian evolution now wins as theinference to the best explanation. Dawkins' analogy (which is slightly
different in details in his book versus Sober's rendition), though

QUESTIONS ABOUT DESIGN 221
transparently false, appears to have captured the imagination of some
philosophers of biology. Besides Sober, Michael Ruse has used a similar
example in his book Darwinism Defended, as has Daniel Dennett in
Darwin's Dangerous Idea.
What is wrong with the Dawkins-Sober analogy? Only everything. It
purports to be an analogy for natural selection, which requires a function
to select. But what function is there in a lock combination that is wrong?
Suppose that after spinning the disks for a while, we had half of the lettersright, something like MDTUIFKQINIOAFERSCL (every other letter iscorrect). The analogy asserts that this is an improvement over a random
string of letters, and that it would somehow help us open the combination
lock. But if your life depended on opening a lock that had the combination
METHINKSITISAWEASEL, and you tried MDTUIFKQINIOAFERSCL,
you would be pushing up daisies. If your reproductive success dependedon opening the lock, you would leave no offspring. Ironically for Sober andDawkins, a lock combination is a highly specified, irreducibly complex
system that beautifully illustrates why, for such systems, function cannot
be approached gradually.
Evolution, we are told by proponents of the theory, is not goal directed.
But then, if we start from a random string of letters, why do we end up withMETHINKSITISAWEASEL instead of MYDARLINGCLEMENTlNE or
MEBETARZANYOUBEJANE? As a disk turns, who is deciding which
letters to freeze and why? Instead of an analogy for natural selection acting
on random mutation, the Dawkins-Sober scenario is actually an exampleof the very opposite: an intelligent agent directing the construction of anirreducibly complex system. The agent (Sober here) has the target phrase(lock combination) in his mind and guides the result in that direction as
surely as a fortune-teller guides a Ouija board. This hardly seems like asecure foundation upon which to build a philosophy of biology.
The fatal problems with the analogy are not difficult to see. It was
amusingly skewered by Robert Shapiro, a professor of chemistry at New
York University, in his book Origins: A Skeptic's Guide to the Origin oflife, which was published seven years before Sober s book.15 The fact thata distinguished philosopher overlooks simple logical problems that areeasily seen by a chemist suggests that a sabbatical visit to a biochemistrylaboratory might be in order.

222 WHAT DOES THE BOX TELL US?

A HOLE IN THE EYEIn discussions about intelligent design, no objection is more frequently repeated than the argument from imperfection. It can be briefly
summarized: If there exists an intelligent agent who designed life on earth,then it would have been capable of making life that contained no apparent
flaws; furthermore, it would have done so. The argument seems to have ameasure of popular appeal. However, it is just the flip side of Diogenes's
argument: because something does not fit our idea of the way things ought
to be, then that is evidence against design.
The argument has been echoed by prominent scientists and philosophers,
but it is particularly well presented by Kennet Miller, a professor of biology
at Brown University :Another way to respond to the theory of intelligent design is to carefully
examine complex biological systems for errors that no intelligent designer
would have committed. Because intelligent design works from a clean, sheetof paper, it should produce organisms that have been optimally designed
for the tasks they perform. Conversely, because evolution is confined tomodifying existing structures, it should not necessarily perfection. Whichis it?
The eye, that supposed paragon of intelligent design, offers an answer.
We have already sung the virtues of this extraordinary organ, but we havenot considered specific aspects of its design, such as the neural wiring of
its light-sensing units. These photoreceptor cells, located in the retina,pass impulses to a series of interconnecting cells that eventually pass
information to the cells of the optic nerve, which leads to the brain.
An intelligent designer, working with the components of this wiring,
would choose the orientation that produces the highest degree of visualquality. No one, for example, would suggest that the neural connections
should be placed in front of the photoreceptor cells—thus blocking thelight from reaching them—rather than behind the retina.
Incredibly, this is exactly how the human retina is constructed...
A more serious flaw occurs because the neural wiring must poke directly
through the wall of the retina to carry the nerve impulses produced byphotoreceptor cells to the brain. The result is a blind spot in the retina—aregion where thousands of impulse-carrying cells have pushed the sensory
cells aside....

QUESTIONS ABOUT DESIGN 223
None of this should be taken to suggest that the eye functions poorly. It is asuperb visual instrument that serves us exceedingly well... The key to theintelligent design theory ... is not whether an organ or system works well
but whether its basic structural plan is the obvious product of design. The
structural plan of the eye is not.16

Miller elegantly expresses a basic confusion; the key to intelligentdesign theory is not whether a «basic structural plan is the obvious
product of design.» The conclusion of intelligent design for physicallyinteracting systems rests on the observation of highly specified, irreducible
complexity—the ordering of separate, well-fitted components to achievea function that is beyond any of the components themselves. Although
I emphasize that one has to examine molecular systems for evidence ofdesign, let's use Miller's essay as a springboard to examine other problems
with the argument from imperfection.
The most basic problem is that the argument demands perfection atall. Clearly, designers who have the ability to make better designs do notnecessarily do so. For example, in manufacturing, «built-in obsolescence»is not uncommon—a product is intentionally made so it will not last as
long as it might, for reasons that supersede the simple goal of engineering
excellence. Another example is a personal one: I do not give my children
the best, fanciest toys because I don't want to spoil them, and because I
want them to learn the value of a dollar. The argument from imperfection
overlooks the possibility that the designer might have multiple motives,with engineering excellence oftentimes relegated to a secondary role. Most
people throughout history have thought that life was designed despite
sickness, death, and other obvious imperfections.
Another problem with the argument from imperfection is that it
critically depends on a psychoanalysis of the unidentified designer. Yet
the reasons that a designer would or would not do anything are virtually
impossible to know unless the designer tells you specifically what thosereasons are. One only has to go into a modern art gallery to come acrossdesigned objects for which the purposes are completely obscure (to me atleast). Features that strike us as odd in a design might have been placed
there by the designer for a reason—for artistic reasons, for variety, to show
off, for some as-yet-undetected practical purpose, or for some unguessable
reason—or they might not. Odd they may be, but they may still be			224 WHAT DOES THE BOX TELL US?
designed by an intelligence. The point of scientific interest is not theinternal mental state of the designer but whether one can detect design.
In discussing why aliens on other planets might build artificial structuresthat we could observe from earth, the physicist Freeman Dyson wrote:
I do not need to discuss questions of motivation, who would want to dothese things or why. Why does the human species explode hydrogenbombs or send rockets to the moon? It is difficult to say exactly why.17

When considering whether aliens would try to seed other planets withlife, Francis Crick and Leslie Orgel wrote:
The psychology of extraterrestrial societies is no better understood thanterrestrial psychology. It is entirely possible that extraterrestrial societies
might infect other planets for quite different reasons than those we havesuggested.18

In their writings, these authors correctly concluded that design could
be detected in the absence of information about the designer's motives.
The next problem is that proponents of the argument from imperfection
frequently use their psychological evaluation of the designer as positive
evidence for undirected evolution. The reasoning can be written as asyllogism:
1. A designer would have made the vertebrate eye without a blind spot.
2. The vertebrate eye has a blind spot.
3. Therefore Darwinian evolution produced the eye.
It is for reasoning such as this that the phrase non sequitur was invented.
The scientific literature contains no evidence that natural selection working
on mutation can produce either an eye with a blind spot, an eye withouta blind spot, an eyelid, a lens, a retina, rhodopsin, or retinal. The debater
has reached his conclusion in favor of Darwinism based solely on anemotional feeling of the way things ought to be. A more objective observer
would conclude only that the vertebrate eye was not designed by a person
who is impressed with the argument from imperfection; extrapolation toother intelligent agents is not possible.

QUESTIONS ABOUT DESIGN 225
Ken Miller's article was not written for Reader's Digest, but for Technology
Review. The readership is technically sophisticated, able to handle abstractscientific concepts, and used to following difficult arguments to solid
conclusions. The fact that he offers these readers an argument basedon psychology and emotion, instead of hard science, gives the opposite
message than he intends about the relative strengths of intelligent design
versus evolution.

WHAT DOES IT DO?

There is a subcategory of the no-designer-would-have-done-it-thisway argument that requires a different response. Instead of saying thata useful structure contains flaws that should not have been allowed, thewriter points to some feature that has nо apparent use at all. Often thefeature resembles something that is actually used in other species, and so
appears to be something that was in fact used at one time but then lostits function. Vestigial organs play a prominent role in this argument. For
example, evolutionary biologist Douglas Futuyma cites the «rudimentaryeyes of cave animals; the tiny, useless legs of many snakelike lizards;[and] the vestiges of the pelvis in pythons» as evidence that evolution
has occurred.19 Since I'm a biochemist, I prefer molecular versions of thisargument. Ken Miller talks about the several genes that produce different
forms of hemoglobin in humans:
Are the five genes of this complex the elegant products of design, or a seriesof mistakes of which evolution took advantage? The cluster itself, or more
specifically a sixth β-globin gene in the cluster; provides the answer. This
gene is . . . nearly identical to that of the other five genes. Oddly, however,this gene . . . plays no role in producing hemoglobin. Biologists call suchregions «pseudogenes,» reflecting the fact that however much they may
resemble working genes, in fact they are not.20

Miller tells the readers that the pseudogene lacks the proper signals to
inform the rest of the cell's machinery to make a protein from it. He thenconcludes as follows:
The theory of intelligent design cannot explain the presence ofnonfunctional pseudogenes unless it is willing to allow that the designer
made serious errors, wasting millions of bases of DNA on a blueprint full ofjunk and scribbles. Evolution, in contrast, can easily

226 WHAT DOES THE BOX TELL US?
explain them as nothing more than failed experiments in a random
process of gene duplication that persist in the genome as evolutionary
remnants.21
This argument is unconvincing for three reasons. First, because wehave not yet discovered a use for a structure does not mean that no use
exists. The tonsils were once considered to be useless organs, but animportant function in immunity has been discovered for them. A python
pelvis might be doing something useful of which we are ignorant. This
point also applies on the molecular scale; hemoglobin pseudogenes andother pseudogenes, although they are not used to make proteins, may
be used for other things that we don't know about. A couple of potential
uses that spring to mind as I sit here at my desk include bonding to active
hemoglobin genes during DNA replication in order to stabilize the DNA;
guiding DNA recombination events; and aligning protein factors relative tothe active genes. Whether any of these are actual duties of the pseudogene
for hemoglobin does not matter. The point here is that Miller's assertion
rests on assumptions only.
The second reason why Miller's argument fails to persuade is that evenif pseudogenes have no function, evolution has «explained» nothing about
how pseudogenes arose. In order to make even a pseudo-copy of a gene,a dozen sophisticated proteins are required: to pry apart the two DNA
strands, to align the copying machinery at the right place, to stitch thenucleotides together into a string, to insert the pseudocopy back into theDNA, and much more. In his article Miller has not told us how any ofthese functions might have arisen in a Darwinian step-by-step process,nor has he pointed to articles in the scientific literature where we can findthe information. He can't do that, because the information is nowhere to
be found.
Folks such as Douglas Futuyma, who cite vestigial organs as evidenceof evolution, have the same problem. Futuyma never explains how a real
pelvis or eye developed in the first place, so as to be able to give rise to avestigial organ later on, yet both the functioning organ and the vestigialorgan require explanation. I do not purport to understand everything
about design or evolution—far from it; I just cannot ignore the evidence
for design. If I insert a letter into a photocopier, for instance, and it makes
a dozen good copies and one copy that has a

QUESTIONS ABOUT DESIGN 227
couple of large smears on it, I would be wrong to use the smeared copy
as evidence that the photocopier arose by chance.
Arguments based on perceived faults or vestigial genes and organs
run the danger of the argument of Diogenes that the progression ofseasons shows intelligent design. It is scientifically unsound to make any
assumptions of the way things ought to be.

LONG, LONG TIME AGO

The third reason why Miller's argument misses the mark is actuallyquite understandable. It arises from the confusion of two separate ideas—
the theory that life was intelligently designed and the theory that the earth
is young. Because religious groups who strongly advocate both ideas havebeen in the headlines over the past several decades, much of the public
thinks that the two ideas are necessarily linked. Implicit in Ken Miller's
argument about pseudogenes, and absolutely required for his conclusions,is the idea that the designer had to have made life recently. That is not apart of intelligent-design theory. The conclusion that some features of life
were designed can be made in the absence of knowledge about when thedesigning took place. A child who looks at the faces on Mt. Rushmore
immediately knows that they were designed but might have no idea of
their history; for all she knows, the faces might have been designed the
day before she got there, or might have been there since the beginning oftime. An an museum might display a statue of a bronze cat purportedly
made in Egypt thousands of years ago—until the statue is examined bytechnologically advanced methods and shown to be a modern forgery. In
either case, though, the bronze cat was certainly designed by an intelligent
agent.
The irreducibly complex biochemical systems that I have discussed
in this book did not have to be produced recently. It is entirely possible,
based simply on an examination of the systems themselves, that they were
designed billions of years ago and that they have been passed down tothe present by the normal processes of cellular reproduction. Perhaps a
speculative scenario will illustrate the point. Suppose that nearly fourbillion years ago the designer made the first cell, already containing allof the irreducibly complex biochemical systems discussed here and manyothers. (One can postulate that the designs for systems that were228 WHAT DOES THE BOX TELL US?
to be used later, such as blood clotting, were present but not «turned
on.» In present-day organisms plenty of genes are turned off for a while,sometimes for generations, to be turned on at a later time.) Additionally,
suppose the designer placed into the cell some other systems for which, wecannot adduce enough evidence to conclude design. The cell containing thedesigned systems then was left on autopilot to reproduce, mutate, eat andbe eaten, bump against rocks, and suffer all the vagaries of life on earth.
During this process, pace Ken Miller, pseudogenes might occasionallyarise and a complex organ might become nonfunctional. These chance
events do not mean that the initial biochemical systems were not designed.
The cellular warts and wrinkles that Miller takes as evidence of evolution
may simply be evidence of age.
Simple ideas can take a surprising amount of time to be properly
developed. One way in which a simple idea can be sidetracked is throughconflation with an extraneous idea. When it is considered by itself—away
from logically unrelated ideas—the theory of intelligent design is seen to
be quite robust, easily answering the argument from imperfection.

A COMPLICATED WORLD

The production of some biological improvements by mutation andnatural selection—by evolution—is quite compatible with intelligent
design theory. Stephen Jay Gould of Harvard University has made muchof the panda's «thumb.»The giant panda lives on a diet of bamboo. To strip
the leaves off bamboo shoots the panda grips them in its paw with a bonyprotuberance that emanates from its wrist; the normal five digits are alsopresent. Gould argues that a designer would have given the panda a real
opposable thumb, and so he concludes that the panda's thumb evolved.
Gould's conclusion, though, suffers from the problems I have discussed
earlier. He assumes the designer would act as he would, that pandas' thumbs«ought» to be arranged a different way. He then takes those assertions
to be positive evidence for evolution. Gould has never done the science
to support his idea: he has not shown or calculated what the minimum
extension of the wristbone would have to be to help the panda; he has notjustified the behavioral changes that would be necessary to take ad-

QUESTIONS ABOUT DESIGN 229
vantage of the change in bone structure; and he has not mentioned how
pandas ate before acquiring the thumb. He has not done anything except
to spin a tale.
But let's ignore those questions for now; let's assume that the story
actually happened. Even then, why is Gould's panda scenario incompatible
with intelligent-design theory? The panda's thumb is a black box. It is
entirely possible that in the production of the panda's thumb, no newirreducibly complex systems were required in the cell. It is possible that thesystems that were already present—the systems that make muscle proteinsand nerve fibers, that lay down bone and matrix protein, that cause cells
to divide for a while and then cease division— were enough. It is possiblethat these systems were quite sufficient to cause a bone protuberance whensome chance event perturbed their normal pattern of operation, and it
is possible that natural selection then favored this change. Design theory
has nothing to say about a biochemical or biological system unless all
the components of the system are known and it is demonstrated that thesystem is composed of several interacting parts. Intelligent-design theory
can coexist quite peacefully with the panda's thumb.
We live in a complex world where lots of different things can happen.
When deciding how various rocks came to be shaped the way theуare, a geologist might consider a whole range of factors: rain, wind, themovement of glaciers, the activity of moss and lichens, volcanic action,
nuclear explosions, asteroid impact, or the hand of a sculptor. The shapeof one rock might have been determined primarily by one mechanism,
the shape of another rock by another mechanism. The possibility of ameteor's impact does not mean that volcanos can be ignored; the existenceof sculptors does not mean that many rocks are not shaped by weather.
Similarly, evolutionary biologists have recognized that a number of factors
might have affected the development of life: common descent, natural
selection, migration, population size, founder effects (effects that may
be due to the limited number of organisms that begin a new species),
genetic drift (the spread of «neutral,» nonselective mutations), gene flow(the incorporation of genes into a population from a separate population),
linkage (occurrence of two genes on the same chromosome), meiotic drive(the preferential selection during sex cell production of one of the twocopies of a gene inherited from an organism's parents), transposition (thetransfer of a gene between widely separated species by nonsexual

230 WHAT DOES THE BOX TELL US?
means), and much more. The fact that some biochemical systems may
have been designed by an intelligent agent does not mean that any of theother factors are not operative, common, or important.

WHAT WILL SCIENCE DO?

The discovery of design expands the number of factors that must be
considered by science when trying to explain life. What will be the effectof the awareness of intelligent design on different branches of science?
Biologists who are working at the cellular level or above can continue
their research without paying much attention to design, because above thecellular level organisms are black boxes, and design is difficult to prove.
So those who labor in the fields of paleontology, comparative anatomy,
population genetics, and biogeography should not invoke design until themolecular sciences show that design has an effect at those higher levels.
Of course, the possibility of design should cause researchers in biology
to hesitate before claiming that a particular biological feature has been
produced substantially by another mechanism, such as natural selection
or transposition. Instead, detailed models should be produced to justify
the assertion that a given mechanism produced a given biological feature.
Unlike Darwinian evolution, the theory of intelligent design is new tomodern science, so there are a host of questions that need to be answered
and much work lies ahead. For those who work at the molecular level, thechallenge will be to rigorously determine which systems were designed andwhich might have arisen by other mechanisms. To reach a conclusion ofdesign will require the identification of the components of an interacting
molecular system and the roles they play, as well as a determination that thesystem is not a composite of several separable systems. To reach a strong
presumption of nondesign will require the demonstration that a system
is not irreducibly complex or does not have much specificity between
its components. To decide borderline cases of design will require theexperimental or theoretical exploration of models whereby a system might
have developed in a continuous manner, or a demonstration of points
where the development of the system would necessarily be discontinuous.
Future research could take several directions. Work could be under-QUESTIONS ABOUT DESIGN 231
taken to determine whether information for designed systems could
lie dormant for long periods of time, or whether the information would
have to be added close to the time when the system became operational.
Since the simplest possible design scenario posits a single cell—formed
billions of years ago—that already contained all information to produce
descendant organisms, other studies could test this scenario by attempting
to calculate how much DNA would be required to code the information(keeping in mind that much of the information might be implicit). If DNA
alone is insufficient, studies could be initiated to see if information could
be stored in the cell in other ways—for example, as positional information.
Other work could focus on whether larger, compound systems (containing
two or more irreducibly complex systems) could have developed graduallyor whether there are compounded irreducibilities.
The preceding are just the obvious questions that flow from a theory ofdesign. Undoubtedly, more and better-formed questions will be generated
as more and more scientists grow curious about design. The theory ofintelligent design promises to reinvigorate a field of science grown stalefrom a lack of viable solutions to dead-end problems. The intellectual
competition created by the discovery of design will bring sharper analysis
to the professional scientific literature and will require that assertions bebacked by hard data. The theory will spark experimental approaches andnew hypotheses that would otherwise be untried. A rigorous theory ofintelligent design will be a useful tool for the advancement of science in anarea that has been moribund for decades.

CHAPTER 11

SCIENCE, PHILOSOPHY, RELIGION

THE DILEMMA

Over the past four decades modem biochemistry has uncovered thesecrets of the cell. The progress has been hard won. It has required tens of
thousands of people to dedicate the better parts of their lives to the tediouswork of the laboratory. Graduate students in untied tennis shoes scraping
around the lab late on Saturday night; postdoctoral associates working
fourteen hours a day seven days a week; professors ignoring their children
in order to polish and repolish grant proposals, hoping to shake a little
money loose from politicians with larger constituencies to feed—these are
the people that make scientific research move forward. The knowledge we
now have of life at the molecular level has been stitched together frominnumerable experiments in which proteins were purified, genes cloned,
electron micrographs taken, cells cultured, structures determined,
sequences compared, parameters varied, and controls done. Papers were
published, results checked, reviews written, blind alleys searched, and newleads fleshed out.
The result of these cumulative efforts to investigate the cell—toinvestigate life at the molecular level—is a loud, clear, piercing cry of«design!» The result is so unambiguous and so significant that it must232

SCIENCE, PHILOSOPHY, RELIGION 233
be ranked as one of the greatest achievements in the history ofscience. The discovery rivals those of Newton and Einstein, Lavoisierand SchrÖdinger, Pasteur, and Darwin. The observation of the intelligent
design of life is as momentous as the observation that the earth goesaround the sun or that disease is caused by bacteria or that radiation isemitted in quanta. The magnitude of the victory, gained at such great costthrough sustained effort over the course of decades, would be expected tosend champagne corks flying in labs around the world. This triumph ofscience should evoke cries of «Eureka!» from ten thousand throats, shouldoccasion much hand-slapping and high-fiving, and perhaps even be an
excuse to take a day off.
But no bottles have been uncorked, no hands slapped. Instead, acurious, embarrassed silence surrounds the stark complexity of the cell.
When the subject comes up in public, feet start to shuffle, and breathing
gets a bit labored. In private people are a bit more relaxed; many explicitly
admit the obvious but then stare at the ground, shake their heads, and let
it go at that.
Why does the scientific community not greedily embrace its startling
discovery? Why is the observation of design handled with intellectual
gloves? The dilemma is that while one side of the elephant is labeledintelligent design, the other side might be labeled God.
A non-scientist might ask the obvious question: so what? The idea thata being such as God exists is not unpopular—far from it. Polls show that
more than 90 percent of Americans believe in God, and that about halfattend religious services regularly. Politicians invoke the name of God withgreat regularity (more often around election time). Many football coaches
pray with their teams before games, musicians compose hymns, artists
paint pictures of religious events, organizations of businessmen gather
for prayers. Hospitals and airports have chapels; the army and Congress
employ chaplains. As a country we honor people, such as Martin LutherKing, whose actions were deeply rooted in a belief in God. With all of thispublic affirmation, why should science find it difficult to accept a theory
that supports what most people believe anyway? There are several reasons.
The first is a problem that many of us are prone to—simple chauvinism.
The other reasons depend on historical and philosophical relationshipsthat are peculiar to science. These various reasons all interact with one
another in complex ways, but let's try to tease them apart.

234 WHAT DOES THE BOX TELL US?

ALLEGIANCE

People who dedicate their lives to a noble pursuit often become fiercely
loyal to it. For example, a college president may devote all her efforts tostrengthening her school, because educating people is an estimable service.
A career army officer will work to improve his branch of the service, because
defending one's country is a worthy purpose. Sometimes, however, loyalty
to a particular institution causes a conflict of interest with the purpose theinstitution serves. The officer might rush his troops into battle so that thearmy will be credited with victory, even though it might be prudent to let
the air force see the first action. The college president might persuade herstate's congressmen to earmark federal money for a new building on her
campus, even though the money might serve education better elsewhere.
Science is a noble pursuit that can engender fierce loyalty. The purposeof science is to explain the physical world—a very serious enterprise.
However, other academic disciplines (principally philosophy and theology)
also are in the business of explaining parts of the world. Although mostof the time these disciplines stay out of each other's way, sometimes they
conflict. When that happens some dedicated people put their discipline
ahead of the goal it is supposed to serve.
A good example of disciplinary chauvinism can be seen in Robert
Shapiro's fine book, Origins: A Skeptic's Guide to the Creation of Lifeon Earth. After presenting a very readable, very devastating critique ofscientific studies on the origin of life, Shapiro proclaims his steadfast
loyalty—not to the goal of «explaining the physical world,» but to science:
Some future day may yet arrive when all reasonable chemical experiments
run to discover a probable origin for life have failed unequivocally. Further,
new geological evidence may indicate a sudden appearance of life on theearth. Finally, we may have explored the universe and found no trace oflife, or process leading to life, elsewhere. In such a case, some scientists
might choose to turn to religion for an answer. Others, however, myself
included, would attempt to sort out the surviving less probable scientificexplanations in the hope of selecting one that was still more likely than theremainder.1

Shapiro goes on gamely to say that things don't look quite so bleak rightnow, pretty much contradicting everything he had written to that point.

SCIENCE, PHILOSOPHY, RELIGION 235
He can rest secure in the knowledge that there will never be a time
when all experiments have «failed unequivocally,» just as there will never
be a time when the existence of the Loch Ness Monster has been absolutely
ruled out. And the time when the universe will have been fully explored is
comfortably far off.
Now, a nonpartisan might think that if none of the most likely
scientific hypotheses panned out, then maybe a fundamentally different
explanation is called for. After all, the origin of life was an historicalevent—not like, say, the search for a cancer cure, where science can keep
trying till it succeeds. Maybe the origin of life just didn't happen by
undirected chemical reactions, as Shapiro hopes. To an active participant
in the search, however, a conclusion of design can be deeply unsatisfying.
The thought that knowledge of the mechanisms used to produce life
might be forever beyond their rearch is admittedly frustrating to many
scientists. Nonetheless, we must be careful not to allow dictate for a theory
to prejudice us against a fair reading of the data.
Loyalty to an institution is fine, but bare loyalty is not an argument. All
in all, the effect of scientific chauvinism on theories of the developmentof life is an important sociological artifact to consider, but ultimately its
intellectual importance for the topic of intelligent design is nil.

HISTORY LESSON

The second reason for the reluctance of science to deal with the elephantcomes from history. From the time it was first proposed, some scientists
have clashed with some theologians over Darwin's theory of evolution.
Although many scientists and theologians thought that Darwinianevolution could be reconciled rather easily with the basic beliefs of mostreligions, publicity always focuses on conflict. The tone was probably set forgood when Anglican bishop Samuel Wilberforce debated Thomas Henry
Huxley, a scientist and strong advocate of evolution, about a year after
Darwin's seminal book was published. It was reported that the bishop—agood theologian but poor biologist— ended his speech by asking, «I beg
to know, is it through his grandfather or grandmother that Huxley claims
his descent from a monkey?» Huxley muttered something like, «The Lord
has delivered him into my hands,» and proceeded to give the audience236 WHAT DOES THE BOX TELL US?
and the bishop an erudite biology lesson. At the end of his exposition
Huxley declared that he didn't know whether it was through his
grandmother or grandfather that he was related to an ape, but that hewould rather be descended from simians than be a man possessed of thegift of reason and see it used as the bishop had used it that day. Ladies
fainted, scientists cheered, and reporters ran to print the headline: «War
Between Science and Theology.»
The event in America that defined the public perception of therelationship of science to theology was the Scopes trial. In 1925 John
Scopes, a high school biology teacher in the tiny town of Dayton,
Tennessee, volunteered to be arrested for violating a previously unenforced
state law forbidding the teaching of evolution. The involvement of highprofile lawyer Clarence Darrow for the defense and three-time losing
presidential candidate William Jennings Bryan for the prosecution
guaranteed the media circus that ensued. Although Scopes's team lost attrial, his conviction was overturned on a technicality. More importantly,
the publicity set a tone of antagonism between religion and science.
The Scopes trial and the Huxley-Wilberforce debate happened long
ago, but more recent events have kept the conflict simmering. Overthe past several decades groups that, for religious reasons, believe thatthe earth is relatively young (on the order of ten thousand years) have
tried to have their viewpoint taught to their children in public schools.
The sociological and political factors involved in the situation are quite
complex—a powerful mix of such potentially divisive topics as religious
freedom, parental rights, government control of education, and stateversus federal rights—and are made all the more emotional because thefight is over children.
Because the age of the earth can be inferred from physical measurements,
many scientists quite naturally felt that the religious groups had entered
their area of expertise and called them to account. When the groups offered
physical evidence that they said supported a young earth, scientists hooted
it down as incompetent and biased. Tempers flared on both sides, andmuch ill will was built up. Some of the ill will has been institutionalized;
for example, an organization called the National Center for Science
Education was set up a dozen years ago—when several states were passing
laws congenial to creationism—battle creationists whenever they try toSCIENCE, PHILOSOPHY, RELIGION 237
influence public school policy.
These conflicts reverberate into the present. In 1990 Scientific American
asked a science writer named Forrest Mims to write several columns forthe «Amateur Scientist» feature of their magazine. «Amateur Scientist»
treats topics such as measuring the length of lightning bolts, building
portable solar observatories, and making a home seismometer to record
earth movements—fun projects for those whose hobby is science. The
understanding was that if the editors and readers liked the columns, Mims
would be hired as a permanent writer. The trial columns all went very well,
but when Mims came to New York for a final interview he was asked if hebelieved in evolution. Mims replied, well, no, he believed in the biblicalaccount of creation.
The magazine refused to hire him. Scientific American was afraidthat merely having a creationist on the staff would hurt its reputation
among scientists, even though Mims was well qualified and had no plansto write about evolution. Undoubtedly scenes from Inherit the Wind
(the movie based loosely on the Scopes trial) and news clips of battles
between creationists and their political foes flickered through the mindsof the magazine's editors. Such widely reported mini-conflicts as theMims affair—even though they have nothing directly to do with the real
intellectual issues about how life on earth came to be—fuel the historicalflames of conflict between science and religion, and persuade many people
that you must belong to one camp or to the other.
The historical events in which scientists have clashed with religious
groups are real and cause real emotional reactions. They make some wellmeaning people think that a demilitarized zone should be maintained
between the two, with no fraternization allowed. Like scientificchauvinism, however, the importance of the historical clashes for actual
scientific understanding of the development of life is essentially zero. I
am not naively hoping that biochemistry's discoveries can be evaluatedfree from the shadows of history, but to the greatest extent possible, theyshould be.
Unlike chauvinist and historical arguments, philosophical argumentsthat seek to head off a conclusion of intelligent design are substantive; theyaffect the issues on an intellectual level, not just an emotional one. There
are several different philosophical issues. Let's examine them.

238 WHAT DOES THE BOX TELL US?

THE RULE

Richard Dickerson is a prominent biochemist, an elected memberof the elite National Academy of Sciences who specializes in X-ray
crystallography studies of proteins and DNA. He and the workers in hislaboratory have made notable contributions to our understanding of thestructure of the molecules of life. He is not the most prominent scientist
in the United States, and his contributions have not been the flashiest, but
Dickerson is in many ways the paradigm of a dedicated scientist. He is thesort of person, and his the sort of professional situation, that thousandsof graduate students have in mind as they labor day and night in thelaboratory, dreaming of the day when they too will be respected membersof the scientific community.
Dickerson's published opinions nicely capture the way many scientists
view the world of religion. A few years ago Dickerson wrote a short essay
summarizing his views on science vis-a-vis religion and had the essay
published in both the Journal of Molecular Evolution (a secular scientificjournal) and Perspectives on Science and Christian Faith (a journal
published by the American Scientific Affiliation, which is an organizationof scientists who are also evangelical Christians). So it is safe to conclude
that Dickerson was not just directing his remarks to people who alreadyshared his ideas—he was making an honest effort to present what hethought were reasonable and convincing views to persons with diverging
opinions. Because of its consonance with most scientists' view of science,
Dickerson's essay makes a useful springboard for considering how thetheory of intelligent design fits into science:
Science, fundamentally, is a game. It is a game with one overriding anddefining rule:
Rule No. 1: Let us see how far and to what extent we can explain the
behavior of the physical and material universe in terms of purely physicaland material causes, without invoking the supernatural.
Operational science takes no position about the existence ornonexistence of the supernatural; it only requires that this factor is not to be
invoked in scientific explanations. Calling down special-purpose miracles
as explanations constitutes a form of intellectual «cheating.» A chess player
is perfectly capable of removing his opponent's King physically from theboard and smashing it in the midst of a tournament. But this would not

SCIENCE, PHILOSOPHY, RELIGION 239
make him a chess champion, because the rules had not been followed.
A runner may be tempted to take a short-cut across the infield of an oval
track in order to cross the finish line ahead of his faster colleague. But herefrains from doing so, as this would not constitute «winning» under therules of the sport.2

Let's rephrase Dickerson's rule to the following: Science must invoke
only natural causes, and explain by reference only to natural law.3 The
reformulation makes explicit what is strongly implied by the phrase «letus see how far.»
In his essay, then, Dickerson does not say scientific evidence has shownthat the supernatural has never affected nature (for those concerned about
the definition of supernatural, substitute «higher intelligence»). Rather, heargues that in principle, science should not invoke it. The clear implicationis that it should not be invoked whether it is true or not. It is relevant to ourevaluation of his argument that Dickerson is a member of the American
Scientific Affiliation, so he believes in God. He has no a priori reason
to think that nothing beyond nature exists, but he thinks it is not goodscience to offer the supernatural as an explanation for a natural event.
(Incidentally, scientists who believe in God or a reality beyond nature
are much more common than popular media stories lead one to believe—
there is no reason to think that the figure of 90 percent of the general
population that believes in God is much different for scientists. Ken Miller,
whose argument from imperfection I analyzed in the last chapter, is likemyself a Roman Catholic, and he makes the point in public talks that
belief in evolution is quite compatible with his religious views. I agree with
him that they are compatible.4 The compatibility or lack of compatibility,
however, is irrelevant to the scientific question of whether Darwinianevolution of biochemical systems is true.)
It is important to note that Dickerson's argument is not itself a scientific
one—it was not discovered by an experiment in a laboratory; it is not theresult of mixing chemicals in a test tube; it is not a testable hypothesis.
Rather, the argument is philosophy. It may be good philosophy, or it may
not. Let's examine it more closely.
Most people would be surprised to learn that «science, fundamentally,
is a game.» Certainly the taxpayers who fund science to the tune240 WHAT DOES THE BOX TELL US?
of several tens of billions of dollars a year would be surprised. They
probably think they're spending their money to find cures and treatments
for cancer, AIDS, and heart disease. Citizens concerned about diseases
they have or may acquire in old age want science to be able to cure thedisease, not to play a game that has no bearing on reality. I doubt thatDarwin or Newton or Einstein thought of science this way. The giantsof science were motivated by a thirst to know the real world, and some(such as Galileo) paid a price for their knowledge. For students, science
textbooks do not present science as a game but as a noble search for truth.
Most people, from ordinary taxpayers to prominent scientists, would more
likely view science not as a game but as a vigorous attempt to make true
statements about the physical world.
The assertion that science is a game does not stand up to even a cursory
examination. No one would seriously maintain that position very long ifquestioned about it. Richard Dickerson himself would probably quickly
retract his statement if he had to defend it in front of a skeptical audience.
Clearly Dickerson has something else in mind. Perhaps he means thatscience, like games, is a rule-bound activity. Other serious activities,
like criminal trials and political campaigns, are rule-bound activities. Is
science also? If so, what are the rules?
Let's focus on the second question. Dickerson mentions just one rule,the one disbarring the supernatural. Where did he get it? Is it written ina textbook? Is it found in the by-laws of scientific societies? No, of coursenot. You can scan all the textbooks that are used for science instruction
in all of the major universities of this country, and you will not see the«one overriding and defining rule.» Nor will you see any other generalrules proscribing how science is to be conducted (other than safety rules,
exhortations to honesty, and the like).
Nonetheless, let us ask, how does Dickerson's rule help? Does the ruletell us what subjects are beyond science's competence? Does it give us
guidelines for discriminating science from pseudo science? Does it evengive a definition of what science is? The answer to all of these questions
is no. A few years ago an article by a Nobel laureate was published in aprestigious scientific journal; the article analyzed the rationality of people
who forgo having children in order to help others (such as, say, Mother
Teresa) in terms of evolutionary reproductive strategies.5 Such «science»
does not violate Dickerson's rule. Dickerson's «one overriding

SCIENCE, PHILOSOPHY, RELIGION 241
and defining rule» would happily tolerate the discredited nineteenthcentury science of phrenology (the attempt to discern the intelligenceand character of people from the shape of their skulls). His rule gives
us no guidance about the legitimacy of Marxism and Freudianism, the«sciences» of history and the mind, respectively. The rule does not help
us decide in advance if putting leeches on sick people or bleeding themto reduce their fever will work. So it seems that many things could claim
the tide of «science» under Dickerson's rule, as long as they invoke only
material forces, however vague and elusive.
In fact, Dickerson's rule is more like a professional aphorism—like«the customer is always right» or «location, location, location.» It iswhat the old professionals have lived by, what they think works, and it
encapsulates some of the wisdom that they wish to pass on to the younger
professional generation. Behind Dickerson's rule are vague images of
Vikings attributing thunder and lightning to the work of the gods, andof witch doctors trying to drive out evil spirits from sick people. Closer
to modern science are memories of Isaac Newton himself proposing that
God occasionally intervened to stabilize the solar system. The anxiety isthat if the supernatural were allowed as an explanation, then there would
be no stopping it—it would be invoked frequently to explain many things
that in reality have natural explanations. Is this a reasonable fear?
No one can predict the behavior of human beings, but it seems to me
that the fear of the supernatural popping up everywhere in science is vastly
overblown. If my graduate student came into my office and said that theangel of death killed her bacterial culture, I would be disinclined to believe
her. The Journal of Biological Chemistry is unlikely to start a new section
on the spiritual regulation of enzyme activity. Science has learned over the
past half millennium that the universe operates with great regularity thegreat majority of the time, and that simple laws and predictable behavior
explain most physical phenomena. Historians of science have emphasizedthat science was born from a religious culture—Europe in the Middle
Ages—whose religious traditions included a rational God who made arational, understandable, law-bound universe.6 Both science and religion
expect that the world will almost always spin according to the fixed law ofgravity.

242 WHAT DOES THE BOX TELL US?
There are, of course, exceptions. Sometimes unique historical events
must be invoked to explain an effect. The fossil record shows that about
60 million years ago, the dinosaurs all died out within a geologically brieftime period. One theory offered to explain this is that a large meteor
crashed into the earth, sending clouds of dust high into the atmosphereand perhaps causing many plants to die, disrupting the food chain. Some
indirect evidence supports the hypothesis—levels of the element iridium,rarely found on earth but more frequent in meteors, are elevated inrocks from that time period. The hypothesis has been accepted by many
scientists. Nonetheless, there has not been a rush to postulate meteors
as the cause of all sorts of things. No one has said that meteors caused
the Grand Canyon, or the extinction of horses in North America. No
one has said that the dust of tiny, invisible meteorites causes asthma, orthat meteorites initiate tornados. The hypothesis of the involvement of ameteor in the extinction of the dinosaurs was evaluated on the basis of thephysical evidence for the particular historical event. There is every reason
to expect that evidence will be evaluated on a case-by-case basis if meteors
are invoked to explain other historical events.
Similarly, hypotheses for the involvement of an intelligent agent in thedevelopment of life or other historical events have to be evaluated on acase-by-case basis. As noted in Chapter 9, the evidence is overwhelming
for some biochemical systems, undetectable for others. If a scientist
postulates the involvement of intelligence in some other event, then theonus will be on him or her to support that assertion with observableevidence. The scientific community is not so frail that its healthy
skepticism will turn into gullibility.
Another concern that might lie behind Dickerson's essay is for the«scientific method.» Hypothesis, careful testing, replicability—all thesehave served science well. But how can an intelligent designer be tested?
Can a designer be put in a test tube? No, of course not. But neither can
extinct common ancestors be put in test tubes. The problem is thatwhenever science tries to explain a unique historical event, careful testing
and replicability are by definition impossible. Science may be able to study
the motion of modern comets, and test Newton's laws of motion that
describe how the comets move. But science will never be able to study thecomet that putatively struck the earth many millions of years ago.

SCIENCE, PHILOSOPHY, RELIGION 243
Science can, however, observe the comet's lingering effects on themodern earth. Similarly, science can see the effects that a designer has hadon life.
The final point I wish to make about Richard Dickerson's argument isthat although he certainly didn't intend it, it is a prescription for timidity.
It tries to restrict science to more of the same, disallowing a fundamentallydifferent explanation. It tries to place reality in a tidy box, but the universe
will not be placed in a box. The origin of the universe and the developmentof life are the physical underpinnings that resulted in a worldful ofconscious agents. There is no a priori reason to think that those bedrock
events are to be explained in the same way as other physical events. Science
is not a game, and scientists should follow the physical evidence whereverit leads, with no artificial restrictions.

GHOSTBUSTERS

The fourth and most powerful reason for science's reluctance to embracea theory of intelligent design is also based on philosophical considerations.
Many people, including many important and well-respected scientists,
just don't want there to be anything beyond nature. They don't want asupernatural being to affect nature, no matter how brief or constructive theinteraction may have been. In other words, like young-earth creationists,they bring an a priori philosophical commitment to their science that
restricts what kinds of explanations they will accept about the physicalworld. Sometimes this leads to rather odd behavior.
It was only about seventy years ago that most scientists thought theuniverse was infinite in age and size. That view had been held by some
Greek philosophers in antiquity, as well as by diverse religious groups,
and by those who thought there was nothing beyond nature. In contrast
Judaism and then Christianity thought that the universe was created intime and was not eternal. Having few scientists among them, the earlyJews did not try to adduce evidence for the finiteness of the universe, andin the Middle Ages Thomas Aquinas, the eminent theologian, said that it
could be known only through faith that the universe had a beginning. Buttime marches on. Earlier this century Einstein discovered that his general
theory of relativity predicted an unstable universe—one that would

244 WHAT DOES THE BOX TELL US?
either expand or contract, but would not remain stationary. Einstein
was repulsed by such a universe and, in what he later admitted was thegreatest mistake of his career, inserted a «correction factor» into his
equations solely to make them predict a stationary, eternal universe.
As parents and teachers always say, cheaters never prosper. A short timelater the astronomer Edwin Hubble observed that wherever in the sky
he pointed his telescope, the stars appeared to be moving away from theearth. (He couldn't actually see the stars moving. Rather, he inferred theirmotion from a phenomenon called a «Doppler shift,» in which stars thatmove away from an observer emit light of a slightly longer wavelength—thefaster they move, the greater the change in the wavelength.) Furthermore,
the speed with which the stars were receding was proportional to theirdistance from the earth. This was the first observational evidence that
Einstein's unfudged equations were correct in their prediction concerning
the expansion of the universe. And it did not take a rocket scientist(although plenty were around) to mentally reverse the expanding universeand conclude that at some time in the past, all of the matter in the universe
was concentrated into a very small space. This was the beginning of the
Big Bang hypothesis.
To many the notion of the Big Bang was loaded with overtones of asupernatural event—the creation, the beginning of the universe. The
prominent physicist A.S. Eddington probably spoke for many in voicing
his utter disgust with such an idea:
Philosophically, the notion of an abrupt beginning to the present order of
Nature is repugnant to me, as I think it must be to most; and even those
who would welcome a proof of the intervention of a Creator will probably
consider that a single winding-up at some remote epoch is not really thekind of relation between God and his world that brings satisfaction to themind.7

Nonetheless, despite its religious implications, the Big Bang was ascientific theory that flowed naturally from observational data, not fromholy writings or transcendental visions. Most physicists adopted the Big
Bang theory and set their research programs accordingly. A few, like
Einstein before them, didn't like the extra-scientific implications of thetheory and labored to develop alternatives.
In the middle part of the century the astronomer Fred Hoyle cham-

SCIENCE, PHILOSOPHY, RELIGION 245
pioned another theory of the universe, called the steady-state theory.
Hoyle proposed that the universe was infinite and eternal, but he also
admitted that the universe was expanding. Since a universe that has
been expanding for an infinite period of time would become infinitely
thinned out, even if it started with an infinite amount of matter, Hoyle
had to explain why our present universe is relatively dense. The eminentscientist proposed that matter was continually coming into existence inouter space at the rate of about one hydrogen atom per cubic mile of spaceper year. Now, it must be emphasized that Hoyle was proposing creation ofhydrogen from nothing and with no cause. The matter simply popped into
existence at the required rate. Since he had no observational evidence tosupport this notion, why did Hoyle propose it? It turns out that Hoyle, like
Eddington, thought that the Big Bang strongly implied the supernaturaland found the prospect extremely distasteful.
Hoyle's steady-state theory always had a difficult time explaining
much of the observational evidence from astronomy. In the 1960s theastronomers Penzias and Wilson finally put the theory out of its miserywith their observation of background radiation. They saw that microwaves
are bombarding the earth from every direction with an astonishing
uniformity of intensity. Such background radiation was predicted to be
an indirect result of the Big Bang. The observation of the backgroundradiation was, and still is, taken to be the crowning glory of the Big Bangtheory.
It is impossible to deny that the Big Bang has been an enormously
fruitful physical model of the universe and, even though large questions
remain (as they inevitably do in basic science), that the model was justified
by the observational data. Scientists such as Einstein, Eddington, andHoyle fudged and twisted in their efforts to resist a scientific theory
that flowed naturally from the data because they thought they would beforced to accept unpleasant philosophical or theological conclusions. They
weren't; they had other options.

DON'T FENCE ME IN

The success of the Big Bang model had nothing to do with its religious
implications. It seemed to agree with the Judaeo-Christian dogma of abeginning to the universe; it seemed to disagree with other religions

246 WHAT DOES THE BOX TELL US?
that believed the universe to be eternal. But the theory justified itself
by reference to observational data—the expansion of the universe— andnot by invoking sacred texts or the mystical experiences of holy men. The
model came straight from the observational evidence; it was not fit to a
Procrustean bed of religious dogma.
But it should also be noticed that the Big Bang, although friendly to areligious point of view, does not forcibly compel that belief. No person isrequired by dint of logic to reach any particular supernatural conclusion
solely on the basis of scientific observations and theories. This is seen
initially in Einstein's and Hoyle's attempt to come up with alternativemodels that would fit the observational data and avoid the unpleasantthought of a start to the universe. When the steady-state theory was finallydiscredited, other theories sprang up that would obviate the philosophicalbind of an absolute beginning. The most popular option was the idea ofa cycling universe, in which the expansion that started with the Big Bangwould eventually slow down and, under the force of gravity, all matter
would collapse again in a «Big Crunch.» From there, the story goes,perhaps another Big Bang would occur, and endless repetitions of thiscycle would recapture a nature that was infinite in time. It is interesting(though scientifically irrelevant) that the notion of a cycling universe
would be compatible with many religions, including those of the ancient
Egyptians, Aztecs, and Indians.8
The idea of a cycling universe seems to be out of favor in physics thesedays. Insufficient matter to cause a future gravitational collapse has
been observed—and even if such matter existed, calculations show thatsuccessive cycles would become longer and longer, eventually ending witha non-contracting universe. But even if this option is discredited, otherideas are available to take the sting out of the Big Bang. A more recent
proposal would have it that the actual universe is enormously larger thanwhat we observe, and that the portion of the universe that we see is merelya «bubble» in an infinite universe. And physicist Stephen Hawking has
proposed that although the universe is finite, it would not have a beginning
if something in his mathematical equations that he calls «imaginary time»
actually existed. Another idea is that infinitely many universes exist, andthat the universe in which we find ourselves just happens to have thenarrow conditions required for life. This idea was popularized under thename of the «anthropic principle.» In essence the anthropic principle

SCIENCE, PHILOSOPHY, RELIGION 247
states that very many (or infinitely many) universes exist with varying
physical laws, and that only the ones with conditions suitable for life willin fact produce life, perhaps including conscious observers. So perhaps azillion barren universes exist somewhere; we live in the zillion and first
universe because it has the physical properties that are compatible withlife.
The anthropic principle strikes most people as plain silly, probably
because they aren't quite sure where we would put all those other universes.
Other ideas, however, are available for the person who still does not want toinvoke the supernatural. In quantum physics it is believed that microscopic
entities called «virtual particles» can pop into existence by borrowing
energy from the surroundings (confusingly called the «vacuum,» eventhough the word is not used by physicists to mean «nothing»). Some
physicists have taken this idea just a bit further and proposed that theentire universe simply popped into existence, not from any surroundings,
but from absolutely nothing—»a quantum fluctuation from nonbeing
to being»—and without a cause. This shows how some scientists havelearned to think big compared to the days when Fred Hoyle was modestly
proposing the occasional uncaused creation of hydrogen atoms.
No experiment has been done to support the notion of bubble universes,
imaginary time, or the zillion anthropic universes. Indeed, it seems thatno experiment could detect them in principle. Since they or their effects
cannot be observed, then they are metaphysical postulates, no moreaccessible to experimental investigation than an admittedly supernatural
being. They do science no good. Their only use is as an escape hatch fromthe supernatural.
The point of the above discussion is that even though the Big Bang
hypothesis may appear at first blush to support a particular religious
idea, no scientific theory can compel belief in a positive religious tenet bysheer force of logic. Thus, to explain the universe a person can postulate
unobservables, like the theory that there are infinitely many universes andthe theory that ours is just a bubble in a larger universe. Or one can holdout the hope that theories that look implausible today, such as the steadystate theory or the theory of the oscillating universe, might look moreplausible tomorrow when calculations are redone or new measurements
are taken. Or one can simply abandon the principle of causation, as seen intheories that propose that the universe came into being uncaused.

248 WHAT DOES THE BOX TELL US?
Most other people may regard the ideas as pretty giddy; nonetheless,they don't violate the observational evidence.

ALIENS AND TIME TRAVELERS

Saying that the universe began in a Big Bang is one thing, but saying
life was designed by an intelligence is another. The phrase Big Bang itself
evokes only images of an explosion, not necessarily a person. The phrase
intelligent design seems more urgent and quickly invites questions about
who the designer might have been. Will persons with philosophicalcommitments against the supernatural be painted into a corner by thetheory? No. The human imagination is too powerful.
By any measure, Sir Francis H. C. Crick is a smart man. Over forty
years ago, while still a graduate student at Cambridge University, Crickand James Watson used X-ray crystallographic data to deduce the double
helical structure of DNA, an accomplishment for which they later received
the Nobel prize. Crick went on to contribute to the elucidation of thegenetic code and to pose provocative conceptual questions on the functionof the brain. Well into his seventies, he is pushing science further andfaster than most of us will at the pinnacle of our powers.
Francis Crick also thinks that life on earth may have begun when aliens
from another planet sent a rocket ship containing spores to seed the earth.
This is no idle thought; Crick first proposed it with chemist Leslie Orgelin 1973 in an article entitled «Directed Panspermia» in a professional
science journal called Icarus. A decade later Crick wrote a book, Life Itself,reiterating the theory; in a 1992 interview in Scientific American on theeve of the publication of his latest book, Crick reaffirmed that he thinks
the theory is reasonable.
The primary reason Crick subscribes to this unorthodox view is thathe judges the undirected origin of life to be a virtually insurmountableobstacle, but he wants a naturalistic explanation. For our present purposes,
the interesting part of Crick's idea is the role of the aliens, whom he has
speculated sent space bacteria to earth. But he could with as much evidence
say that the aliens actually designed the irreducibly complex biochemicalsystems of the life they sent here, and also designed the irreduciblycomplex systems that developed later. The only difference is a switch to thepostulate that aliens constructed life, whereas Crick originally

SCIENCE, PHILOSOPHY, RELIGION 249
speculated that they just sent it here. It is not a very big leap, though,to say that a civilization capable of sending rocket ships to other planetsis also likely to be capable of designing life—especially if the civilization
has never been observed. Designing life, it could be pointed out, does
not necessarily require supernatural abilities; rather, it requires a lot of
intelligence. If a graduate student in an earthbound lab today can plan andmake an artificial protein that can bind oxygen, then there is no logicalbarrier to thinking that an advanced civilization on another world might
design an artificial cell from scratch.
This scenario still leaves open the question of who designed thedesigner—how did life originally originate? Is a philosophical naturalist
now trapped? Again, no. The question of the design of the designer canbe put off in several ways. It could be deflected by invoking unobserved
entities: perhaps the original life is totally unlike ourselves, consisting offluctuating electrical fields or gases; perhaps it does not require irreduciblycomplex structures to sustain it. Another possibility is time travel, which
has been seriously proposed by professional physicists in recent years.
Scientific American informed the readers of its March 1994 issue thatfar from being a logical absurdity ... the theoretical possibility of taking
such an excursion into one's earlier life is an inescapable consequence offundamental physical principles.

Perhaps, then, biochemists in the future will send back cells to the early
earth that contain the information for the irreducibly complex structures
we observe today. In this scenario humans can be their own aliens,
their own advanced civilization. Of course, time travel leads to apparent
paradoxes (things like grandsons shooting grandfathers before theiroffspring are born), but at least some physicists are ready to accept them.
Most people, like me, will find these scenarios entirely unsatisfactory,
but they are available for those who wish to avoid unpleasant theologicalimplications.
In The Blind Watchmaker Richard Dawkins tells his readers that even if
a statue of the Virgin Mary waved to them, they should not conclude they
had witnessed a miracle.9 Perhaps all the atoms of the statue's arm justhappened to move in the same direction at once—a low-probability event
to be sure, but possible. Most people who saw a statue come to life would

250 WHAT DOES THE BOX TELL US?
tell Dawkins that there are more things in heaven and earth than are
dreamt of in his philosophy, but they couldn't make him join the Churchof England.

LIVE AND LET LIVENor should they try. In a very real sense, the separateness of the spheresof science versus philosophy and religion is as it should be. Every person
has available the data of his or her senses and, for the most part, can agreewith other people on what that data is. To a large extent people of different
philosophical and theological bents can also agree on scientific theories,
such as gravitation or plate tectonics or evolution, to organize the data (evenif the theories are ultimately incorrect). But the fundamental philosophicalprinciples that underlie reality and the theological principles, or lack ofprinciples, that can be garnered from philosophy and historical experience
are at root chosen by the individual. A man or woman must be free tosearch for the good, the true, and the beautiful.
Refusal to give others broad latitude for their defining beliefs has led
time and again to disaster. Intolerance does not arise when I think that I
have found the truth. Rather it comes about only when I think that, because
I have found it, everyone else should agree with me. Richard Dawkins has
written that anyone who denies evolution is either «ignorant, stupid or
insane (or wicked—but I'd rather not consider that.)»10. It isn't a big stepfrom calling someone wicked to taking forceful measures to put an end
to their wickedness. John Maddox, the editor of Nature, has written in
his journal that «it may not be long before the practice of religion must
be regarded as anti-science.»11 In his recent book Darwin's Dangerous
Idea, philosopher Daniel Dennett compares religious believers—90
percent of the population—to wild animals who may have to be caged,
and he says that parents should be prevented (presumably by coercion)from misinforming their children about the truth of evolution, which isso evident to him.12 This is not a recipe for domestic tranquility. It is one
thing to try to persuade someone by polemics; it is entirely different topropose to coerce those who disagree with you. As the weight of scientificevidence shifts dramatically, this point should be kept prominently inmind. Richard Dawkins has said that Darwin made it possible to be an«intellectually fulfilled atheist.»13 The failure of Darwin's theory

SCIENCE, PHILOSOPHY, RELIGION 251
on the molecular scale may cause him to feel less fulfilled, but no one
should try to stop him from continuing his search.
The scientific community contains many excellent scientists who thinkthat there is something beyond nature, and many excellent scientists who
do not. How then will science «officially» treat the question of the identity ofthe designer? Will biochemistry textbooks have to be written with explicit
statements that «God did it»? No. The question of the identity of the designer
will simply be ignored by science. The history of science is replete with
examples of basic-but-difficult questions being put on the back burner. For
example, Newton declined to explain what caused gravity, Darwin offered
no explanation for the origin of vision or life, Maxwell refused to specify amedium for light waves once the ether was debunked, and cosmologists ingeneral have ignored the question of what caused the Big Bang. Although
the fact of design is easily seen in the biochemistry of the cell, identifying
the designer by scientific methods might be extremely difficult. In thesame way, Newton could easily observe gravity, but specifying its cause
lay centuries in the future. When a question is too difficult for science todeal with immediately, it is happily forgotten while other, more accessible
questions are investigated. If philosophy and theology want to take a crack
at the question in the meantime, we scientists should wish them well, but
reserve the right to jump back into the conversation when science hassomething more to add.

CURIOUSER AND CURIOUSER

The reluctance of science to embrace the conclusion of intelligent
design that its long, hard labors have made manifest has no justifiable
foundation. Scientific chauvinism is an understandable emotion, but
it should not be allowed to affect serious intellectual issues. The historyof skirmishes between religion and science is regrettable and has caused
bad feelings all around. Inherited anger, however, is no basis for making
scientific judgments. The philosophical argument (made by some theists)that science should avoid theories which smack of the supernatural is an
artificial restriction on science. Their fear that supernatural explanations
would overwhelm science is unfounded. Further, the example of the Big
Bang theory shows that scientific theories with supernatural

252 WHAT DOES THE BOX TELL US?
ramifications can be quite fruitful. The philosophical commitment ofsome people to the principle that nothing beyond nature exists should not
be allowed to interfere with a theory that flows naturally from observable
scientific data. The rights of those people to avoid a supernaturalconclusion should be scrupulously respected, but their aversion should not
be determinative.
As we reach the end of this book, we are left with no substantive defense
against what feels to be a strange conclusion: that life was designed by an
intelligent agent. In a way, though, all of the progress of science over thelast several hundred years has been a steady march toward the strange.
People up until the Middle Ages lived in a natural world. The stable earth
was at the center of things; the sun, moon, and stars circled endlessly togive light by day and night; the same plants and animals had been known
since antiquity; kings ruled by divine right. Surprises were few.
Then it was proposed, absurdly, that the earth itself moved, spinning
while it circled the sun. No one could feel the earth spinning; no one could
see it. But spin it did. From our modem vantage, it's hard to realize what an
assault on the senses was perpetrated by Copernicus and Galileo; they saidin effect that people could no longer rely on even the evidence of their eyes.
Things got steadily worse over the years. With the discovery of fossils
it became apparent that the familiar animals of field and forest had notalways been on earth; the world had once been inhabited by huge, aliencreatures who were now gone. Sometime later Darwin shook the world
by arguing that the familiar biota was derived from the bizarre, vanishedlife over lengths of time incomprehensible to human minds. Einstein told
us that space is curved and time is relative. Modern physics says that solid
objects are mostly space, that subatomic particles have no definite position,that the universe had a beginning.
Now it's the turn of the fundamental science of life, modern biochemistry,
to disturb. The simplicity that was once expected to be the foundation oflife has proven to be a phantom; instead, systems of horrendous, irreducible
complexity inhabit the cell. The resulting realization that life was designedby an intelligence is a shock to us in the twentieth century who have gotten
used to thinking of life as the result of simple natural laws. But othercenturies have had their shocks, and there is no reason

SCIENCE, PHILOSOPHY, RELIGION 253
to suppose that we should escape them. Humanity has endured as thecenter of the heavens moved from the earth to beyond the sun, as thehistory of life expanded to encompass long-dead reptiles, as the eternal
universe proved mortal. We will endure the opening of Darwin's blackbox.

254 WHAT DOES THE BOX TELL US?

AFTERWORDTEN YEARS LATER

AS I WAS SAYING«Now it's the turn of the fundamental science of life, modem
biochemistry, to disturb.» File that remark under the heading:
Understatements, Big. When I wrote that sentence near the conclusionof Darwin's Black Box ten years ago, I had no inkling of how very
unsettling some people would find the concept of intelligent design1 (ID).
Today, with fresh denunciations issuing almost weekly from scientificsocieties and newspaper editorial boardrooms alike, it might seem a trifle
premature to declare victory. Yet, although the cultural dynamic is stillplaying itself out, a decade after the publication of Darwin's Black Box thescientific argument for design is stronger than ever. Despite the enormous
progress of biochemistry in the intervening years, despite hundreds ofprobing commentaries in periodicals as diverse as The New York Times,
Nature, Christianity Today, Philosophy of Science, and Chronicle of Higher
Education, despite implacable opposition from some scientists at thehighest levels, the book's argument for design stands. Other than updating
the list of my children in the Acknowledgements (append Dominic, Helen,
and Gerard), there is very little of the original text I would change if I
wrote it today. There is, however; much I could add.
255

256 WHAT DOES THE BOX TELL US?
For modern science, ten years is an eon. As an analogy, think of how
the Internet has developed. In the mid 1990s e-mail was clumsy and the
Web was a shadow of what it has become. In the same time interval, bysome measures biochemistry has advanced as much as the Internet. A
little over a decade ago the very first genome sequence of a free livingorganism—a tiny bacterium named Haemophilus influenzae—had justbeen published. The genome sequence of the first eukaryote—the Baker's
yeast Saccharomyces cerevisiae—followed the next year. Now hundredsof genomes have been sequenced, mostly those of single-celled creatures,
including the murderous malarial parasite, but also those of its malevolent
multi-celled partner the mosquito, the food staple rice, man's best friend
the dog, humanity's closest relative the chimp. And of course the humangenome as well, whose completion was jointly announced with great
fanfare by U.S. President Clinton and Great Britain's Prime Minister Tony
Blair in the year 2000.
Progress in elucidating genomes has been matched by progress inunderstanding how the machinery of life works. Most proteins in the cellare now known to work as teams of half a dozen or more, rather thanby themselves. Ten years ago the regulation of the activity of genes wasthought to be the job just of proteins. Now a new, unimagined categoryof nucleic acids called micro RNAs has been discovered that helps control
many genes. The mechanisms cells use to construct the cilia and flagelladescribed in Chapter 4 were almost totally obscure when this book was firstwritten. Today they're known to be stunningly sophisticated molecularsystems themselves, like automated factories that make outboard motors.
In short, as science advances relentlessly, the molecular foundation of life
is not getting any less complex than it seemed a decade ago; it is getting
exponentially more complex. As it does, the case for the intelligent designof life becomes exponentially stronger.
Nonetheless, the hurlyburly of the public intellectual marketplace canmake it difficult for a person to soberly judge the strength of a controversial
idea. So over the next few pages I'll address some confusions about theargument for intelligent design that have inevitably cropped up as people
opposed to, or just unacquainted with, the book's reasoning chimed in thevigorous public discussion of the past decade. The most important sourcesof confusion include misunderstandings about the concept

TEN YEARS LATER 257
of irreducible complexity and the nature of the argument for design.
After touching on them I'll also briefly re-visit a few of the biochemical
examples from Chapters 3 through 7 to see how the opposition—Darwinian
theory—has fared since the mid 1990s in trying to account for them.

WHAT'S IN A NAME?

Ten years ago I used the phrase «irreducible complexity»2 (IС) to shinea spotlight on a large and then-substantially-unappreciated problem
for Darwinian evolution—like a mousetrap, almost all of the elegant
molecular machinery of the cell needs multiple parts to work. Because of
the need for many parts, it is extraordinarily difficult to rigorously envision
how systems such as the cilium, flagellum, or blood clotting cascade could
have arisen from simpler systems by the «numerous, successive, slight
modifications» imagined by Charles Darwin.
I define irreducible complexity on page 39—«a single system which iscomposed of several well-matched, interacting parts that contribute to
the basic function, and where the removal of any one of the parts causes
the system to effectively cease functioning.» Now, I am a scientist—I'm nophilosopher. The purpose of the definition was to highlight the empiricaldifficulty for Darwinian gradualism posed by complex interactive systems
in a real biological context, not to play word games. Nonetheless, somerejoinders to Darwin's Black Box have be sought to sweep the evolutionary
problem for natural selection under the rug by picking at the phrase«irreducible complexity,» or by subtly altering its definition. In the next
three sections we'll look at three examples.

CLOCKS FROM CLOCKSIn 1999 the philosopher of science Robert Pennock argued in Towerof Babel that irreducible complexity was no problem for Darwinism. As
philosophers will do, he focused not on the science, but on the definition,
or at least what he construed as the definition:[E]ven if a system is irreducibly complex with respect to one defined basic
function, this in no way implies that nearby variations might not serve
other nearby functions. Behe claims that there could never be any258 WHAT DOES THE BOX TELL US?
functional intermediates that natural selection could have selected for on
the way to any irreducibly complex system, but he can't get the empiricalconclusion from his «by definition» conceptual argument. The strong
empirical premise he needs is false.3

Pennock, however, simply substituted his own concept of irreducible
complexity for mine. I never wrote that «there could never be any
functional intermediates that natural selection could have selected foron the way to any irreducibly complex system.» Those are Pennock's
words. On the contrary, on page 40, I point out that, although irreducible
complexity does rule out direct routes, it does not automatically rule out
indirect ones. I did go on to argue that indirect routes seem very unlikely,
and that the more complex the system the more unlikely indirect routes
become. But I did not assert that indirect routes were logically impossible,
as he implies. That would be silly. No scientific evidence can show thatsomething is logically impossible, since logical impossibility is concerned
only with self-contradictory statements (like «he's a married bachelor»)rather than with nature (like «DNA is usually a double helix»). For example,
geocentrism isn't logically impossible—it's just wrong. No scientific theory
has ever had to, or ever could, rule out rival explanations by showing them
to be logically impossible, and neither must intelligent design. Scientifictheories succeed simply by explaining the data better than rival theories.
The bottom line is that Pennock constructed his own rigid, strawman definition for IС in order to make the argument for design seem as
brittle as possible. Then problems for Darwinism could be whistled away.
With the argument thus twisted out of shape, Pennock didn't think heeven needed to talk about biology. Instead, in Tower of Babel he wrote ofa chronometer, which is an exceptionally precise timepiece that is helpful
for sailors who need to determine longitude at sea. If a chronomoter brokejust a little bit, cerebrated Pennock, then maybe like a less-precise watch
the device could still keep time on land.
If one or another of these [two dumbbell-shaped bar balances and four
helical balance springs, each of which helped to compensate for the
motions of the ship] were to have broken, the clock would no longer havefulfilled its specific function aboard ship, but it could still have performed a

TEN YEARS LATER 259
slightly different function in a different environment, such as on a calmer
lake or solid ground.4

Hmm. So one logically possible way to get a complex watch is to startwith a more-complex chronometer, and then break it? Of course, that's it.
As Thomas Huxley said in another context, «How stupid of me not to havethought of it!» But how do we get a chronometer in the first place? Well,
you see, just start with a watch:[I]f Paley's imagined self-replicating watches existed and operated in a
Darwinian fashion whereby random variations occurred in the replication
process, then given appropriate selective pressure, these could potentiallyevolve to solve the longitude problem.5

So in the vortex of the philosopher's circular reasoning a more
precise chronometer breaks to yield a less precise watch which then itself
somehow6 gives rise to the original, more precise chronometer. QED.
What any of that has to do at all with biologically relevant questions
concerning evolution, however, remains unclear.
Pennock's book has been warmly endorsed by prominent Darwinianphilosophers and scientists, and is officially recommended by no less thanthe National Academy of Sciences. Apparently, if it serves the cause, there
is no argument too zany for some Darwinian acolytes to certify.

MOUSETRAPS FROM TOOTHPICKS

Like Robert Pennock, Brown University cell biologist Kenneth
Miller was keen to show that irreducible complexity is not a problem for
Darwinian evolution. Like Pennock, Miller concocted his own, private
definition of irreducible complexity, and then argued against that. But
unlike Pennock, Miller was wondrously lax in imagining the sorts of jobs
that a deconstructed, irreducibly complex system might settle for. Pennockat least tried to keep the function in the ballpark of the original one—after all, both watches and chronometers do keep time. Miller had nosuch qualms. He imagined promising Darwinian precursors behind every
door—whatever could have a «function» as simple as that of a paperweightor toothpick. Miller redefined irreducible complexity to mean that

260 WHAT DOES THE BOX TELL US?
none of the component parts of an IС system could have its ownfunction separate from the system.7 In a story entitled «Evolution Critics
Come Under Fire for Flaws In 'Intelligent Design,'» Wall Street Journal
columnist Sharon Begley channeled Miller's views:
In 1996, biochemist Michael Behe ... offered a stronger argument against
evolution. Complex living structures, he argued in his book «Darwin's
Black Box,» possess «irreducible complexity.» That is, they can't function
until all their components are assembled, much as a mousetrap isn't muchgood until the base, spring, bar, and all the rest are connected. Moreover,the individual parts of complex structures supposedly serve no function[emphasis added].8

Unfortunately, although the first part reflects my actual argument,
the italicized «Moreover ...» sentence is made up out of whole cloth. The«flaw» in intelligent design that Begley reported was invented by Miller!
It's not hard to see why he would redefine IС like that—«the individual
parts of complex structures supposedly serve no function.» For rhetorical
purposes, like Pennock, Miller wanted to make the argument for design
seem as brittle as possible. In Miller's thinking, if he could point out that,say, a piece of a mousetrap could be used as a paperweight (which isn't too
difficult, since almost anything could be used to weigh down papers) thenan «individual part» could serve a «function,» «irreducible complexity»
would vanish by definitional edict, and all good Darwinists could breathe
easier once more.
Yet there's no reason that individual components of an irreduciblycomplex system could not be used for separate roles, or multiple separate
roles, and I never wrote that they couldn't. Rather, for an IС system I wrotethat «the removal of any one of the parts causes the system to effectively
cease functioning»—system, not parts. For example, Miller could detachthe mousetrap's holding bar, but the mousetrap-ping system would then
immediately be broken. The bar could be used as a toothpick, the residueof the trap be used as a paperweight, but nothing would any longer beworking as a mousetrap.9 To illustrate further, pieces of a child's Lego®
set might be used individually as, yes, paperweights, or might be used toconstruct all manner of objects such as a toy ship or airplane or maybe amousetrap. But even if the pieces could be used to build

TEN YEARS LATER 261
many things, a Lego mousetrap similar to that pictured in Chapter 2
would still not work unless all the pieces were present, and would fail if
one of the pieces were removed.
The system is irreducible, not the parts. By Miller's reasoning you
couldn't distinguish between a jumbled pile of Lego parts and an
elaborately designed Lego machine. Apparently they would both look thesame to him.
«It's like discovering the mousetrap bar was a fine toothpick long
before it got together with the other parts to kill rodents,» scribed Begley,10
echoing a Miller analogy. She should have read Chapter 4 of Darwin's
Black Box more closely.
Following Professor Doolittle's example we could propose a route by which
the first mousetrap was produced: The hammer appears as the result of the
duplication of a crowbar in our garage. The hammer comes into contact
with the platform, the result of shuffling several Popsicle sticks. The spring
springs forth from a Grandfather clock that had been used as a timekeeping
device. The holding bar is fashioned from a straw sticking out of a discarded
Coke can. The catch is unleashed from the cap on a bottle of beer. But it justdoesn't happen that way unless someone or something else is guiding theprocess, (p. 96)

I was writing tongue-in-cheek of course, confident that most people
would see the silliness of a mousetrap arising from an accidental
assemblage of objects used for other purposes. But Miller and Begley werereally serious.
In a more technical vein, Miller excitedly announced that somecomponents of IС biochemical systems I discuss have other roles in
the cell, such as the ciliary proteins tubulin and dynein.11 But I myself
pointed that out when I first wrote Darwin's Black Box ten years ago! For
example, in Chapter 3 I wrote that «microtubules occur in many cells
and are usually used as mere structural supports, like girders, to propup cell shape.12 Furthermore, motor proteins also are involved in othercell functions, such as transporting cargo from one end of the cell toanother.» Nonetheless, I emphasized that such other roles don't help with
the irreducible complexity of the cilium: «an evolutionary story for thecilium must envision a circuitous route, perhaps adapting parts that wereoriginally used for other purposes to build a cilium.» And I went on toshow why indirect routes are quite implausible.13 Toothpicks do not262 WHAT DOES THE BOX TELL US?
explain mousetraps, and tubulin and dynein don't explain cilia. Miller
himself offers no serious Darwinian explanation for the cilium at all, but
is content to rest his case on toothpicks.

«PART (А)» AND «PART (В)»

In a review of Darwin's Black Box for the MIT-published Boston Review,
University of Rochester evolutionary biologist Allen Orr rejected out ofhand the maybe-a-toothpick-turned-into-a-mousetrap reasoning ofKenneth Miller.
[W]e might think that some of the parts of an irreducibly complex systemevolved step by step for some other purpose and were then recruitedwholesale to a new function. But this is also unlikely. You may as wellhope that half your car's transmission will suddenly help out in the airbag
department. Such things might happen very, very rarely, but they surely do
not offer a general solution to irreducible complexity.14

Nonetheless, Orr was certain he saw a simple way around the problemof irreducible complexity.
Behe's colossal mistake is that, in rejecting these possibilities [that is, either
fantastically lucky accident or toothpick-to-mousetrap evolution ala Ken
Miller], he concludes that no Darwinian solution remains. But one does.
It is this: An irreducibly complex system can be built gradually by adding
parts that, while initially just advantageous, become—because of laterchanges—essential. The logic is very simple. Some part (A) initially doessome job (and not very well, perhaps). Another part (B) later gets added
because it helps A. This new part isn't essential, it merely improves things.
But later on, A (or something else) may change in such a way that B now
becomes indispensable. This process continues as further parts get folded
into the system. And at the end of the day, many parts may all be required.15

So, thinks Orr, contrary to my argument, an irreducibly complex
system might indeed be produced directly. He might have had a very
limited point if he were restricting his thinking to something exceedingly
simple like, say, a mound of stones. If a taller mound were an improvement(to act, say, as a bigger barrier), then piling rocks on top of each otherwould be

TEN YEARS LATER 263
beneficial. Since removing a stone from the bottom might make themound crumble, one could then say that in some uninteresting sense themound was irreducible, yet was built gradually stone by stone. Nonetheless,
Orr's abstract argument says absolutely nothing about the concrete sorts ofexamples I cited, or that commonly occur in the cell, where different kindsof parts have to act on each other. Exactly what is the marvelous «part (А)»
that could act by itself as a mousetrap or flagellum? And what is the «part(В)» that would then come along to improve it? How did he spell out thedetails of his imaginary pathway? Astoundingly, Orr had nothing at all tosay either about the mousetrap or about any of the biochemical examples
from Darwin's Black Box. Apparently his one remaining Darwiniansolution is mute on real, biological irreducible complexity.16
Like Robert Pennock and Kenneth Miller, Allen Orr seems interested
only in banishing the specter of intelligent design from biology, rather
than in seriously engaging the problem I highlighted with the term
irreducible complexity. So if the embarrassment can be papered over withwords about a fanciful «part (А)» and «part (B),» then that's enough—noneed ever to attempt a real explanation. Orr's original review was written
in 1996. Nine years later he wrote a long essay for The New Yorker which
repeated the same vague, hypothetical explanation.17 Nine years and no
progress. Apparently some are willing to pay that high price, and more, toavert their eyes from design.

ACCENTUATE THE POSITIVE

In addition to confusion about the concept of irreducible complexity,
some displeased reviewers have professed perplexity about the positiveargument for intelligent design, or wondered aloud if there even is such athing. Is the argument simply, as some have caricatured it, that we don't
know how Darwinism accounts for biological complexity; and so wenaively jump to the conclusion of design? Is it just an «argument fromignorance»?18
Of course not. As I wrote in Chapter 9, design is positively apprehended
in the purposeful arrangement of parts. Looked at this way, irreduciblycomplex systems such as mousetraps and flagella serve both as negativearguments against gradualistic explanations like Darwin's and as positivearguments for design. The negative argument is that such interactive

264 WHAT DOES THE BOX TELL US?
systems resist explanation by the tiny steps that a Darwinian pathwould be expected to take. The positive argument is that their parts appear
arranged to serve a purpose, which is exactly how we detect design.
Let me reinforce the positive argument here with the remarks ofsomeone else who is very concerned about the appearance of intelligent
design in life. «Biology is the study of complicated things that give theappearance of having been designed for a purpose.» Thus spoke Richard
Dawkins on the first page of the first chapter of his classic defense of
Darwinism, The Blind Watchmaker. Let me repeat, Dawkins says that's
the very definition of biology—the study of things that appear designed.
In his typically clear prose, Dawkins concisely stated the positive case fordesign in biology, which of course he was intent on demolishing. What is it
about living things that make them appear to have been designed, even tosuch a stalwart Darwinist as himself? Design isn't some default conclusion
we draw when we can't think of anything else, nor is it based on, say, ourwarm, fuzzy feelings at seeing a pretty sunset. Rather, says Dawkins, it's
what we conclude when we get in touch with our inner engineer:
We may say that a living body or organ is well designed if it has attributes
that an intelligent and knowledgeable engineer might have built into it inorder to achieve some sensible purpose, such as flying, swimming, seeing... It is not necessary to suppose that the design of a body or organ is the bestthat an engineer could conceive of. . . . But any engineer can recognize an
object that has been designed, even poorly designed, for a purpose, and hecan usually work out what that purpose is just by looking at the structureof the object.19

In other words, we conclude design from the physical evidence, when
we see a number of elements coming together to accomplish an identifiable
function—the purposeful arrangement of parts.
Dawkins doesn't just grudgingly acknowledge some faint impression ofdesign in life; he insists that the appearance of design, which he ascribes tonatural selection, is overpowering:«Yet the living results of natural selection overwhelmingly impress uswith the appearance of design as if by a master watchmaker, impress uswith the illusion of design and planning.»20
The positive case for design in life is exactly as Dawkins sees: (1) it

TEN YEARS LATER 265
based on the physical arrangement of parts, where the parts work
together to fulfill a function; and (2) it is overwhelming. And because
fhe positive case for design is indeed so overwhelming, it requires
comparatively less explication. On the other hand, more attention isrequired to make it crystal clear why random mutation and natural
selection, especially at the molecular level, are not the powerfulexplanations of life that they are so often touted to be—pace Richard
Dawkins—which is why the bulk of Darwin's Black Box is devoted tothem. By the end of the book we see: that there is little relevant evidence toshow how Darwinian processes might account for the elegant complexityof molecular machinery; that there is a formidable structural obstacle(irreducible complexity) to thinking that such a mechanism can do thejob; and that the appearance of design is even more overwhelming at themolecular level than at higher levels of biology.
Here, then, is the argument for design in a nutshell: (1) We infer design
whenever parts appear arranged to accomplish a function. (2) The strengthof the inference is quantitative and depends on the evidence; the more parts,and the more intricate and sophisticated the function, the stronger is ourconclusion of design. With enough evidence, our confidence in design canapproach certitude. If while crossing a heath we stumble across a watch(let alone a chronometer), no one would doubt—as Paley rightly said—
that the watch was designed; we would be as certain about that as about
anything in nature. (3) Aspects of life overpower us with the appearanceof design. (4) Since we have no other convincing explanation for thatstrong appearance of design, Darwinian pretensions notwithstanding,then we are rationally justified in concluding that parts of life were indeed
purposely designed by an intelligent agent.
A crucial, often-overlooked point is that the overwhelming appearanceof design strongly affects the burden of proof: in the presence of manifest
design, the onus of proof is on the one who denies the plain evidence of
his eyes. For example, a person who conjectured that the statues on Easter
Island or the images on Mount Rushmore were actually the result of
unintelligent forces would bear the substantial burden of proof the claim
demanded. In those examples, the positive evidence for design would bethere for all to see in the purposeful arrangement of parts to produce theimages. Any putative evidence for the claim that the images were actually
the result of unintelligent processes (perhaps erosion shaped by some

266 WHAT DOES THE BOX TELL US?
vague, hypothesized chaotic forces) would have to clearly show that thepostulated unintelligent process could indeed do the job. In the absenceof such a clear demonstration, any person would be rationally justified toprefer the design explanation.
I think these factors account to a large degree for why, much to theconsternation of Darwinian biologists, the bulk of the public rejects
unintelligent processes as sufficient explanations for life. People perceive
the strong appearance of design in life, are unimpressed with Darwinianarguments and examples, and will reach their own conclusions, thank youvery much. Without strong, convincing evidence to show that Darwin cando the trick, the public is quite rational to embrace design.21

STILL SPECULATING AFTER ALL THESE YEARSIn the past decade Darwin's Black Box has been roundly denounced
in official scientific circles. There is hardly a professional-scientificsociety board that hasn't issued some urgent call to its members to help
resist the spread of the pernicious idea of the intelligent design of life.22
So a goodly fraction of the scientific community is highly motivated todiscredit design. Of course, the best way to legitimately discredit design
would be to show that the Darwinian process really can do what its
boosters claim it can do—account for the functional complexity of themolecular foundation of life. Nonetheless, despite the burning motivation,and despite the enormous progress in biochemistry in the past decade at
describing how life works, there have been no serious attempts to accountin Darwinian terms for the examples showcased in Darwin's Black Box—just a few more speculative stories. Although Internet fans of Darwin havebeen busily imagining all manner of transformations, serious Darwinianaccounts would be published in science journals. Let's take a look at just a
few recent journal papers that discuss examples from Chapter 3 through 7.
The first example of an irreducibly complex system discussed in
Chapter 3, the cilium, is an outrageously intricate molecular machine withhundreds of protein parts. In 1996 only a few papers had been publishedtrying to account for the cilium in even the haziest evolutionary terms.

TEN YEARS LATER 267
Yet a serious Darwinian account of such an elegant machine—one
that really sought to answer the question of how such a device could have
evolved—would have to deal with the myriad critical details that allow
the cilium to work, and show how they could each arise with reasonableprobability by random mutation and natural selection, with each tiny
mutational step improving on the last, without causing more problems thanit was worth, and without veering off into temporarily-advantageous-butdead-end structures. It would take at least as much work to figure out how
such a structure could evolve by random mutation and natural selection as
it did to figure out how it works in the first place. At an absolute minimumthat would be expected to result in hundreds of papers—both theoreticaland experimental—many reviews, books, meetings, and more, all devoted
to the question of how such an intricate structure could have evolved in a
Darwinian fashion.
In the last decade the scientific community has made marvelous
progress in understanding how the cilium works, including its unexpectedrole in disease.23 However, in these same years—even as genome upon
genome was sequenced, even as new levels of complexity in the cell were
unearthed—nothing remotely approaching such an evolutionary accountof the cilium has been developed. Darwinian theory has remained deadin the water. The quickest way to illustrate the point is with the very titleof a recent paper on the cilium: «Speculations on the evolution of 9+2
organelles and the role of central pair microtubules.» [emphasis added,
both here and below] In other words, more interesting conjecture, morebeguiling surmise, which have never been in short supply in Darwinian
circles. The abstract of the paper shows the pivotal role of imagination in
the story:[Rlecent advances . . . suggest that these organelles may have served
multiple roles in early eukaryotic cells... we speculate that protocilia
were the primary determinants of cell polarity and directed motility
in early eukaryotes ... we believe that addition of an asymmetric central
apparatus ... provided refined directional control. . . . This paper presents
hypothesized steps in this evolutionary process, and examples to support
these hypotheses.24

The word «selection» appears nowhere in the paper, let alone the phrase«natural selection.» Nor does the word «mutation» occur, let alone the268 WHAT DOES THE BOX TELL US?
phrase «random mutation» or the mention of any specific mutation. All
sciences begin with speculation; only Darwinism routinely ends with it.25«THREE DARWINIAN AXIOMS»

The situation is pretty much the same for all the other examples citedin Darwin's Black Box as for the cilium. The bacterial flagellum, whose
striking mechanical appearance (as seen in the frontispiece) has madeit perhaps the most recognized illustration of the design argument, wasreviewed by the eminent Yale biochemist Robert Macnab for Annual
Review of Microbiology before his untimely death in 2003. The 7,000-word
article does not mention «evolution» or any of its derivatives except once,in the very last sentence. Referring to the flagellum and another structure
called a type III secretory system (TTSS) that in some ways resembles
it, Macnab remarked: «Clearly, nature has found two good uses for thissophisticated type of apparatus. How they evolved is another matter[emphasis added], although it has been proposed that the flagellum is themore ancient device . . .»26 The phrase «natural selection» appears not at
all.
The discovery that the flagellum is more complex than first supposed,that it also contains an unpredicted, sophisticated protein-pumping
mechanism, and that structures resembling the protein pump canoccur independently, briefly set Darwinian hearts aflutter. The innocent
optimism was based on Ken Miller's rhetorical redefinition of irreducible
complexity, which decreed that parts of IС systems could not have anyother function. Since a subset of the flagellum appeared to be part of theTTSS, then that violated Miller's dictum, and cheered some of the more
unreflective Darwinists.
But as I pointed out above, there's no reason that parts or subassemblies
of irreducibly complex systems can't have one or more other functions, andwordplay can't masquerade as a real explanation. Neither the TTSS, theflagellum, nor any transitions between them have been soberly investigatedin a Darwinian framework in the professional science literature. The bestplace to see this is in a recent paper entitled, «Bioinformatics, genomics,
and evolution of non-flagellar type-III secretion systems: a Darwinian
perspective.»27 In it we learn that «A type-III secretion system is an
exquisitely engineered [emphasis added] molecular pump,

TEN YEARS LATER 269
harnessing hydrolysis of ATP to the export of proteins from thebacterial cytoplasm across both the inner and outer membranes and the
periplasm...»Yet the paper simply examines DNA-sequence data arising from genome
sequencing projects. Although they can lead to interesting insight, as I
explain in Chapter 8, even in principle sequence comparisons can't showwhether a structure arose by random mutation and natural selection. The
data, we learn, are viewed «in the light of three Darwinian axioms: (1)Evolution matters...; (2) Variation matters...; (3) Expect imperfection...»[emphasis in original]. Vague aphorisms, however, are not data, andscience does not progress when it confuses the two.
Chapter 6 of Darwin's Black Box describes the intricate immune systemand the challenges it presents to a Darwinian framework. In 2005 a paper
appeared bearing the promising title «The descent of the antibody-based
immune system by gradual evolution.»28 Whatever interesting things it
speculated about gradual evolution, however, it had nothing to say about
Darwinian evolution.29 In fact neither Darwin's name nor any derivative
word appeared in the paper. Nor did the phrase «natural selection» appear;«selection» is used once. «Mutation» appears twice, but the envisioned
mutations are not specified. Words that do occur often include «probably,»«imagine,» «may have,» «might have,» and so on. At the end of the paper
the authors suggest several experiments to be done at some unspecified
point in the future; otherwise, they say, their scenario would «remain
hopelessly in the realm of mere speculations.» In other words, the authors
themselves acknowledge that their paper is speculative. All scientificexplanations may begin in speculation, but none can end there.
Chapter 4 discusses the clotting cascade. In 2003 Russell Doolittle
and a co-worker published a paper entitled «The evolution of vertebrate
blood coagulation as viewed from a comparison of puffer fish and sea
squirt genomes.» As the title indicates, it simply compares sequences. As I
pointed out in Chapter 4 ten years ago, sequence comparison can give aninteresting overall picture of what proteins came first and second, and of
who is related to whom, but can't even begin to tell what is driving a process.
Another paper appearing the same year with the juicy title «Molecular
evolution of the vertebrate blood coagulation network»30 also is just an
exercise in sequence comparisons, with a few paragraphs of speculation.

270 WHAT DOES THE BOX TELL US?
Today the situation remains unchanged from what it was ten years ago.
As I wrote in Chapter 8:
There is no publication in the scientific literature—in prestigious
journals, specialty journals, or books—that describes how molecular
evolution of any real, complex, biochemical system either did occur
or even might have occurred. There are assertions that such evolution
occurred, but absolutely none are supported by pertinent experiments or
calculations.

THE PAYOFF QUESTION

The papers I cite here on the cilium, flagellum, blood clotting, andimmune systems are the best work by Darwinists on the origin of complex
molecular machinery available since 1996 in the science literature. In recent
essays aimed at the general public, the argument for design is generally
caricatured, and the payoff question—what is the evidence for the power ofnatural selection?31—given short shrift. In 2005 the University of Chicago
evolutionary biologist Jerry Coyne wrote a 14,000-word article entitled«The Case Against Intelligent Design» for the magazine The New Republic.
In the essay Coyne ranged far and wide, from the Scopes Monkey Trial, tothe use of the word «theory» in science, to Henry Morris and the Institutefor Creation Research, to the flightless kiwi bird of New Zealand. Andof all that space he allotted just two sentences to the payoff question, theevidence for the power of random mutation and natural selection:
Biologists have now observed hundreds of cases of natural selection,
beginning with the well-known examples of bacterial resistance toantibiotics, insect resistance to DDT and HIV resistance to antiviral drugs.
Natural selection accounts for the resistance of fish and mice to predators
by making them more camouflaged, and for the adaptation of plants to
toxic minerals in the soil.32

Yet antibiotic resistance, resistance to DDT and resistance of HIV todrugs have all been known for decades. All of Coyne's examples were
well known when Darwin's Black Box first appeared a decade ago, they all
involve tiny, simple molecular changes, and none helps to explain any ofthe examples of the book. With all that space he still avoids engaging

TEN YEARS LATER 271
the real arguments ot intelligent design. What does Professor Coyne
say about sophisticated molecular machinery? Well sure he reluctantly
agrees, «There is no doubt that many biochemical systems are dauntingly
complex.» But don't jump to any hasty conclusions, because «biologists
are beginning to provide plausible scenarios for how 'irreducibly complex'
biochemical pathways might have evolved [emphasis added].
Plausible scenarios—like those for the cilium, flagellum, and immune
system in the papers I cited above. In his review of Darwin's Black Box
shortly after its publication in 1996 University of Chicago microbiologist
James Shapiro declared, «There are no detailed Darwinian accounts forthe evolution of any fundamental biochemical or cellular system, only avariety of wishful speculations.»33 Ten years later, nothing has changed.
Call them wishful speculations or call them plausible scenarios—both justmean a lack of real answers.

FUTURE PROSPECTS

The future prospects for design are excellent, because they rest not
on any person's or group's preferences, but on the data. The rise of theintelligent design hypothesis is not due to anything I or any other individual
has written or said, but to the great advance of science in understanding
life. In Darwin's day, the cell was thought to be so simple that first-ratescientists such as Thomas Huxley and Ernst Haeckel could seriously thinkthat it might arise spontaneously from sea mud, which would be quite
congenial to Darwinism. Even just fifty years ago it was a lot easier tobelieve that Darwinian evolution might explain the foundation of life,
because so much less was known. But as science quickly advanced andthe astonishing complexity of the cell became clear, the idea of intelligent
design has become more and more compelling. The conclusion of
intelligent design is strengthened by each new example of elegant, complex
molecular machinery or system that science discovers at the foundationof life. In 1996 that elegance already could be clearly seen, and in the pastten years it has greatly increased. There is no reason to expect it to level off
any time soon.
It is a hard fact that the scientific case for the intelligent design hypothesis
is getting much stronger. A separate, more dicey topic, however, concerns
people's reaction to intelligent design. How will the idea of intelligent

272 WHAT DOES THE BOX TELL US?
design be regarded by the public and by the scientific community in years
to come? That's more a question of sociology and politics than of science.
On the one hand, although newspaper editorialists might disapprove, polls
show that the great majority of the public already is convinced of design.
On the other hand, because it has been raised on Darwinism, much of
the scientific community is used to thinking exclusively in Darwinian
terms. Nonetheless, even there it seems, the times they are a-changin'. A
recent news article in the journal Nature reported on an invitation-only
meeting where up-and-coming students could rub elbows with Nobel
prize winning scientists. For this year's meeting the organizing committee. . . invited scientific academies and other agencies around the world toopen competitions for young scientists to attend, then whittled down a listof nearly 10,000 applicants. The final 2005 list of 720 invitees represented
a new profile of participant: academically excellent, familiar with societal
impacts of their research and fluent in English. They are generally under
thirty, but the majority are now Ph.D. students or postdocs.

But the students asked surprising questions.
«It is curious to see the questions that students from different cultures
ask,» [Günter Blobel (medicine, 1999)] remarked after a discussion on
evolutionary biology led by Christian de Duve (medicine, 1974). He wastaken aback to find some students expressing so much interest in the«creative guiding hand» of intelligent design.34

APPENDIX
THE CHEMISTRY OF LIFE
This appendix will give the interested reader an overview of biochemical
principles that undergird life. It is not necessary to read the appendix tofollow the arguments in the book, but it will set those arguments withina larger framework. Here I will discuss cells and the structures of several
major classes of biomolecules—proteins and nucleic acids and, briefly,
lipids and carbohydrates. I will then focus on the question of how genetic
information is expressed and propagated. Of course, in such a short space
the description must be sketchy, so I urge those who become intrigued by
the mechanisms of life to borrow an introductory biochemistry text fromthe library. A fascinating Lilliputian world awaits.

CELLS AND MEMBRANESThe human body is composed of hundreds of trillions of cells. Other
large animals and plants also are conglomerations of enormous numbersof cells. As the size of an organism decreases, however, the number of cells
decreases also; for example, the small worm C. elegans contains only about
a thousand cells. As we travel down the size scale we273

274 WHAT DOES THE BOX TELL US?
ultimately reach the unicellular phyla such as yeast and bacteria. No
independent life occurs below this level.
Examination of its structure shows why the cell is the fundamental unitof life. The defining feature of a cell is a membrane—a chemical structurethat divides the outside world from the interior of the cell. With theprotection of a membrane, a cell can maintain different conditions inside
than prevails outside. For example cells can concentrate nutrients in theirinterior so that they are available for energy production and can prevent
newly made structural materials from being washed away. In the absenceof a membrane, the large array of metabolic reactions necessary to sustain
life would quickly dissipate.
Cell membranes are made from amphiphilic molecules that are similar
in ways to the soaps and detergents used in household cleaning. The word
amphiphilic is from the Greek meaning «loves both»; an amphiphilicmolecule «loves» two different environments: oil and water. The shape ofthe molecules is roughly similar to a lollipop with two sticks coming out
the same side of the candy ball. The sticks usually consist of hydrocarbons(made from atoms of carbon and hydrogen) and, like other hydrocarbons
such as gasoline, do not mix well with water. This is the oil-loving part ofthe molecule. Such regions of molecules are called hydrophobic, from theGreek for «water-fearing.» The ball of the lollipop molecule, in contrast,
generally has a chemical group that, like table salt or sugar, positively enjoys
being in water. Such regions are called hydrophilic («water-loving»). The
two opposite parts of membrane molecules are chemically tied together
and, like Siamese twins, must travel together despite dissimilar properties.
But if one part of the molecule wants to be in water and the other partwants to be out of water, where does the molecule settle down?
Amphiphilic molecules solve their dilemma by associating with otheramphiphilic molecules. When a large number of amphiphiles associate,
the hydrophobic tails all huddle together to exclude water while thehydrophilic heads touch the water. An efficient way for the tails to beshielded from water while still allowing the water-loving groups accessto water is to form two sheets (Figure A-l), called a lipid bilayer. If thetwo sheets remained flat, however, the hydrocarbons at the edges of the
sheets would remain exposed to water. So the sheets close up, like a soap
bubble.
Since the middle of the membrane bilayer is oily, many moleculesTHE CHEMISTRY OF LIFE 275
FIGURE A-1
A segment of a lipid bilayer.

that strongly prefer a watery environment (such as salts and sugars)
cannot cross the membrane. Thus we have a structure with an enclosed
interior that can be different from the outside environment— the first stepin making a cell.
The living world contains two fundamentally different type of cells:
the eukaryotes, in which a second membrane, different from the cell
membrane, encloses the nucleus of the cell; and the prokaryotes, which
do not have this feature.1 Prokaryotic organisms are invariably unicellularand are, in many ways, much simpler than eukaryotes.
Besides the cell membrane only a few features stand out inphotographs of prokaryotes.2 One is the nucleoid, the mass of cellular
DNA (deoxyribonucleic acid) resting comfortably in the middle ofthe cytoplasm (the soluble cell contents). In addition to a membrane,
prokaryotes have a second structure surrounding the cell, called the cellwall. Unlike the membrane, the cell wall is made of polysaccharide thatis rigid and freely permeable to nutrients and small molecules. It confers
mechanical strength, preventing the cell from rupturing under stress.
Several structures stick out from the membrane of many prokaryotic cells.
The function of the hairlike pili is largely unknown. The bacterial flagellum
is used for locomotion; flagella rotate rapidly like a propeller to move theprokaryote along.
The second category of cells is the eukaryotes, which compose allmulticellular organisms, as well as some single-celled organisms like

276 WHAT DOES THE BOX TELL US?
yeast. Eukaryotic cells contain a number of subcellular spaces that are
separated from the cytoplasm by their own membranes; these are calledorganelles, because they are reminiscent of the organs found in the bodyof an animal. Organelles allow the eukaryotic cell to conduct specialized
functions in specialized compartments.
The first specialized organelle is the nucleus, which contains the cell'sDNA. The membrane surrounding the nucleus is a highly specialized
structure, perforated by large, eight-sided holes called nuclear pores. The
pores are not passive punctures, however; they are active gatekeepers. No
large molecule (like proteins or RNA) gets past the nuclear pores without
the correct «password.» This keeps molecules that belong in the cytoplasm
out of the nucleus, and vice versa.
A number of other organelles stud the cytoplasm. Mitochondria arethe «power plants» of the cell; they specialize in the chemical reactions
that turn calorie-laden nutrient molecules into forms of chemical energythat the cell can use directly. Mitochondria have two membranes. The
controlled «burning» of nutrient molecules generates a difference between
the acidity of the space enclosed by the inner membrane and that enclosed
between the inner and outer membranes. The controlled flow of acidbetween the two compartments generates energy, like the flow of waterover a dam generates electrical power.
Lysosomes are small organelles bounded by a single membrane;essentially, they are bags of enzymes which degrade molecules that haveoutlived their usefulness. Molecules destined to be degraded in thelysosomes are transported there in small, coated vesicles (see Chapter 5).
The acidity in the lysosome is one hundred to one thousand times greaterthan that in the cytoplasm. The increased acidity makes tightly folded
proteins open up, and the open structures are then easily attacked bydegradative enzymes.
The endoplasmic reticulum (ER) is an extensive, flattened, convoluted
membrane system that is divided into two different components: therough ER and the smooth ER. The rough ER gets its craggy appearance
from numerous ribosomes attached to it; ribosomes are the cellularmachinery that synthesize proteins. The smooth ER synthesizes lipids—
fatty molecules. The Golgi apparatus (named for Camillo Golgi, who firstobserved it) is a stack of flattened membranes to which many proteinsmade in the ER go for modification.
A cell can take on shapes radically different from spherical (for ex-THE CHEMISTRY OF LIFE 277
ample, a sperm cell), and can change shape in response to changes in theenvironment. The shape of the cell is supported by the cytoskeleton, which,as its name implies, is the cell's structural framework. The cytoskeleton
is composed of three major structural materials: microtubules,
microfilaments, and intermediate filaments. Microtubules serve a numberof functions. Among these are formation of the mitotic spindle—theapparatus that, during cell division, pushes one copy of each chromosome
into each daughter cell. Microtubules are also the spine of eukaryotic
cilia, which, like oars, can move the cell through its environment.
Finally, microtubules can act as «railroad tracks» for molecular motors
to carry cargo to distant parts of the cell. Microfilaments, thinner than
microtubules, are made of the protein actin, which is also a major
component of muscle. Microfilaments grab onto each other and slide tocontract. This shapes the cell by folding the cellular membrane at the rightplaces. Intermediate filaments, which are thicker than microfilaments but
thinner than microtubules, seemingly act simply as structural supports(like steel girders). Intermediate filaments are the most diverse structuresof the cytoskeleton.
Almost all eukaryotic cells contain the organelles described above.
Plant cells, however, contain several additional organelles. The chloroplast is the site of photosynthesis. Chloroplasts are, in many ways, similar
to mitochondria since they both have energy-generating responsibilities.
Chloroplasts contain the pigment chlorophyll, which acts as an antenna tocatch light. The energy of the light is passed to extremely complex molecularmachinery that generates differences in acidity across the membranes of
the chloroplast. Plant cells also have a large, clear, membrane-enclosed
space called the vacuole. The vacuole is a reservoir for wastes, nutrients,
and pigments, and it also has a structural role. The vacuole occupies about
90 percent of the volume of some plant cells and is under high osmoticpressure. The pressure, pushing against a strong plant cell wall, stiffens
the cell.

PROTEIN STRUCTURE

Thе cells and organelles described above, although quite tiny byeveryday standards, are very large compared to the building materials of
which they are composed. The building materials of cells and subcellular
structures are ultimately composed of atoms stitched together

278 WHAT DOES THE BOX TELL US?
into molecules. A chemical bond, or covalent bond, forms when eachof two atoms contributes an electron to share between them. By sharing
negatively charged electrons, the atoms more efficiently screen theirpositively charged atomic nuclei. A molecule is two or more atoms covalently bonded to each other.
Surprisingly, the types of atoms found in biological molecules are few.
Almost all biomolecules are made of atoms of six elements: carbon (C),oxygen (O), nitrogen (N), hydrogen (H), phosphorous (P), and sulfur(S). Some other elements (such as chlorine, sodium, calcium, potassium,magnesium, and iron) are found as ions in biological systems. (Ions areelectrically charged particles that float more or less freely in water.)Atoms of С, H, O, N, P, and S can bond with each other. Carbon canbond with up to four different atoms at once, and biological phosphorus
can also bond four different atoms (almost always four oxygens). Nitrogencan form three bonds (four in special cases), and oxygen and sulfur canform two. Hydrogen can form only one bond to another atom. Carbon is
unique among the elements in that it can form stable bonds with othercarbon atoms to form long chains. Since a carbon in the middle of a chain
has used only two of its bonds—one to bond to the carbon on its right, andthe other to bond to the carbon on its left—it still has two more bonds tomake. It can use one to bond, say, a nitrogen atom and the other perhaps
to bond to another chain of carbon atoms.
The number of molecules that can be built from carbon and the otherbiological elements is very large indeed. Biological systems, however, don't
use a large number of completely different molecules. Rather; a limited
number of molecules are made and the large, «macro» molecules of life—
such as proteins, nucleic acids, and polysaccharides—are constructed bystringing together in different arrangements molecules from the limited
set. This can be likened to making an enormous number of different words
and sentences from the twenty-six letters of the alphabet.
The building blocks of proteins are called amino acids. The twenty
different amino acids that compose virtually all proteins have a common
structure. On the left side of the molecule is a nitrogen-containing groupcalled an amine, and on the right, joined to the amine by a central carbon
atom, is a carboxylic acid group (hence the name amino

THE CHEMISTRY OF LIFE 279
acid). Also attached to the central carbon, in addition to a hydrogenatom, is another group, called the side chain (Figure A-2). The side chainvaries from one type of amino acid to another. It is the side chain thatgives an amino acid its particular character.
Amino acids can be grouped into several categories. The first groupcontains hydrocarbon side chains (side chains with only carbon andhydrogen atoms). These side chains are oily, like gasoline, and prefer toavoid contact with water molecules. The next group is the electricallycharged amino acids; there are three positively and two negatively charged
members. Charged side chains prefer to be in contact with water. Anothergroup is the polar amino acids. Polar molecules, although not fully
charged, have partially charged atoms in them. This arises when one atom
pulls more strongly on the electrons than its partner atom in a chemicalbond, bringing the electrons closer to it. The atom with the lion's share of
the electrons has a somewhat negaFIGURE A-2(Top) Four amino acids. The amino acids differ only in their side
chains. (bottom) the four amino acids have been chemicallyjoined. proteins are long chains of many chemically joinedamino acids.

280 WHAT DOES THE BOX TELL US?
tively charged character, while the atom with a deficiency of electrons
has a partial positive charge. Interactions between positively and negatively
charged side chains, and between the partially positively and partiallynegatively charged atoms of polar side chains, can be very important in
the structure of proteins.
During the synthesis of proteins, two amino acids are chemicallyjoined together by reacting the amino group of one amino acid with thecarboxylic acid group of another to form a new group called a peptide bond(Figure A-2). The new molecule still has a free amino group at one end anda free carboxyl at the other end, so another amino acid can be joined bycontributing its amino end to form another peptide bond. This process
can be repeated indefinitely until a macromolecule, containing hundreds
or thousands of amino acid «residues» (the part left after the chemical
reaction joining two amino acids), has been formed. Such macromolecules
are known as polypeptides or proteins.
A typical protein contains anywhere from about fifty to about three
thousand amino acid residues. The amino acid sequence of a protein iscalled its primary structure. The completed protein still has a free aminogroup at one end, referred to as the N-terminal end, and a free carboxyl
at the other end, called the C-terminal end. The amino acid sequence ofa protein is conventionally written starting from the N-terminal to the
C-terminal end. The atoms of the protein joined in a line from the N to theС terminal are called the protein backbone; this includes all atoms except
those of the side chains.
A freshly made protein does not float around like a floppy chain. In aremarkable process, virtually all biological proteins fold up into discreteand very precise structures (Figure A-3) that can be quite different fordifferent proteins. This is done automatically through interactions such as
a positively charged side chain attracting a negatively charged side chain,
two hydrophobic side chains huddling together to squeeze out water, largeside chains being excluded from small spaces, and so forth. At the end of
the folding process, which typically takes anywhere from fractions of asecond to a minute, two different proteins can be folded to structures asprecise and different from each other as a three-eighths-inch wrench anda jigsaw. And, like the household tools, if their shapes are significantly
warped, then they fail to do their jobs.
When proteins fold, they do not flop together like a string crushedTHE CHEMISTRY OF LIFE 281

282 WHAT DOES THE BOX TELL US?
in your hand; there are regularities to the folding. Before a protein
folds, its polar backbone atoms—the oxygen and nitrogen and hydrogen atoms in each peptide bond—form what are called hydrogen bonds
to water molecules. A hydrogen bond occurs when a partially negatively
charged peptide oxygen or nitrogen atom associates closely with thepartially positively charged hydrogen atoms of water. When a protein
folds, however, it must squeeze out all (or almost all) of the water so thatthe oily side chains can pack efficiently. This poses a problem: the polar
peptide atoms must find oppositely charged partners in the folded protein,or else the protein will not fold.
There are two ways proteins solve this problem. First, segments of theprotein can form an α-helix. In this structure the protein backbone spirals.
The geometry of the spiral makes the oxygen atom of a peptide group point
directly towards, and hydrogen bond with, the hydrogen of the peptidegroup found four amino acid residues back along the chain (Figure A-3).
The next residue hydrogen bonds with the subsequent residue four backfrom it, and so on. Usually an α-helix has anywhere from five to twentyfive amino acid residues before the helical structure (but not necessarily
the protein chain) ends. An α-helix permits a protein to fold into a compact
shape while still forming hydrogen bonds to peptide atoms. A second
structure that allows regular hydrogen bonding of peptide atoms is calleda β-pleated sheet, or simply a β-sheet. In this structure the backbone ofthe protein goes up and down, like pleats in a sheet, and the peptide atoms
stick out perpendicular to the direction of the protein chain. The chain
then curls around, comes back, and the oxygen atoms in the peptide groupof the returning strand hydrogen bond to the peptide group of the firststrand. As with α-helices, β-sheets allow polar backbone atoms to formhydrogen bonds.
α-helices and β-sheets are known as the secondary structure of theprotein. A typical protein has about 40 to 50 percent of its amino acidresidues involved in helices and sheets. The remainder of the residues
are involved in turns between portions of secondary structure, or else
form irregular structures. Helices and sheets pack against each other toform, in most cases, a compact, globular protein. The exact way in which
the elements of secondary structure pack is called the tertiary structure(Figure A-3) of the protein. The driving force for the packing of the helices
and sheets comes from the oily nature of many protein side chains.

THE CHEMISTRY OF LIFE 283
Just as oil separates from water to form a distinct layer, so the oily,hydrophobic side chains huddle together to form a water-free zone in theinterior of the protein. Recall, however, that some protein side chains areeither polar or charged, and they want to stay in the water. The pattern ofoily and polar side chains along the amino acid sequence, and the needfor the protein chain to fold so that most of the hydrophobic groups are in
the interior of the protein and most of the hydrophilic groups are on theexterior, provides the information that drives a specific protein to fold toa specific structure.
Another factor also contributes to the specificity of protein folding.
In all folded proteins some polar side chains inevitably get buried. If theburied polar atoms do not find hydrogen-bonding partners, then theprotein is destabilized. In most proteins about 90 percent of the buried
polar side chain atoms are, in fact, hydrogen bonded to other side chainsor to the protein backbone in a catch-as-catch-can manner. The foldingof a typical protein—with its requirements to accommodate hydrophobic
and hydrophilic groups and to form a network of hydrogen bonds—can belikened to a three-dimensional jigsaw puzzle.
Frequently, several separate polypeptides stick together in a very
specific way to form a composite structure that functions as one entity.
In these cases it is the custom to refer to the associated polypeptides as asingle protein composed of several «subunits.» For example, the oxygencarrying protein hemoglobin is composed of four polypeptides, and theamalgamated protein has oxygen-binding properties that the component
polypeptides lack. Thus the functional biological protein is the complex of
the four polypeptides. The specific arrangement of separate polypeptides
in a protein is called its quaternary structure (Figure A-3).

NUCLEIC ACID STRUCTURE

Like proteins, nucleic acids are polymers of a small number of building
blocks, called nucleotides. A nucleotide itself has several parts. The firstpart is a carbohydrate, either ribose (in RNA) or deoxyribose (in DNA).
To ribose is attached one of four bases, either adenine (A), cytidine (C),guanine (G), or uracil (U). If the carbohydrate is deoxyribose then U is
replaced by a similar base called thymine (T); A, C, and G are also usedwith deoxyribose. Attached to a different part of the car-284 WHAT DOES THE BOX TELL US?
bohydrate ring (to the 5'-OH or «five-prime hydroxyl» group) is a
phosphate group. The sugar-phosphate portion of a nucleotide is analogous
to the backbone portion of an amino acid, and the base is analogous to anamino acid side chain. It is only in its base that one nucleotide differs fromanother.
Two nucleotides can be joined chemically by reacting the phosphate of
one nucleotide with the 3-OH group of the carbohydrate portion of thesecond nucleotide (Figure A-4). This still leaves a free phosphate group on
one end and a free 3-OH group on the other end, which can be further
reacted with other nucleotides. Repetition of this process can generate very
long polynucleotides indeed. Cellular RNA ranges from about seventy toabout fifty thousand nucleotides in length. One single molecule of DNA
ranges from several thousand to about a billion nucleotides. The sequenceof a polynucleotide is conventionally written starting from the 5' end to
the 3' end.
Cellular RNAs are found as single polynucleotide chains. There areseveral biological classes of RNA. The first is called messenger RNA(mRNA); members of this class are produced as faithful transcripts of
DNA genes; the genetic information carried by mRNA is then interpretedby the protein synthetic apparatus to produce a protein. The second typeof RNA is called ribosomal RNA (rRNA). Polynucleotides in this classassociate with a large number of different proteins to form the ribosome,the primary engine of protein synthesis. The last major category of RNA
is called transfer RNA (tRNA). Members of this class are relatively small,seventy to ninety nucleotides in length, and serve as «adaptors» between
the mRNA and the growing protein that is produced by the action of theribosome.
Cellular DNA is found as a double-stranded molecule—two intertwined
polynucleotides (the famous double helix) that are strongly held together
by hydrogen bonding. To understand the reason for this we must look at
the structure of the bases of the nucleotides (Figure A-4). The nucleotides
can be divided into two categories—the purines (A and G), which carrythe larger bases (composed of two fused rings), and the pyrimidines (Cand T), which have only one ring. If A and T are correctly oriented, they
can form two hydrogen bonds with each other, and G can form threehydrogen bonds with C. In cells, wherever there is a G in one strand of
DNA there is а С in the second strand, and vice versa; and wherever there
is an A in one strand there is a T in

THE CHEMISTRY OF LIFE 285
FIGURE A-4
A PIECE OF DNA CONTAINING FOUR NUCLEOTIDES.

286 WHAT DOES THE BOX TELL US?
the second strand, and vice versa. Thus the two strands are called«complementary» to each other. To be correctly oriented for hydrogenbonding the two strands must be pointed in different directions, with one
running 5' to 3' from left to right and the other going 5' to 3' from right toleft. The DNA of eukaryotes consists of two complementary linear strands,
but the DNA of many bacteria consists, surprisingly, of two complementary
circular strands.
The amount of DNA in a cell varies roughly with the complexity of theorganism. Bacteria have about several million nucleotides of DNA. The
amount of eukaryotic DNA ranges from a low of several tens of millions of
nucleotides in fungi to a high of several hundred billion in some flowering
plants. Humans come in at around three billion nucleotides.

LIPIDS AND POLYSACCHARIDES

Two other major categories of biomolecules are lipids and polysaccharides.
Polysaccharides are polymers of sugar molecules or their derivatives andplay a variety of roles. They can be used as structural materials, such as thecellulose found in woody plants and trees, and as repositories of energy,
such as the glycogen which is stored in the liver. Lipids, unlike proteins,
nucleic acids, and polysaccharides, are not polymers made from discretebuilding blocks; rather, each lipid molecule must be synthesized fromvery basic starting materials. Lipids are not macromolecules, but they can
associate to form large structures such as membranes.

TRANSCRIPTION

DNA, the repository of genetic information, is a polynucleotide. But the
information it carries tells the cell how to make polypeptides— proteins.
How does the information get translated from one polymer «language»
to the other? Shortly after the discovery of the double helical structureof DNA physicist George Gamow proposed the very non-chemical ideathat genetic information is stored in coded form, and that expressing
the information involves decoding the polynucleotide and translating
the message into the polypeptide language of proteins.3 Although he
was wrong about the specific nature of the code, Gamow's intuition wasprophetic.

THE CHEMISTRY OF LIFE 287
During the early 1960s the code was broken. Nobel laureates MarshallNirenberg, Severo Ochoa, H. Gobind Khorana, and their associates showedthat in the genetic code three contiguous nucleotides correspond to one
amino acid (Figure A-5). Since there are sixty-four possible combinations offour bases taken three at a time, there are more than enough permutations
to code for all twenty amino acids. All possible three base «codons» areused by the cell, so the genetic code is redundant, meaning that several
different codons can designate the same amino acid. For example ACU,
ACC, АСА, and ACG all code for the amino acid threonine. Most aminoacids have two or more codons designating them; several, however, have
only one. A total of sixty-one of the possible sixty-four codons designateamino acids; the remaining three are used as «stop» codons. When the
decoding apparatus encounters one of these special signals, it halts its
production of protein at that point.
The large number of steps involved in extracting the information
contained in DNA can be divided into two conceptual categories called
transcription and translation. Briefly, in transcription a cell makes an
RNA copy of a small portion of its DNA (termed a gene) that
FIGURE A—5 THE GENETIC CODE.

288 WHAT DOES THE BOX TELL US?
codes for a protein; in translation the information in the RNA is used
to produce a protein.
The transcription of a gene entails a number of decisions, the first ofwhich is where along the huge DNA chain to start. The beginning positionis generally marked by several special DNA sequences, called «promoters.»
In prokaryotes a sequence of DNA nucleotides (usually TCTTGACAT)
called the «–35 region» occurs about thirty-five nucleotides before a gene;another sequence (usually TATAAT) called the «Pribnow box» occurs
five to ten base pairs prior to the transcription initiation site. In addition
to similar signals, eukaryotes have DNA sequences called «enhancers»
thousands of base pairs away from the transcription start site; enhancers
can greatly affect the rate at which a gene is transcribed.
To begin transcription, in prokaryotes a multisubunit enzyme
called RNA polymerase binds to DNA. RNA polymerase consists of five
polypeptide chains. Initially the enzyme binds loosely, moving along the
DNA like cars on a roller coaster until it finds the promoter region of agene. When it does, one of the protein's subunits, called σ, recognizes
the promoter DNA sequence. Right after RNA polymerase finds thepromoter sequence σ floats away, its job finished. In the absence of σ, RNApolymerase binds quite tightly to the DNA and can no longer move freely.
Now its work begins. The RNA polymerase «melts» about ten base pairsof DNA, separating the two polynucleotide strands from each other overthat region. This is necessary so that the RNA chain that will be made can«read» the DNA template by hydrogen bonding to it. Now the polymerase
binds the activated form of a ribonucleotide that is complementary to
the first DNA base where transcription starts. Next it binds the second
ribonucleotide, complementary to the second DNA base.
Once the first two correct ribonucleotides are matched to the template,the RNA polymerase chemically joins them. The polymerase then moves
down one position along the DNA template, keeping the DNA strands
separate as it goes. It matches the third position with its corresponding
activated ribonucleotide, and joins that to the growing chain. These steps
are repeated along the gene at a very high rate, moving at approximately
twenty to fifty nucleotides per second.
Transcription causes a problem: the movement of the polymerase
through the interwound, helical DNA causes the DNA ahead of theTHE CHEMISTRY OF LIFE 289
polymerase to become tightly overwound.4 This would cause
transcription to slow down or halt completely except that another protein,called topoisomerase, untangles the DNA. It does this by a complicatedmaneuver—cutting one strand of the tangled DNA, passing the uncut
DNA strand through the cut strand, and then resealing the cut.
Transcription stops when the RNA polymerase runs into a special DNA
sequence. In prokaryotes it is a palindromic5 region containing about six
or seven GC base pairs followed by a region of the same length rich in AT
base pairs. Some, but not all, genes require an additional protein, called ρ,
to make the polymerase fall off the DNA.

GENE REGULATION

A typical bacterial cell contains thousands of genes, and a typicalmammalian cell contains tens of thousands. How does a cell know when totranscribe a gene, and how does it select a specific gene from the thousands
available? The problem of «gene regulation» is a major focus of research.
Many details have been uncovered, but much remains murky. One of thesimplest examples of gene regulation is the regulation of the life cycle ofbacteriophage λ. Bacteriophages—the prokaryotic analogs to viruses—arebits of DNA wrapped in a protein coat. In order to make copies of itself,a bacteriophage must find a suitable bacterial cell, attach itself to the cell,and inject its DNA into the host. The DNA from the phage is quite small,coding for only about fifty genes. This is not sufficient to make its own
replication machinery so, cleverly, the phage hijacks the host's machinery.
Thus the phage is a parasite, unable to provide completely for itself.
Sometimes when bacteriophage λ invades a cell, the cell makes so many
copies of λ that it bursts. This is called the lytic cycle. At other times, however,
λ inserts its own DNA into the bacterial DNA, making a single moleculefrom two. There the λ DNA can rest quietly, be replicated along with therest of the bacterial DNA when the cell divides, and bide its time. This iscalled the lysogenic cycle. When the bacterium, perhaps many generations
later, runs into trouble (by, say, encountering high doses of ultraviolet
light), the λ DNA in the bacterial DNA switches to the lytic mode. Only
now does the phage make thousands of copies of itself, bursting the celland spilling out new bacteriophages.

290 WHAT DOES THE BOX TELL US?
What switches bacteriophage λ from the lysogenic to the lytic cycle?
When bacteriophage DNA enters the cell, RNA polymerase binds toa bacteriophage λ transcription promoter. One of the first genes to be
expressed is for an enzyme, called an «integrase,» that chemically inserts
the λ DNA into the bacterial DNA. The enzyme does this by cutting thecircular λ DNA at a specific site that has a sequence similar to a site in thehost DNA, which the integrase also cuts. This leaves both pieces of DNA
with complementary, «sticky» ends that hydrogen bond to each other. The
integration enzyme then joins the pieces of DNA.
Another λ gene codes for a protein called a «repressor.» The repressor
binds strongly to a sequence of λ DNA which RNA polymerase mustbind to start the lytic cycle. When λ repressor is there, however; RNApolymerase cannot bind, so the lytic cycle is switched off. There are actually
three binding sites for repressor—all in a row. Repressor binds the first site
more strongly than the second site, and the second more strongly than thethird. The third site overlaps the promoter for the gene that codes for the
repressor itself. This arrangement allows the repressor to be synthesized
continuously until the third site is filled, at which point synthesis stops. If
the concentration of repressor falls to the point where it dissociates fromthe third site, then the repressor gene is again turned on.
By this mechanism λ repressor regulates its own production. In thepresence of some chemicals, ultraviolet light, or other damaging agents,
however, a gene for an enzyme that specifically destroys λ repressor isswitched on. When the repressor is removed from the first site, the gene
for a protein called Cro is activated. Cro protein binds strongly to thethird λ repressor binding site, shutting it off forever, and launching thebacteriophage into the lytic cycle. All the genes necessary for making copiesof the λ DNA and packaging them into protein coats are now transcribed.
The control of the life cycle of bacteriophage λ is one of the simplest
examples of gene regulation. The regulation of other gene systems,
especially in eukaryotes, can involve dozens of proteins. Nonetheless, it isthought that most genes are regulated by systems analogous to that of λ,with feedback controls and multiple factors conniving to decide whether asingle gene should be turned on.

THE CHEMISTRY OF LIFE 291

TRANSLATION

Once the messenger RNA has been produced, the task turns totranslating the message into a protein. This process is best understood inprokaryotes.
The transcribed mRNA is bound by a particle called a ribosome. Ribosomes are huge complexes consisting of fifty-two separate proteins (ofwhich several are present in multiple copies) and three pieces of RNA withlengths of 120, 1,542, and 2,904 nucleotides. The ribosome can be readily
broken down into two large pieces, called the 30S sub-unit and the 50S
subunit.6 Incredibly, the ribosome is self-assembling. Experiments haveshown that when ribosomes are separated into their components and thenremixed, under the right conditions the components will spontaneously
reform ribosomes.
The ribosome has a problem similar to that of RNA polymerase: theribosome must find the point in the mRNA at which to begin translation.
In prokaryotes the site is marked by a tract called the Shine-Dalgarno
sequence, about ten nucleotides upstream from the initiation site. Initiation
occurs at the first subsequent AUG sequence. (AUG codes for the aminoacid methionine.) In eukaryotes, initiation usually begins simply at thefirst AUG sequence from the 5'-end of the mRNA.
Ribosomes cannot bind directly to mRNA by themselves; several
other factors are required. In prokaryotes three proteins called initiation
factors—labeled IF-1, IF-2, and IF-3—are necessary. To begin translation,
IF-1 and IF-3 bind to the 30S ribosomal subunit. This complex thengoes on to bind (1) to a previously-formed complex of a tRNA molecule
carrying methionine and bound to IF-2, and (2) to the mRNA molecule atthe initiation site. Next, the 50S ribosomal subunit binds to the growing
complex, causing IF-1, IF-2, and IF-3 to fall off. In eukaryotes, translation
initiation goes through similar steps, but the number of initiation factors
can be as high as ten or more.
In the next step a second tRNA molecule, associated with a protein
named elongation factor Tu (EF-Tu), comes in carrying the appropriate
amino acid and binds to the ribosome. A peptide bond forms between the
two amino acids held on the ribosome. The first tRNA molecule now has
lost its amino acid, and the two covalently bonded amino acid residues arelinked to the second tRNA. At this point the first292 WHAT DOES THE BOX TELL US?
tRNA dissociates from the ribosome, the second tRNA moves into
the site on the ribosome previously occupied by the first tRNA, and theribosome moves precisely three nucleotides down on the mRNA. Thistranslocation process requires another protein called EF-G for some asyet-unknown function.
These steps are repeated until the ribosome reaches a three-nu-cleotide
sequence that corresponds to a stop codon. Another protein, called releasefactor, binds to the stop codon, preventing the ribosome from moving
there. Additionally, the release factor changes the behavior of the ribosome.
Instead of simply sitting on the mRNA waiting for the release factor to
move, the ribosome cuts the completed polypeptide chain from the final
tRNA molecule to which it is still attached, and the protein floats free into
solution. The inactive ribosome then dissociates from the mRNA, floats
away, and is free to begin another round of protein synthesis.
Other factors, too numerous to mention in this brief sketch, arealso necessary for a functioning translation system. These include the
enzymes that chemically place the correct amino acid onto the correcttRNA, various mechanisms to «proofread» the translation, and the roleof chemical energy, in the form of the activated nucleotide GTP at every
stage of translation. Nonetheless, this outline may give the reader both an
idea of the process by which genetic information is expressed and also anappreciation for the intricacies involved in that expression.

DNA REPLICATION

There comes a time in the life of every cell when it turns to thoughtsof division. One major consideration in cell division is ensuring that thegenetic information be copied and handed down uncorrupted; a great dealof effort is invested in that task.
In 1957 Arthur Komberg demonstrated that a certain enzyme could
polymerize the activated forms of deoxynucleotides into a new DNA
molecule that was an exact copy of whatever «template» DNA Komberg
threw into the reaction mixture. He called the enzyme DNA polymerase
I (Pol I). The scientific community was ecstatic about the find. Overthe years, however, it has been shown that Pol I's primary role is not tosynthesize DNA during cell division; rather, it is to repair DNA that has
been damaged by exposure to ultraviolet light, chemical mu-

THE CHEMISTRY OF LIFE 293
tagens, or other environmental insults. Two other DNA polymerases,
Pol II and Pol III, were later discovered. The role of Pol II remains murky:mutant cells lacking the enzyme exhibit no observable defects, Pol III
has been identified as the major enzyme involved in DNA replication inprokaryotes.
DNA polymerase III is actually a complex of seven different sub-units,
ranging in length from about 300 to about 1,100 amino acid residues. Only
one of the subunits does the actual chemical joining of nucleotides; theother subunits are involved in critical accessory functions. For instance,
the polymerizing subunit tends to fall off the template DNA after joining
only ten to fifteen nucleotides. If this happened in the cell the polymerase
would have to hop back on hundreds of thousands of times before
replication was complete, slowing replication enormously. However, thecomplete Pol III—with all seven sub-units—does not fall off until theentire template DNA (which can be more than a million base pairs long)is copied.
In addition to a polymerizing activity Pol III possesses, ironically, a
3'5' nuclease activity. This means that it can degrade polymerized DNA
into free nucleotides, starting at a free 3' end and working back toward the
5' end. Now, why would a polymerase also degrade DNA? It turns out thatthe nuclease activity of Pol III is very important in ensuring the accuracyof the copying procedure. Suppose that the wrong nucleotide became
incorporated into the growing DNA chain. Pol Ill's nuclease function
allows it to step back and remove the incorrect, mis-paired nucleotide.
Correctly paired nucleotides are resistant to the nuclease activity. This
activity is called «proofreading»; without it, thousands of times moreerrors would creep in when DNA was copied.
DNA replication begins at a certain DNA sequence, known appropriately
as an «origin of replication,» and proceeds in both directions at once
along the parent DNA. The first task to be tackled during replication, as
for transcription, is the separation of the two parent DNA strands. Thisis the job of the DnaA protein. After the strands are separated two otherproteins, called DnaB and DnaC, bind to the single strands. Two more
proteins are recruited to the growing «bubble» of open DNA: single strand
binding protein (SSB), which keeps the two parent DNA strands separated
while the DNA is copied; and gyrase, which unknots the tangles that occur
as the complex plows through double stranded DNA.

294 WHAT DOES THE BOX TELL US?
At this point DNA polymerase can begin synthesis. But several
problems arise. DNA polymerase cannot start synthesizing by joining
two nucleotides the same way that RNA polymerase starts transcription;
the DNA enzyme can only add nucleotides to the end of a preexistingpolynucleotide. Thus the cell employs another enzyme to make a shortstretch of RNA on the exposed DNA template. This enzyme can begin
RNA synthesis from two nucleotides. Once the RNA chain has gotten to
be about ten nucleotides long, the DNA polymerase can then use the RNA
as a «primer,» adding deoxynucleotides to its end.
The second problem occurs as the replication «fork» opens up. The
synthesis of one strand of new DNA can proceed without difficulty;
this is the strand that the polymerase makes as it reads the templatein a 3'5' direction, making a new strand in a 5'3' orientation, as allpolymerases do. But how to synthesize the second strand? If done directly, the polymerase would have to read the template in a 5'3' direction
and thus synthesize the new strand in a 3'5' direction. Although there
is no theoretical reason why this could not occur, no known polymerase
synthesizes in a 3'5' direction. Instead, after a stretch of DNA has been
opened up, an RNA primer is made near the fork and DNA synthesis
proceeds backward, away from the replication fork, in a 5'3' direction.
Further synthesis on this «lagging» strand must wait until the replication
fork opens up another stretch of DNA; another RNA primer must thenbe made, and DNA synthesis proceeds backward toward the previously
synthesized fragment. The RNA primers must then be removed, the gaps
filled in with DNA, and the ends of the DNA pieces «stitched together.»This requires several more enzymes.
The above description of prokaryotic DNA replication has been pieced
together by the enormous efforts of a large number of laboratories. The
replication of eukaryotic DNA appears to be much more complex, andtherefore much less is known about it.

NOTES

Preface
1. Cameron, A. G. W. (1988) «Origin of the Solar System,» Annual Review ofAstronomy and Astrophysics, 26, 441-472.
2. Johnson, P E. (1991) Darwin on Trial, Regnery Gateway, Washington, DC, chap.
5; Mayr, E. (1991) One Long Argument, Harvard University Press, Cambridge,
MA, pp. 35-39.
Chapter 1
1. By biochemistry I mean to include all sciences that investigate life at themolecular level, even if the science is done in a department with another name,such as molecular biology, genetics, or embryology.
2. The historical sketch presented here draws mainly from Singer, C. (1959) A
History of Biology, Abelard-Schuman, London. Additional sources include
Taylor, G. R. (1963) The Science of Life, McGraw-Hill, New York; and Magner,
L. N. (1979) A History of the Life Sciences, Marcel Dekker, New York.
3. Described in Weiner, J. (1994) The Beak of the Finch, Vintage Books, New York.
4. Darwin, C. (1872) Origin of Species, 6th ed. (1988), New York University Press,
New York, p. 151.

295

296 WHAT DOES THE BOX TELL US?
5. A good summary of the biochemistry of vision can be found in Devlin, T. M.
(1992) Textbook of Biochemistry, Wiley-Liss, New York, pp. 938-954.
6. For example, as the expected pattern left by speciation events that occurred inisolated populations.
7. Farley, J. (1979) The Spontaneous Generation Controversy from Descartes to
Oparin, Johns Hopkins University Press, Baltimore, p. 73.
8. Mayr, E. (1991) One Long Argument, Harvard University Press, Cambridge,
chap. 9.
Chapter 2
1. Mann, C. (1991) «Lynn Margulis: Science's Unruly Earth Mother,» Science,
252, 378-381.
2. Eldredge, N. (1995) Reinventing Darwin, Wiley, New York, p. 95.
3. Eldredge, N., and Gould, S.J. (1973) «Punctuated Equilibria: An Alternative toPhyletic Gradualism» in Models in Paleobiology, ed. T. J. M. Schopf, Freeman,
Cooper and Co., San Francisco, pp. 82-115.
4. Beardsley, T. «Weird Wonders: Was the Cambrian Explosion a Big Bang or a
Whimper?» Scientific American, June 1992, pp. 30-31.
5. Ho, M. W., and Saunders, P.T. (1979) «Beyond Neo-Darwinism—An Epigenetic
Approach to Evolution,» Journal of Theoretical Biology 78, 589.
6. McDonald, J. F. (1983) «The Molecular Basis of Adaptation,» Annual Review of
Ecology and Systematics 14, 93.
7. Miklos, G. L. G (1993) «Emergence of Organizational Complexities During
Metazoan Evolution: Perspectives from Molecular Biology, Paleontology and
Neo-Darwinism,» Memoirs of the Association of Australasian Paleontologists,
15, 28.
8. Orr, H. A., and Coyne, J. A. (1992) «The Genetics of Adaptation: A
Reassessment,» American Naturalist, 140, 726.
9. Endler, J. A., and McLellan, T. (1988) «The Process of Evolution: Toward a
Newer Synthesis,» Annual Review of Ecology and Systematics, 19, 397.
10. Yockey, H. (1992) Information Theory and Molecular Biology, Cambridge
University Press, Cambridge, England, chap. 9.
11. Kaplan, M. (1967) «Welcome to Participants» in Mathematical Challenges to
the Neo-Darwinian Interpretation of Evolution, ed. P. S. Moorhead and M. M.
Kaplan, Wistar Institute Press, Philadelphia, p. vii.
12. Schützenberger, M. P. (1967) «Algorithms and the Neo-Darwinian Theory of
Evolution» in Mathematical Challenges to the Neo-Darwinian Interpretationof Evolution, ed. P S. Moorhead and M. M. Kaplan, Wistar Institute Press,
Philadelphia, p. 75.
13. Kauffman, S. (1993) The Origins of Order, Oxford University Press, Oxford,
England, p. xiii.

NOTES 297
14. Smith, J. M. (1995) «Life at the Edge of Chaos?» New York Review, March 2,
pp. 28-30.
15. Mivart, St. G. (1871) On the Genesis of Species, Macmillan and Co., London,
p. 21.
16. Aneshansley, D. J., Eisner, Т., Widom, J. M., and Widom, B. (1969)«Biochemistry at 100°C: Explosive Secretory Discharge of Bombardier
Beetles,» Science, 165, 61; Crowson, R. A, (1981) The Biology of the Coleoptera,
Academic Press, New York, chap. 15.
17. Hitching, F. (1982) The Neck of the Giraffe, Pan, London, p. 68.
18. Dawkins, R. (1985) The Blind Watchmaker, W. W. Norton, London, pp. 86-87.
19. Eisner, T., Attygalle, А. В., Eisner, M., Aneshansley, D. J., and Meinwald,
J. (1991) «Chemical Defense of a Primitive Australian Bombardier Beetle(Carabidae): Mystropomus regularis,» Chemoecology, 2, 29.
20. Eisner, T., Ball, G. E., Roach, В., Aneshansley, D. J., Eisner, M., Blankespoor,
C. L., and Meinwald, J. (1989) «Chemical Defense of an Ozanine Bombardier
Beetle from New Guinea,» Psyche, 96, 153.
21. Hitching, pp. 66-67.
22. Dawkins, pp. 80-81.
23. Dawkins, pp. 85-86.
24. Darwin, C. (1872) Origin of Species, 6th ed. (1988), New York University
Press, New York, p. 154.
25. Dawkins, R. (1995) River Out of Eden, Basic Books, New York, p. 83.
Chapter 3
1. A good general introduction to cilia can be found in Voet, D., and Voet, J. G.
(1995) Biochemistry, 2nd ed., John Wiley and Sons, New York, pp. 1253-1259.
2. There are also other connectors in this system. For example, the contacts
the dynein arm makes with the microtubule also serve as a connector. As
mentioned previously, a system can be more complex than the simplest system
imaginable, and the cilium is an example of such a system.
3. Cavalier-Smith, T. (1978) «The Evolutionary Origin and Phylogeny ofMicrotubules, Mitotic Spindles, and Eukaryote Flagella,» BioSystems, 10, 93114.
4. Szathmary, E. (1987) «Early Evolution of Microtubules and Undulipodia,»
BioSystems, 20, 115-131.
5. Bermudes, D., Margulis, L., and Tzertinis, G. (1986) «Prokaryotic Origin of
Undulipodia,» Annals of the New York Academy of Science, 503, 187-197.
6. Cavalier-Smith, T. (1992) «The Number of Symbiotic Origins of Organelles»,
BioSystems, 28, 91-106; Margulis, L. (1992) «Protoctists and Polyphyly:

298 WHAT DOES THE BOX TELL US?
Comment on 'The Number of Symbiotic...' by T. Cavalier-Smith,» BioSystems,
28, 107-108.
7. A search of Science Citation Index shows that each paper receives an average ofless than one citation per year.
8. A good general introduction to flagella can be found in Voet and Voet, pp. 12591260. Greater detail about the flagellar motor can be found in the following:
Schuster, S. C., and Khan, S. (1994) «The Bacterial Flagellar Motor,» Annual
Review of Biophysics and Biomolecular Structure, 23, 509-539; Caplan, S. R.,
and Kara-lvanov, M. (1993) «The Bacterial Flagellar Motor,» International
Review of Cytology, 147, 97-164.
9. Voet and Voet, p. 1260.
Chapter 4
1. A good general introduction to blood coagulation can be found in Voet, D.,
and Voet, J. G. (1995) Biochemistry, John Wiley & Sons, New York, pp. 11961207. For more detailed descriptions see any of the following: Furie, В., andFurie, В. C. (1988) «The Molecular Basis of Blood Coagulation,» Cell, 53,
505-518; Davie, E. W., Fujikawa, K., and Kisiel, W. (1991) «The Coagulation
Cascade: Initiation, Maintenance, and Regulation,» Biochemistry, 30, 1036310370; Halkier, T. (1991) Mechanisms in Blood Coagulation, Fibrinolysis andthe Complement System, Cambridge University Press, Cambridge, England.
2. The suffix -ogen designates the inactive progenitor of an active molecule.
3. The word factor is often used during research when it is not certain what thenature of a substance under investigation is—whether protein, fat, carbohydrate,
or something else. Even after its identity is pinned down, however, sometimes
the old name continues to be used. In the blood-clotting pathway, all «factors»
are proteins.
4. A gene is a portion of DNA that instructs the cell how to make a protein.
5. Doolittle, R. F. (1993) «The Evolution of Vertebrate Blood Coagulation: A Caseof Yin and Yang,» Thrombosis and Haemostasis, 70, 24-28.
6. The proteins involved in blood clotting are frequently referred to by Roman
numerals, such as Factor V and Factor Vlll. Doolittle uses that terminology in
his article in Thrombosis and Haemostasis. For clarity and consistency I haveused the common names of the proteins in the quotation.
7. TPA has a total of five domains. Two domains, however, are of the same type.
8. The odds are not decreased if the domains are hooked together at different
times—with domains 1 and 2 coming together in one event, then later on
domain 3 joining them, and so on. Think of the odds of picking four blackballs from a barrel containing black balls and white balls. If you take out fourat once, or take two at the first grab and one apiece on the next two grabs, theodds of ending up with four black balls are the same.

NOTES 299
9. This calculation is exceedingly generous. It only assumes that the four types ofdomains would have to be in the correct linear order. In order to work, however,the combination would have to be located in an active area of the genome, thecorrect signals for splicing together the parts would have to be in place, theamino acid sequences of the four domains would have to be compatible witheach other, and other considerations would affect the outcome. These further
considerations only make the event much more improbable.
10. It is good to keep in mind that a «step» could well be thousands of generations.
A mutation must start in a single animal and then spread through the
population. In order to do that, the descendants of the mutant animal must
displace the descendants of all other animals.
Chapter 5
1. Alberts, В., Bray, D., Lewis J., Raft M., Roberts, K, and Watson, J. D. (1994)
Molecular Biology of the Cell, 3rd ed., Garland Publishing, New York, pp. 556557.
2. Komfeld, S., and Sly, W. S. (1995) «I-Cell Disease and Pseudo-Hurler
Polydystrophy: Disorders of Lysosomal Enzyme Phosphorylation andLocalization,» in The Metabolic and Molecular Bases of Inherited Disease, 7thed., ed. C. R. Scriver; A. L. Beaudet, W S. Sly, and D. Valle, McGraw-Hill, New
York, pp. 2495-2508.
3. Pryer, N. K., Wuestehube, L. J., and Schekman, R. (1992) «Vesicle-MediatedProtein Sorting,» Annual Review of Biochemistry, 61, 471-516.
4. Roise, D., and Maduke, M. (1994) «Import of a Mitochondrial Presequence
into P. Denitrificans,» FEBS Letters, 337, 9-13; Cavalier-Smith, T. (1987)«The Simultaneous Symbiotic Origin of Mitochondria, Chloroplasts andMicrobodies,» Annals of the New York Academy of Science, 503, 55-71;
Cavalier-Smith, T. (1992) «The Number of Symbiotic Origins of Organelles,»
BioSystems, 28, 91-106; Hartl, F., Ostermann, J., Guiard, В., and Neupert, W.
(1987) «Successive Translocation into and out of the Mitochondrial Matrix:
Targeting of Proteins to the Inner Membrane Space by a Bipartite Signal
Peptide,» Cell, 51, 1027-1037.
5. Alberts et al., pp. 551-651.
Chapter 6
1. Good introductions to the immune system can be found in Voet, D., and Voet,
J. G. (1995) Biochemistry, 2nd ed., John Wiley & Sons, New York, pp. 12071234; and Alberts, В., Bray, D., Lewis, J., Raff, M., Roberts, K., and Watson, J.
D. (1994) Molecular Biology of the Cell, 3rd ed.. Garland Publishing, New York,chap. 23.

300 WHAT DOES THE BOX TELL US?
2. The cells are actually called В cells because they were fast discovered in the
Bursa fabricius of birds.
3. The cell goes to enormous trouble to splice together gene pieces—employing
very complex machinery to align the ends properly and stitch together
the pieces. Except in the case of antibody genes, however, the reason that
«interrupted genes» exist at all is still a mystery.
4. Except for cells that make special classes of antibodies. I won't discuss thatfurther complication.
5. Bartl, S., Baltimore, D., and Weissman, I. L. (1994) «Molecular Evolution of the
Vertebrate Immune System.» Proceedings of the National Academy of Sciences,91, 10769-10770.
6. Farries, T. C., and Atkinson, J. P. (1991) «Evolution of the Complement System,»
Immunology Today, 12, 295-300.
7. Examples include: DuPasquier, L. (1992) «Origin and Evolution of the
Vertebrate Immune System,» APMIS, 100, 383-392; Stewart, J. (1994) The
Primordial VRM System and the Evolution of Vertebrate Immunity, R. G.
Landes Co., Austin; Sima, P., and Vetvicka, V. (1993) «Evolution of Immune
Reactions,» Critical Reviews in Immunology, 13, 83-114.
Chapter 7
1. RNA is made of the four nucleotides A, C, G, and U.
2. Several other simplifications will be used. The hydrogen atoms of the molecule
will not be discussed or indicated in Figure 7-1. Hydrogen atoms for the mostpart just ride along with other atoms in the synthesis of AMP so it really isn't
necessary to pay attention to them to get the idea across. Additionally, double
bonds and single bonds will not be distinguished, since we are only interested
in connectivity.
3. Zubay, G., Parson, W. W., and Vance, D. E. (1995) Principles of Biochemistry,
Wm. C. Brown Publishers, Dubuque, IA, pp. 215-216.
4. Although it was previously thought that this step did not require ATP,
more recent work has shown that ATP is necessary for the reaction to go at
physiological concentrations of bicarbonate. Voet, D., and Voet, J. G. 1995.
Biochemistry, 2nd ed., John Wiley & Sons, New York, p. 800.
5. Hall, R. H. (1971) The Modified Nucleosides in Nucleic Acids, Columbia
University Press, New York, pp. 26-29.
6. OrÒ, J. (1961) «Mechanism of Synthesis of Adenine from Hydrogen Cyanide
Under Plausible Primitive Earth Conditions,» Nature, 191, 1193-1194. It should
be kept in mind that just the base adenine is made by reactions of ammonia
and hydrogen cyanide. The nucleotide AMP is extremely difficult to produce
under plausible early earth conditions, as noted in Joyce, G. F. (1989) «RNA
Evolution and the Origins of Life,» Nature, 338, 217-224.

NOTES 301
7. Quoted in Joyce, G. F., and Orgel, L. E. 1993. «Prospects for Understanding
the Origin of the RNAWorld,» in The RNA World, ed. R. F. Gesteland and J. F.
Atkins, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, p. 18.
8. Except by the degradation of ATP, which must be made from AMP in the firstplace.
9. Creighton, T. (1993) Proteins: Structure and Molecular Properties, W. H.
Freeman and Co., New York, p. 131.
10. Alberts, В., Bray, D., Lewis, J., Raff, M., Roberts, K., and Watson, J. D. (1994)
Molecular Biology of the Cell, 3rd ed., Garland Publishing, New York, p. 14.
11. Ferris, J. P, and Hagan, W. J. (1984) «HCN and Chemical Evolution: The
Possible Role of Cyano Compounds in Prebiotic Synthesis,» Tetrahedron, 40,
1093-1120. It should be kept in mind that the compounds described in thispaper do not have the foundation attached.
12. Bloom, A. (1987) The Closing of the American Mind, Simon and Schuster,
New York, p. 151.
13. Horowitz, N. H. (1945) «On the Evolution of Biochemical Syntheses,»
Proceedings of the National Academy of Sciences, 31, 153-157.
14. For consistency with other descriptions, I have switched the letters A and D
in Horowitz's paper.
15. Kauffman, S. (1993) The Origins of Order, Oxford University Press, New York,
p. 344.
16. Smith, J. M. (1995) «Life at the Edge of Chaos?» New York Review, March 2,
pp. 28-30.
Chapter 8
1. The atmosphere of the early earth is now thought to have been quite different
from the one Miller assumed, and much less likely to produce amino acids byatmospheric processes.
2. Dose, K. (1988) «The Origin of Life: More Questions than Answers,»
Interdisciplinary Science Reviews, 13, 348.
3. Shapiro, R. (1986) Origins: A Skeptic's Guide to the Creation of Life on Earth,Summit Books, New York, p. 192.
4. Cech won the Nobel prize for his work. The awarding citation alludes to theimpact of Cech's work on origin-of-life studies. Cech himself however, rarely
mentions the origin of life in connection with his work.
5. Joyce, G. F., and Orgel, L. E. (1993) «Prospects for Understanding the Origin of
the RNA World» in The RNA World, ed. R. F. Gesteland and J. F. Atkins, Cold
Spring Harbor Laboratory Press, Cold Spring Harbor, NY, p. 19.
6. Joyce and Orgel, p. 13.
7. Although many statements within the scientific community's own journals
and books are pessimistic, public statements to the news media tend to be of

302 WHAT DOES THE BOX TELL US?
the everything-is-under-control variety. University of Memphis rhetorician
John Angus Campbell has observed that «huge edifices of ideas—such as
positivism—never really die. Thinking people gradually abandon them andeven ridicule them among themselves, but keep the persuasively useful parts
to scare away the uninformed.» Campbell, J. A. (1994) «The Comic Frameand the Rhetoric of Science: Epistemology and Ethics in Darwin's Origin,»
Rhetoric Society Quarterly, 24, 27-50. This certainly applies to the way thescientific community handles questions on the origin of life.
8. Schlesinger, G. and Miller, S. L. (1983) «Prebiotic Syntheses in Atmospheres
Containing CH4, CO, and CO2,» Journal of Molecular Evolution, 19, 376-382.
9. Niketic, V, Draganic, Z. D., Neskovic, S., Jovanovic, S., and Draganic, I.
G. (1983) «Radiolysis of Aqueous Solutions of Hydrogen Cyanide (pH 6):
Compounds of Interest in Chemical Evolution Studies,» Journal of Molecular
Evolution, 19, 184-191.
10. Kolb, V. M., Dworkin, J. P., and Miller, S. L. (1994) «Alternative Bases in the
RNA World: The Prebiotic Synthesis of Urazole and Its Ribosides,» Journal of
Molecular Evolution, 38, 549-557.
11. Hill, A. R., Jr., Nord, L. D., Orgel, L. E., and Robins, R. K. (1989) «Cyclization of
Nucleotide Analogues as an Obstacle to Polymerization,» Journal of Molecular
Evolution, 28, 170-171.
12. Nguyen, T., and Speed, T. P. (1992) «A Derivation of All Linear Invariants
for a Nonbalanced Transversion Model,» Journal of Molecular Evolution, 35,
60-76.
13. Adell, J. C., and Dopazo, J. (1994) «Monte Carlo Simulation in Phylogenies:
An Application to Test the Constancy of Evolutionary Rates,» Journal of
Molecular Evolution, 38, 305-309.
14. Otaka, E., and Ooi, T. (1987) «Examination of Protein Sequence Homologies:
IV Twenty-Seven Bacterial Ferredoxins,» Journal of Molecular Evolution, 26,257-268.
15. Alexandraki, D., and Ruderman, J. V. (1983) «Evolution of α-and β-Tubulin
Genes as Inferred by the Nucleotide Sequences of Sea Urchin cDNA clones,»
Journal of Molecular Evolution, 19, 397-410.
16. Kumazaki, T., Hori, H., and Osawa, S. (1983) «Phylogeny of Protozoa Deduced
from 5S rRNA Sequences,» Journal of Molecular Evolution, 19, 411-419.
17. Wagner, A., Deryckere, F., McMorrow, Т., and Gannon, F. (1994) «Tail-to-Tail
Orientation of the Atlantic Salmon Alpha-and Beta-Globin Genes,» Journal of
Molecular Evolution, 38, 28-35.
18. Indeed, some proteins we have discussed in this book have sequences or
shapes similar to other proteins. For example, antibodies are shaped similarly
to a protein called superoxide dismutase, which helps protect the cell against
damage by oxygen. And rhodopsin, which is used in vision, is similar to aprotein found in bacteria, called bacteriorhodopsin, which is involved in the

NOTES 303
production of energy. Nonetheless, the similarities tell us nothing about how
vision or the immune system could develop step-by-step.
One would have hoped that finding proteins with similar sequences would
lead to the proposal of models for how complex biochemical systems might havedeveloped. Conversely, the fact that such sequence comparisons do not help us
understand the origins of complex biochemical systems weighs heavily against atheory of gradual evolution.
19. I have counted in this category papers that are listed in the journal index under
the titles «Molecular Evolution,» «Protein Evolution,» and some miscellaneous
topics.
20. Kimura, M. (1983) The Neutral Theory of Evolution, Cambridge University
Press, New York.
21. Kauffman, S. A. (1993) The Origins of Order: Self-Organization and Selection
in Evolution, Oxford University Press, New York.
22. Selander, R. K., Clark, A. G., & Whittam, T. S. (1991) Evolution at the
Molecular Level, Sinauer Associates, Sunderland, MA.
23. Cold Spring Harbor Symposia on Quantitative Biology (1987), vol. 52,
Evolution of Catalytic Function, Cold Spring Harbor Laboratory Press, Cold
Spring Harbor, NY.
24. Lehninger, A. L. (1970) Biochemistry, Worth Publishers, New York, p. 17.
25. Lehninger, A. L., Nelson, D. L., and Cox, M. M. (1993) Principles ofBiochemistry, 2nd ed., Worth Publishers, New York, p. viii.
26. Lehninger et al. (1993), p. 244.
27. Conn, E. E., Stumpf, P. K., Bruening, G., and Doi, R. H. (1987) Outlines ofBiochemistry, 5th ed., John Wiley & Sons, New York, p. 4.
28. Voet, D., and Voet, J. G. (1995) Biochemistry, 2nd ed., John Wiley & Sons,
New York, p. 19.
29. To its credit, the Voet and Voet text contains a disclaimer at the beginning of
the standard discussion of a Stanley Miller-like origin-of-life scenario, whichstates that there are «valid scientific objections to this scenario.»
Chapter 9
1. Kauffman, S. A. (1991) «Antichaos and Adaptation,» Scientific American,
August, p. 82.
2. Kauffman, S. A. (1993) The Origins of Order, Oxford University Press, Oxford,
England.
3. Detecting design in patterns of coin flips or other systems that do not physicallyinteract is done in other ways. See Dembski, W. (1996) The Design Inference:
Eliminating Chance Through Small Probabilities, Ph.D. dissertation, University
of Illinois.

304 WHAT DOES THE BOX TELL US?
4. This is a judgment call. One can never prove that a particular function is the
only one that might be intended—or even that it is intended. But our evidence
can get pretty persuasive nonetheless.
5. It is hard to quantify design, but it is not impossible, and future research should
proceed in this direction. An excellent start has been made by Bill Dembski
in his dissertation (Dembski, 1996), which attempts to quantify the design
inference in terms of what he calls the «probabilistic resources» of a system.
6. Dawson, К. M., Cook, A., Devine, J. M., Edwards, R. M., Hunter, M. G., Raper,
R. H., and Roberts, G. (1994) «Plasminogen Mutants Activated by Thrombin,»
Journal of Biological Chemistry, 269, 15989-15992.
7. Reviewed in Gold, L., Polisky, В., Uhlenbeck, O. & Yams, M. (1995) «Diversityof Oligonucleotide Functions,» Annual Review of Biochemistry 64, 763-797.
8. Joyce, G. F. (1992) «Directed Molecular Evolution,» Scientific American,
December, p. 90.
9. Benkovic, S. J. (1992) «Catalytic Antibodies,» Annual Review of Biochemistry61, 29-54.
10. Dawkins, R. (1995) River Out of Eden, Basic Books, New York, pp. 17-18.
Chapter 10
1. Cited in Barrow, J. D., and Tipler, F.J. (1986) The Anthropic Cosmological
Principle, Oxford University Press, New York, p. 36.
2. Barrow and Tipler, p. 36.
3. Paley, W. Natural Theology, American Tract Society, New York, pp. 9-10.
4. Dawkins, R. (1985) The Blind Watchmaker, W. W. Norton, London, p. 5.
5. Paley, pp. 110-111.
6. Paley, pp. 199-200.
7. Paley, pp. 171-172.
8. Paley, pp. 184-185.
9. Dawkins, p. 5.
10. Dawkins, p. 6.
11. Sober, E. (1993) Philosophy of Biology, Westview Press, Boulder, Co, p. 34.
12. Sober, pp. 34-35.
13. Sober, p. 35.
14. Sober, pp. 37-38.
15. Shapiro, R. (1986) Origins: A Skeptic's Guide to the Creation of Life on Earth.
Summit Books, New York, pp. 179-180.
16. Miller, K. R. (1994) «Life's Grand Design,» Technology Review February/
March, pp. 29-30.

NOTES 305
17. Dyson, J. F. (1966) «The Search for Extraterrestrial Technology» in Perspectives
in Modem Physics, ed. R. E. Marshak, John Wiley and Sons, New York, pp.
643-644.
18. Crick, F. H. C., and Orgel, L. E. (1973) «Directed Panspermia,» Icarus, 19,344.
19. Futuyma, D. (1982) Science on Trial, Pantheon Books, New York, p. 207.
20. Miller, pp. 31-32.
21. Miller, p. 32.
22. Gould, S.J. (1980) The Panda's Thumb, W. W. Norton, New York.
Chapter 11
1. Shapiro, R. (1986) Origins: A Skeptic's Guide to the Creation of Life on Earth,Summit Books, New York, p. 130.
2. Dickerson's essay can be found in Journal of Molecular Evolution, 34, 277(1992), and Perspectives on Science & Christian Faith, 44, 137-138 (1992).
3. The reformulated rule is essentially identical to what a peripatetic philosopher
of science named Michael Ruse testified were the defining characteristics ofscience during the 1981 trial to determine the constitutionality of the Arkansas«Balanced Treatment for Creation-Science and Evolution-Science Act.» Judge
William Overton's opinion overturning the law relied heavily on Ruse's ideas.
The opinion has been strongly criticized as inept by other philosophers ofscience. Many relevant trial documents are collected in Ruse, M., ed. (1988)
But Is It Science? Prometheus Books, Buffalo, NY.
Judge Overton, echoing Ruse, wrote of science that: «(1) It is guided bynatural law; (2) It has to be explanatory by reference to natural law; (3) It is
testable against the empirical world; (4) Its conclusions are tentative; i.e., are
not necessarily the final word; and (5) It is falsifiable (Testimony of Ruse andother science witnesses).» Overton's opinion was received with scorn by otherphilosophers of science. Philip Quinn wrote, «Ruse's views do not represent a
settled consensus of opinion among philosophers of science. Worse still, someof them are clearly false and some are based on obviously fallacious arguments»(in Ruse, 1988, p. 384). Larry Laudan ticked off the problems. «Some scientifictheories are well-tested; some are not. Some branches of science are presently
showing high rates of growth; others are not. Some scientific theories havemade a host of successful predictions of surprising phenomena; some havemade few if any such predictions. Some scientific hypotheses are ad hoc; others
are not. Some have achieved a 'consilience of inductions'; others have not» (inRuse, 1988, p. 348). Laudan cited many exceptions to Overton's opinion: «This
requirement [for explanation by natural law] is an altogether inappropriate
standard for ascertaining whether a claim is scientific. For centuries

306 WHAT DOES THE BOX TELL US?
scientists have recognized a difference between establishing the existence ofa phenomenon and explaining that phenomenon in a lawlike way. . . . Galileo
and Newton took themselves to have established the existence of gravitational
phenomena, long before anyone was able to give a causal or explanatory
account of gravitation. Darwin took himself to have established the existenceof natural selection almost a half-century before geneticists were able to lay out
the laws of heredity on which natural selection depended» (in Ruse, 1988, p.
354). Laudan saw no cause for rejoicing: «The victory in the Arkansas case washollow, for it was achieved only at the expense of perpetuating and canonizing
a false stereotype of what science is and how it works» (in Ruse, 1988, p. 355).
4. Of course, whether «evolution» and «religion» are compatible depends on yourdefinitions of both. If one takes the position that evolution not only occurred
solely by uninterrupted natural law, but that the process is «purposeless» and«unforeseen» in a metaphysical sense, then that does place «evolution» on acollision course with many religious denominations. Phillip Johnson has done
an admirable job of pointing out the many ways in which the word evolution isused, and how shifting definitions can confuse public discussion of the issue.
Johnson, P. E. (1991) Darwin on Trial, Regnery Gateway, Washington, DC.
5. Simon, H. (1990) «A Mechanism for Social Selection and Successful Altruism,»
Science, 250,1665-1668.
6. The influence of various religious cultures on the development of science is
described in Jaki, S. (1986) Science and Creation, Scottish Academic Press,
Edinburgh.
7. The reaction of science to the Big Bang hypothesis, including Eddington's andother prominent physicists, is recounted in Jaki, S. (1980) Cosmos and Creator,
Regnery Gateway, Chicago.
8. Jaki, S. (1986).
9. Dawkins, R. (1986) The Blind Watchmaker, W. W. Norton, London, p. 159.
10. Dawkins, R. (1989) New York Times, April 9, 1989, sec. 7, p. 34.
11. Maddox, J. (1994) «Defending Science Against Anti-Science,» Nature, 368,
185.
12. Dennett, D. (1995) Darwin's Dangerous Idea, Simon & Schuster, New York,
pp. 515-516.
13. Dawkins, R. (1986), p. 6.
Afterword
1. What exactly is «intelligent design? In an article in 2001 in the philosophy ofscience journal, Biology and Philosophy, I made an important distinction:

NOTES 307«By [intelligent designl someone might mean that the laws of nature themselves
are designed to produce life and the complex systems that undergird it. Without
commenting on the merits of the position, let me just say that that is not themeaning I assign to the phrase. By «intelligent design» (ID) I mean to imply
design beyond the laws of nature. That is, taking the laws of nature as given,
are there other reasons for concluding that life and its component systems havebeen intentionally arranged, just as there are reasons beyond the laws of nature
for concluding a mousetrap was designed? [Unless stated otherwise] wheneverI refer to ID I mean this stronger sense of design-beyond-laws.»
2. The term «irreducible complexity» occurred to me independently. However,I've since learned that the phrase was used earlier in Templets and the
Explanation of Complex Patterns (Cambridge University Press, 1986) by Case
Western Reserve University biologist Michael J. Katz. He appeared to have inmind the same sorts of phenomena as I did.
3. Pennock R. (1999). Tower of Babel: The Evidence Against the New Creationism,
MIT Press, Cambridge, Massachusetts, pp. 267-268.
4. Pennock, 269.
5. Pennock, 269.
6. Pennock doesn't bother to say how those suspiciously complex, dumbbellshaped balances and springs get added. Needless to say, a chronometer is avery complex device. Pictures of several versions of early chronometers built
be John Harrison can be seen at robens.anu.edu.au/student.projects97/naval/hl.htm. Try even turning one into another by «numerous, successive, slight
modifications». Pennock doesn't.
7. «The most important prediction of the hypothesis of irreducible complexity isthat components of irreducibly complex structures should not have functions
that can be favored by natural selection.» www.millerandlevine.com./km/
evol/ design1/article.html That «prediction,» however, was made up by Miller.
8. Begley. Sharon (2004), «Evolution Critics Come Under Fire for Flaws in'Intelligent Design.'» Wall Street Journal, B.l. Feb. 13.
9. Suppose the separated holding bar that's being used as a toothpick and theremainder of the trap that's being used as a paperweight were recombined
to make a working mousetrap. Doesn't that show we can get an irreduciblycomplex mousetrap from parts being used for other purposes? No, it doesn't.
The example is artificial; like Robert Pennock's chronometer breaking to givea watch, it doesn't reflect the situation that would be expected to confront
Darwinian evolution. The example overlooks the fact that the parts wereoriginally taken from the mousetrap, and were already shaped to perform thejob they do in the mousetrap. But evolution would not be expected to pre-adapt
parts being used for one purpose to a wholly different, complex second purpose.
To see the difficulty, imagine trying to put together a mousetrap from a308 WHAT DOES THE BOX TELL US?
real toothpick and real paperweight that you buy at a discount store (without
extensive re-arrangement and intelligent intervention). And the difficulty gets
much worse as the complexity of the system increases beyond comparatively
simple mousetraps.
10. Begley, 2004.
11. www.millerandlevine.com/km/evol/design1/article.htm
12. Actually, microtubules are way cooler than «mere structural supports.»
13. It's also important to keep in mind a subtle but critical distinction I wrote
about in Behe M. J. (2004), «Irreducible Complexity: Obstacle to Darwinian
Evolution,» in: Dembski W. A., and Ruse M, eds., Debating Design: From
Darwin to DNA, Cambridge University Press, pp. 352-370.
«Consider a hypothetical example where proteins homologous to all of theparts of an irreducibly complex molecular machine first had other individualfunctions in the cell. Might the irreducible system then have been put together
from individual components that originally worked on their own, as someDarwinists have proposed? Unfortunately this picture greatly oversimplifies
the difficulty, as I discussed in Darwin's Black Box (Behe 1996, p. 53) Hereanalogies to mousetraps break down somewhat, because the parts of amolecular system have to automatically find each other in the cell. They can't
be arranged by an intelligent agent, as a mousetrap is. To find each other in thecell, interacting parts have to have their surfaces shaped so that they are very
closely matched to each other, such as pictured in Figure 2. Originally, however,
the individually acting components would not have had complementarysurfaces. So all of the interacting surfaces of all of the components would firsthave to be adjusted before they could function together. And only then would
the new function of the composite system appear. Thus, I emphasize strongly,
the problem of irreducibility remains, even if individual proteins homologous
to system components separately and originally had their own functions.»
14. Orr, H. A. (1996), «Darwin v. Intelligent Design (Again).» Boston Review,
Dec/Jan.
15. Orr
16. In one of many examples of the Darwinian echo chamber, in Tower of Babel
Robert Pennock approvingly quotes Orr's reasonsing about hypothetical «partA» and «part (B),» but is equally reticent about spelling out how such reasoning
applies to real mousetraps or biochemical examples.
A cartoonish effort to gradually construct a mousetrap while keeping thefunction of trapping mice constant from the start was mounted on the Internetby University of Delaware biologist John McDonald. However, as I pointed
out in a reply, the effort is steeped in intelligent guidance, which is fatal to any
Darwinian claims. One could also ask, if it's so difficult to see how a simple
mousetrap could be put together by a series of unguided small

NOTES 309
steps, how much more difficult would it be to assemble the stupendously
intricate molecular machinery of the cell? (An animated version is available
at http://udel.edu/~mcdonald/mousetrap.html. His original version is at
http://udel.edu/~mcdonald/oldmousetrap.html. My response, detailingthe involvement of intelligence, is available at www.arn.org/docs/behe/
mb_mousetrapdefended.htm)
17. «But biologists have shown that direct paths to irreducible complexity are
possible, too. Suppose a part gets added to a system merely because the part
improves the system's performance; the part is not, at this stage, essential for
function.» Orr, H. A. Devolution (2005), The New Yorker, May 30. Apparently
in consideration of the magazine's lay readership he left out the technical terms«part (А)» and «part (B).»
18. Blackstone N. W (1997), «Argumentum ad Ignorantium,» Quarterly Review
Biology 72:445-447.
19. Dawkins R. (1986). The Blind Watchmaker, Norton, New York, p. 21.
20. Dawkins.
21. Of course other factors besides the quality of the evidence, such as socialpressure, can affect a person's judgment. In the scientific and academic
communities as a whole there is strong social pressure to dismiss design
explanations for life out of hand. The social situation is quite different for thegeneral public.
22. The National Center for Science Education—a Darwinian watchdog group—
maintains a comprehensive list at www.ncseweb.org, with denunciations
handily categorized by groups.
23. Pazour G.J., and Rosenbaum J.L. (2002), «Intraflagellar Transport and Ciliadependent Diseases,» Trends in Cellular Biology 12:551-555.
24. Mitchell D. R. (2004), «Speculations on the Evolution of 9+2 Organelles andthe Role of Central Pair Microtubules.» Biol. Cell, 96:691-696.
25. In arguing against intelligent design in his 1999 book Finding Darwin's God,
Ken Miller pointed to cilia which he said were simpler than the common «9+2»
cilium pictured in Chapter 3. The implication was that perhaps such structures
might somehow serve as intermediates on the way to the common cilium.
Besides being terminally vague and speculative (after all, the cilium is made of
200 parts), his story doesn't even square with the data. As reported in the paper
mentioned above (Mitchell, 2004),
All present day cilia and (eukaryotic, not bacterial] flagella, motile ornot, clearly evolved from the 9+2 versions. The rarely encountered motile
14+0, 12+0, 9+0, 6+0, or 3+0 axonemes 1/4 , and the widespread non-motile
metazoan 9+0 axonemes, are all derived through loss and modificationfrom ancestral 9+2 organelles.

310 WHAT DOES THE BOX TELL US?
In other words, like Robert Pennock's less-complex watch that is derived
from a more-complex chronometer, variant less-complex cilia appear to be
derived from the standard more-complex kind of cilium. Needless to say, it
is no Darwinian explanation-not even a vague one-tо postulate derived, lessfunctional simplicity from unexplained, more-functional complexity.
26. Macnab R. M. (2003), «How Bacteria Assemble Flagella,» Annual Review
Microbiology 57:77-100.
27. Pallen M. J., Beatson S. A., and Bailey С. M. (2005), «Bioinformatics, Genomics
and Evolution of Non-flagellar Type-Ill Secretion Systems: A Darwinian
Perspective.» FEMS Microbiol Rev. 29:201-229.
28. Klein J., and Nikolaidis N. (2005), «The descent of the antibody-based
immune svstem by gradual evolution,» Pro. National Academy of Science USA
102:169-174.
29. The authors have an expansive idea of «gradual,» whereby they count the first
appearance of any category of protein as sufficient to explain whatever activity
a member of the category is now involved in. That's kind of like saying that the
springs in a mattress explain the springs in a clock.
30. Davidson C. J., Hirt R. E, Lal K., Snell P. Elgar G., Tuddenham E. G., andMcVey J. H. (2003), «Molecular Evolution of the Vertebrate Blood Coagulation
Network,» Thromb Haemost 89:420-428.
31. Some commentators have claimed that evolutionary theory has moved
beyond Darwin, and that mechanisms other than natural selection are
operative in biology. Other mechanisms, however, are irrelevant. In trying to
explain apparent design, only natural selection matters. Here's Jerry Coyne
himself making that point:
Since 1859, Darwin's theories have been expanded, and we now know thatsome evolutionary change can be caused by forces other than natural selection.
For example, random and non-adaptive changes in the frequencies of different
genetic variants-the genetic equivalent of coin-tossing-have produced
evolutionary changes in DNA sequences. Yet selection is still the only known
evolutionary force that can produce the fit between organism and environment(or between organism and organism) that makes nature seem «designed»[emphasis added]. Coyne, J. A. (2005), «The Case Against Intelligent Design.
The Faith That Dare Not Speak Its Name,» The New Republic, August 22.
32. Coyne.
33. Shapiro, J. (1996), «In the Details . . . What?» National Review, Sept. 16, 6265. Shapiro's judgment is seconded by Colorado State University emeritus
professor of biochemistry Franklin Harold in his book The Way of the Cell
(Oxford, 2001): «. . .we must concede that there are presently no detailed

NOTES 311
Darwinian accounts of the evolution of any biochemical system, only a variety
of wishful speculations.»
34. Abbott A. (2005), «Nobel laureates: Close encounters,» Nature 436:170-171.
Appendix
1. Prokaryotes can be subdivided into two categories: archaebacteria and eubacteria. The distinction does not matter for the present purpose of describing theinternal architecture of cells.
2. Since cells are so small, visualizing them requires powerful microscopes. Most
detailed «pictures» of cells are obtained by electron microscopy, in whichelectrons are used instead of light for illumination.
3. Gamow, G. (1954) «Possible Relation Between Deoxyribonucleic Acid andProtein Structure,» Nature, 173, 318; Gamow, G., and Ycas, M. (1958) «The
Cryptographic Approach to the Problem of Protein Synthesis,» in Symposiumon Information Theory in Biology, ed. H. P. Yockey, R. L. Platzman, and H.
Quasder, Pergamon Press, New York, pp. 63-69.
4. The problem can be understood by the following example: Wind one shoestring
several times around another, and ask someone to hold the ends of the strings
tightly in two hands. Now take a pencil, insert it between the strings near one
hand, and push the pencil toward the other hand. The shoestrings in front of
the moving pencil will become more tightly wound. The strings behind thepencil will be, in the jargon of biochemistry, «melted.»
5. A palindrome is a word or sentence that reads the same way backward andforward. An example is «A man, a plan, a canal—Panama.» When applied toDNA, palindrome means a sequence of nucleotides that reads the same in the
5'3' direction on both strands of the double helix.
6. The abbreviation S stands for Svedberg units, and is a measure of how fast a
particle sediments in liquid.

312 WHAT DOES THE BOX TELL US?

ACKNOWLEDGMENTS

The development of this book has benefited greatly fromconversations with many people. Many thanks to Tom Bethell and Phil
Johnson for encouragement, and for showing this lab-bound scientist
how to go about getting a book published. I'm grateful to my editor, Bruce
Nichols, for saving the book from being a text chock-full of technicaljargon, and for showing me how to arrange the pieces of the argument
to make it more easily understood. I'd also like to thank Del Ratzsch andPaul Nelson for helping to firm up the argument, steering me past as many
philosophical pitfalls as they could. Thanks to my Lehigh colleagues Linda
Lowe-Krentz and Lynne Cassimeris for checking the science in the example
chapters. I also appreciate the input of Bill Dembski, Steve Meyer, Walter
ReMine, Peter van Inwagen, Dean Kenyon, Robin Collins, A1 Plantinga,
John Angus Campbell, and Jonathan Wells. The good points of the bookare due to their help. Any deficiencies that remain are my own.
I'm glad to have the opportunity to publicly thank my wife, Celeste,
for her unflagging support and encouragement, and for shouldering
alone the happy but tiring task of running after our children while I spentevenings and weekends in the quiet of the office, pecking at the keyboard.
I apologize to Grace, Ben, Clare, Leo, Rose, Vincent, Dominick, Helen,
and Gerard for trips to the playground not taken and games of Frisbee notplayed. That will now change.
313

ABOUT THE AUTHOR

Michael J. Behe is Professor of Biological Sciencesat Lehigh University. He received his Ph.D. in
Biochemistry from the University of Pennsylvania in
1978. Behe's current research involves delineation ofdesign and natural selection in protein structures. He
lives in Bethlehem, Pennsylvania.