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What Is NIGMS?

The National Institute of General Medical Sciences

(NIGMS) supports basic biomedical research on

genes, proteins, and cells. It also funds studies on

fundamental processes such as how cells communicate, how our bodies use energy, and how we

respond to medicines. The results of this research

increase our understanding of life and lay the

foundation for advances in the diagnosis, treatment,

and prevention of disease. The Institute’s research

training programs produce the next generation of

biomedical scientists, and NIGMS has programs to

encourage minorities underrepresented in biomedical

and behavioral science to pursue research careers.

NIGMS supported the research of most of the 

scientists mentioned in this booklet.
U.S. DEPARTMENT OF 

HEALTH AND HUMAN SERVICES

National Institutes of Health

National Institute of General Medical Sciences

NIH Publication No. 06-4121 

Reprinted August 2006

http://www.nigms.nih.gov 

The Chemistry of Health
Written by Alison Davis, Ph.D., under contracts

263-MD-205019 and 263-MD-212730.

Produced by the Office of Communications and Public Liaison

National Institute of General Medical Sciences

National Institutes of Health

U.S. Department of Health and Human Services
Contents

FOREWORD I V

THE PATHWAYS OF LIFE V I

CHAPTER 1: ACTIONS AND REACTIONS 2

It’s a Gas! 4

Chemical Biology in Action: Just Say NO 5

Folic Acid Saves the Day 6

Building Blocks 8

From Mice to...Bacteria? 10

Chemical Biology in Action: Chemistry to the Rescue 11

Question Box: Computer Labs 12

CHAPTER 2: HARNESSING BIOLOGY’S MAGIC 14

It’s Biology, It’s Chemistry...It’s Engineering! 14

Endless Possibilities 16

Chemistry for a Greener World 17

Tiny Bits of Help 18

Metals Can Be Good for You... 19

...or Metals Can Be Bad for You 20

Metals in Health and Disease 20

Question Box: Future Factories 21

CHAPTER 3: SUGARS AND FATS: ARE WE WHAT WE EAT? 2 2

Form and Function 23

Fats That Protect Bacteria Can Harm People 25

Sugar-Coated Proteins 26

Chemical Biology in Action: Sticky Situations 27

A Complicated Recipe 28

One-Pot Synthesis 31

Question Box: Putting Things in Order 32

CHAPTER 4: A CHEMIST’S TOOLBOX 34

A Model Cell 35

This Is Organic Chemistry? 36

A Room Without Much View 38

Pass the Chip, Please 39

The Many Faces of DNA 41

Question Box: Life on the Edge 44

CHAPTER 5: THE HEALING POWER OF CHEMISTRY 4 6

Looking to Sea 47

Making Medicines 50

Chemical Biology in Action: Library Research Pays Off 51

Getting It Left or Getting It Right? 52

Losing Medicines 55

Chemical Biology in Action: The Shape of Things to Come 56

Making Good Medicines Better 57

Question Box: Tools for New Medicines 58

CHEMISTRY FOR THE FUTURE 60

G LOSSARY 6 1
How could anybody fit all of chemistry into 

66 pages? You’re skeptical that such a feat

could possibly be accomplished, and with 

good reason. The Chemistry of Health cannot

pretend to cover such an enormous area of 

science in so few pages. We wouldn’t even

want to try. Instead, this science education

booklet aims to offer a sampling of how

basic chemistry and biochemistry research

can spur a better understanding of human

health. We also want you to witness the 

fascination of research alive in today’s

chemistry labs.

Chemistry is anything but stale or static. Countless

numbers of chemical reactions work ceaselessly

inside your body, allowing you to think, breathe,

and eat. Chapter 1, “Actions and Reactions,” aims

to convey the essential and wondrous notion that

the chemistry inside your body never stops.

Cascades of repeating biochemical relays keep your

organ systems operating smoothly and efficiently.

Your body’s metabolic factories break down the

food you eat and recycle the components back into

basic building blocks from which your tissues and

organs are built.

Scientists hunger for information since, like

many others, they are curious people. But a key 

reason biological scientists strive to learn how

living systems work is so they can redesign the 

broken metabolic circuits that contribute to many

diseases. Chemists, like most biologists, want to

learn how best to employ primitive organisms 

like bacteria and yeast, not only to probe fundamental biological questions but also to produce the

valuable commodities we call medicines. Chapter 2,

“Harnessing Biology’s Magic,” explores how biotechnology offers rich potential toward bettering

human health.

Perhaps one of the most amazing triumphs 

of the human body is the fact that all you really

need to do to keep your body running is to eat 

and to sleep. The rest seems to take care of itself.

Of course, much sophisticated biochemistry goes

on behind the scenes, as your body efficiently

churns out energy from the sugars, fats, and proteins you eat every day. Chapter 3, “Sugars and

Foreword
The Chemistry of Health I Foreword v

drugs to treat diseases. Scientists take careful note

of the chemical warfare waged among creatures 

of the land and sea. For example, molecules 

produced by microbes for defense against other

organisms their own size can point the way 

toward developing powerful antibiotic drugs to

treat infections in people.

Much of the science described in the pages 

that follow has been funded through U.S. tax 

dollars invested in biomedical research projects at

universities. The National Institute of General

Medical Sciences (NIGMS), which funded most of

these research projects, is unique among the components of the National Institutes of Health (NIH)

in that its main goal is to promote basic biomedical

research that at first may not be linked to any particular body part or disease. In time, however, these

scientific studies on the most fundamental of life’s

processes—what goes on inside and between

cells—can shed brilliant light on important health

issues, including what causes certain diseases and

how to treat them safely and effectively.

Fats: Are We What We Eat?” describes how carbohydrates and lipids (the scientific names for sugars

and fats) provide much of the structural scaffolding

for cells, organs, and tissues. This chapter also 

highlights a new frontier in chemistry research—

how the sugars that adorn the surface of cells affect

the way cells move about in the body. This knowledge holds great promise in helping researchers

devise ways to prevent diseases such as cancer 

and conditions such as inflammation that rely on

cell movement.

As technology advances at a swift pace,

researchers’ tools evolve to be ever smaller and

more efficient. The first computers ever made 

were so huge they nearly filled a room. Today, most

people’s personal computers fit snugly into a desk

corner. Some of the computers of tomorrow may

fit into the palm of your hand, or even perhaps 

be too small to see! Chemists are masters of materials, and an increasing number are looking to

nature’s toolbox to create tiny biological probes

and instruments. Scientists can now eavesdrop 

on the movements of single molecules and create

miniature devices such as robots and computers,

using traditionally “biological” ingredients like the

building blocks of DNA. Chapter 4, “A Chemist’s

Toolbox,” offers a glimpse into the technological

wonder propelling the chemistry of today and

tomorrow.

And finally, Chapter 5, “The Healing Power 

of Chemistry,” visits some unusual places that may

yield future medicines. Medicinal chemists search 

far and wide for molecules that could be useful 
Dear “Ask the Doctor”:

After a recent annual physical exam, my doctor’s

office informed me that I have “elevated liver

enzymes.” Now she says I need to come back 

for further tests. What does all this mean, and 

am I in danger?”

Confused

Anytown, USA

Is Confused in danger? Could be; but most 

likely not. To get to the bottom of questions like 

this, doctors ask patients a lot of questions.

“How do you feel?”

“Have you eaten anything unusual lately?”

“On any new medications?”

And often, doctors will perform more tests,

prompting the patient’s body to yield a hint as 

to what’s wrong—some clue as to why a most 

carefully maintained balance of natural chemicals 

has gone askew.

Like Confused, many of us have an encounter

with biochemistry without even knowing it.

In health and in disease, our bodies are biochemical laboratories abuzz with activity, where

molecules are constantly being made, used, broken

down, and recycled. What does the lion’s share of

the work? Indispensable molecules called enzymes.

When routine blood tests reveal abnormally

high liver enzyme levels, for instance, there are

many potential causes, depending on which

enzyme levels are awry and how off-kilter the 

levels are. The culprit could be as serious as 

alcoholism or infection with one of the hepatitis

viruses, both of which can cripple the liver over

time. Or the cause could be as innocuous as taking

certain common medicines or having a few extra

drinks at a party.

Many of the body’s enzymes reside inside cells.

If cells are damaged, they break apart and spill their

contents into neighboring body fluids, like blood.

The presence of higher-than-normal levels of

enzymes in the blood can signify trouble in the 

tissues or organs (such as the liver) that those 

cells normally populate. But sometimes, abnormal

lab results mean nothing at all. Elevated enzyme

levels caused by the body’s processing of

“toxins”—including substances like chemicals 

in the environment, prescribed medicines, or 

alcohol—usually return to normal once the 

foreign substance is gone from the scene.

The liver is not the only place enzymes hang

out. Every cell in every organ—from the liver to the

heart to the skin—is chock full of enzymes.

The Pathways of Life
In Control

The Chemistry of Health I Foreword vii

multiplying out of control, then its absence can

bring about dire consequences.

Although a scientist may study a couple of

isolated enzymes in the laboratory, inside the 

body enzymes are never lonely. They link up to 

form vibrant networks and pathways. The study of

biochemical pathways and networks, and how they

reverberate and influence each other, is the science

of life and the chemistry of health.

Anything but innocent bystanders, enzymes are the

reason why cells are bustling centers of activity.

Enzymes underlie our ability to move, to think,

to sense our world. Enzymes help us wink an eye,

savor an ice cream cone, and catch a sticky drip

about to fall off the edge of the cone. Enzymes, and

their essential cellular associates—other proteins,

nucleotides, sugars, and fats—allow a stubbed toe

to heal properly and nurture a fetus growing inside

a woman’s body.

But when they are not working properly, enzymes can cause disease. Cancer

can happen when the enzymes that

copy the genetic material DNA make

mistakes, giving rise to an errant

gene that produces a faulty protein, or

no protein at all. If that particular protein

is the one that keeps a given set of cells from

It seems to happen the same way every time:

You go to the doctor for a check-up, and a

couple of days later, you end up with a cold.

Your conclusion: Sitting in the doctor’s waiting room made you sick. Believe it or not, this

everyday situation resembles scenarios scientists face all the time in their labs. A scientist’s

perpetual challenge is to evaluate cause and

effect, and then make conclusions. Key to this

process is researchers’ use of “controls.” A

scientist only knows for sure that A causes B

if he or she knows that during the experiment,

the presence of A was necessary for effect B

to happen. That is—A doesn’t also cause C,

D, E, and F. Or, that B didn’t happen on its

own, without any input from A. In the waiting

room example, for instance, it could be that

going to the doctor truly does make you prone

to getting sick, because in

the waiting room, you are

exposed to more germs

than usual. But perhaps

there’s no relationship at

all—just by coincidence you

happen to get the sniffles

around the time you go

for your yearly checkup. Is it always in the

spring when pollen counts are

rising? Scientists must carefully design 

experiments so that they can account for the

influences of as many variables as they can

think of. Usually, researchers do this by 

comparing the test group with a control, or

untreated, group. Only then do their experiments really “work.”
CHAPTER 1

bi•o•chem•is•try (bi ́o kem ́is tree):

n., the chemistry of living organisms.

starting materials (called substrates) and converting them into finished materials (called reaction

products). One secret to an enzyme’s success in

this endeavor is its shape. An enzyme is shaped so

that it can hug its substrate tightly. This molecular

embrace triggers chemical changes, shuffling

chemical attractive forces called bonds and producing new molecules. Only enzymes that have an

exact fit with their substrates do a decent job of

speeding up chemical reactions. But things don’t

end there; reactions are not singular events. They

re-occur, over and over again. Enzymes are the key

players linking up chain reactions of the chemical

events that culminate in our everyday physiology.

Much like a cascade of dominoes, the product of

one chemical reaction becomes the substrate for

another. Enzymes form the core of these ordered

pathways, which themselves are the basis for

metabolism. In a grand sense, metabolism is the

ven though you’re probably sitting down 

while you’re reading this, your body is anything but static. Thousands of enzymes in your

body toil away every second of every day, breaking

apart the components of the foods you eat into

energy for essential life processes. Vision, movement, memory—you name it, there are enzymes 

at work behind the scenes.

Enzymes work by making it possible for chemical reactions inside your body to take place. While

that might not seem significant, consider 

the fact that without the help of enzymes, the 

conversion of nutrients and minerals into usable

biological molecules such as proteins and nucleic

acids might take weeks, even years. Enzymes can

make this happen in minutes, sometimes seconds.

How do they do it all, and so well? Enzymes act

like the accelerator pedal of a car. But they also

play the role of matchmaker, bringing together

E

Simply stated, biochemistry is life. Practically

stated, biochemistry is our life: what we are and

how we live. Our bodies are very busy factories,

extracting energy from the foods we eat, building cells and tissues, and knitting everything

together into a functioning unit using molecular

tools called enzymes. Creatures as distinct as

bacteria, giraffes, and people use many of the

same biochemical toolsets to survive, eat, move,

and interact with their respective environments.

Biochemistry underlies our health.

What Is Biochemistry?

Actions and Reactions
Fish swim, birds fly, babies crawl. Enzymes,

too, are constantly on the move. The world’s

smallest motor, in fact, is an enzyme found in

the powerhouse of the cell (the mitochondrion)

which generates energy in the form of a molecule called adenosine triphosphate, or ATP.

Often dubbed the energy currency of life, 

ATP shuttles to and fro throughout cells, and

is “traded” during chemical reactions. These

molecular transactions drive reactions forward 

to make a product. Several decades of work

earned three scientists—Paul Boyer of the

University of California, Los Angeles, John

Walker of the Medical Research Council in 

the United Kingdom, and Jens Skou of the

University of Aarhus in Denmark—the Nobel

Prize for figuring out how the motor, a molecule

called ATP synthase, functions as a set of

molecular levers, gears, and ratchets. Other

molecular motors include protein machines that

tote DNA-laden chromosomes or protein cargo

throughout the cell. The enzyme that copies

DNA does its job through what

scientists call a “sliding clamp”

mechanism. As a growing

DNA strand, a future gene

winds through an enzyme

called DNA polymerase like a

thread through a needle. The

energy source for this and all

biological motor-driven

processes is ATP.

The Chemistry of Health I Actions and Reactions 3

The Motion of Life

z Cascades of enzymes make up metabolism.

Product

Enzyme

Substrate

Product

process any organism uses to retrieve energy from Product

the environment and use it to grow. The proper

functioning of small and big body parts hinges

upon effective communication within and between

pathways. That includes everything from tiny

specks of DNA that string together into all of your

genes to a complicated, multicelled organ such as

the heart. By understanding the language of

physiological communication systems, scientists

can devise ways to patch the circuits when they

become broken, in illness and disease.

ADP + Phosphate

ATP

Rotation

Inside Mitochondrion

Substrate

Substrate

Mitochondrial

Inner

Membrane

Outside Mitochondrion

v The world’s smallest motor, ATP synthase, 

generates energy for the cell.
4 National Institute of General Medical Sciences

It’s a Gas!

Tediously long car trips elicit multiple rounds of

word games like “20 Questions,” in which players

take turns thinking of a secret object and having

their opponent ask more and more detailed

questions to identify it. In this game, the first

question is always, “Animal, Vegetable, or Mineral?”

Virtually everything imaginable falls into one of

those three categories.

Chemists could play such a game, in which the

mystery item is a molecule—any molecule. In this

game, the first question would always be, “Solid,

Liquid, or Gas?” Looking outside the window, it’s

easy to think of entries for each of these categories:

Stones are solids, dewdrops are liquids, and the

atmosphere is a blend of many different gases. But

there’s a trick: In theory, any molecule could in fact

be all three, if the conditions were right. In pure

The stereotypical image of a scientist as a

faceless white coat hunched over a microscope in the corner of a lab has never been

accurate, but it’s even more wrong today.

While plenty of scientists spend a lot of time 

in their own workspaces, they rely heavily on

interaction with other scientists to share ideas

and validate concepts—at scientific conferences, at the coffee maker, or via e-mail.

Although a scientist in his or her own lab may

crack away for years at a very small piece of 

a big puzzle—say, how a particular enzyme

works—he or she spends much of the time

communicating with other scientists to further

the understanding of molecular secrets.

Stuck in a Corner?

form, whether a molecule is solid, liquid, or gas

depends on its environment, namely the ambient

temperature and the atmospheric pressure. Water is

an easy example. Everybody knows that below 32

degrees Fahrenheit, water is a solid, and above 32

degrees, water is a liquid. Put a tea kettle on the

stove and witness water turn into a gas.

Our bodies, too, harbor an assortment of

solids, liquids, and gases. But of these three physical states, which chemists call phases, everything

that lives is largely liquid—water is the universal

solvent of life. Fingernails, hair, and bones are

solids, indeed, but only the dead parts. Living cells

resident in bone and its vital bone marrow thrive 

in a watery environment. Gases can also be found

throughout the body; some examples include the

oxygen we breathe in and the carbon dioxide we

breathe out. But inside the body, even these gases
The Chemistry of Health I Actions and Reactions 5

are dissolved in liquids—mainly blood, which

itself is mostly water.

One gas, nitric oxide (whose chemical symbol

is “NO”), serves the body in a host of useful ways.

Scientists were rather surprised not many years ago

when they discovered that the gas NO is a chemical

messenger. Tiny and hard to study in the laboratory, NO eluded scientists for many years. Other

molecular messengers—such as neurotransmitters

and larger proteins—can be relatively easily

extracted from body fluids and studied in a test

tube, where they can remain intact for minutes 

or even hours at body temperatures. NO, on the

other hand, vanishes in seconds. While this

property makes it horrendously difficult to study,

such volatility renders NO a molecule with extraordinary versatility. In a snap, NO can open blood

vessels, help pass electrical signals between nerves,

or fight infections.

But in addition to being a friend, NO can also

be a foe—too much or too little of this gas can be

harmful. Blood vessels that have been widened too

much can lead to potentially deadly shock, a condition in which blood pressure plunges so low that

vital organs cannot get enough blood to survive.

An overactive immune response—fired up by 

NO—can produce a painful syndrome called

inflammatory bowel disease. With all this at stake,

the body works hard to stringently control production

of this powerful gas.

Just Say NO

The molecule that manufactures NO

is an enzyme called nitric oxide synthase (NOS). Owing to nitric oxide’s

many different functions in the body,

three different versions of NOS exist,

specialized for the cardiovascular,

immune, and nervous systems. In

recent years, scientists have achieved a

major victory in beginning to understand how NOS works. Thomas

Poulos of the University of California, Irvine, determined the

structure, or three-dimensional shape, of one form of NOS.

Since intimate associations between an enzyme and its

substrate rely on a snug fit, probing the three-dimensional

shape of an enzyme or other protein can enable scientists 

to begin to understand how the protein works, predict what

other molecules it might fit, and design drugs to boost or

block its activity. After obtaining a sample of NOS protein

from the laboratory of Bettie Sue Masters of the University

of Texas Health Science Center at San Antonio, Poulos

obtained a “picture” of NOS by bombarding a tiny crystal

arrangement of the protein with high-energy X rays, then

piecing together the protein’s shape by tracing the directions

in which the energy was scattered throughout the crystal.

This work, years in the making, paints a portrait of NOS

consisting of two identical units. In a cell, the two units of

NOS assemble head-to-head, creating a new landscape upon

which substrates and helper molecules convene to complete

the task at hand: creating nitric oxide from an amino acid

called arginine. In the case of NOS, the helpers include iron

and a tiny molecule called a cofactor. Enzymes like NOS are

lost without these helpers.

CHEMICAL BIOLOGY

in Action

z Protein crystals of nitric

oxide synthase revealed

its three-dimensional

structure.

T.L. POULOS, H. LI, C.S. RAMAN
Like a ship nestling into its berth, many proteins

require the help of one or more other proteins

to perform their jobs well. However, unlike ships,

proteins docked together often change their

shape as a result of such an encounter. The differently shaped protein is newly and exquisitely

able to capture a substrate and carry out a

chemical reaction. Akin to rearranging seats in 

a room to accommodate more guests, the reshaping of proteins (called conformational

changes) can make extra room for substrates

and products to fit. Such shape changes also

change the electrical “ambience” of an

enzyme’s innards, revealing differently charged

portions of the molecule that can have a big

impact on molecular interactions.

6 National Institute of General Medical Sciences

Folic Acid Saves the Day

In baking, some ingredients are

simply not optional—forget the baking powder,

forget the muffins. Just as baking powder is essential for some recipes, helper molecules called

cofactors are necessary ingredients for many biochemical reactions.

Take folic acid (one of the B vitamins), for

example. Scientists have known for decades that

folic acid can protect against certain birth defects—

such as spina bifida—that develop during the first

few weeks after conception. For this reason, the

Food and Drug Administration recommends that

every woman of child-bearing age supplement 

her diet with 400 micrograms of the vitamin.

Scientists figured out that folic acid does its molecular good deeds by lowering levels of a potentially

harmful compound called homocysteine, which is

also a risk factor for heart attacks and strokes. As it

turns out, folic acid performs this task by speeding

up the conversion of homocysteine to methionine,

a nontoxic amino acid that the body needs.

Folic acid does this by improving the fit

between an enzyme and its cofactor. The enzyme

in this case is known shorthand as MTHFR, and

the cofactor, a molecule called FAD, is also vitamin-derived (from vitamin B2) and is essential for

converting homocysteine to methionine. Martha

Ludwig and Rowena Matthews, both of the

University of Michigan Medical School in Ann

Arbor, determined that by locking FAD onto

MTHFR, folic acid performs this protective role

in the body.

Pulling Into Dock

Before Binding

Cavity A accessible

Protein 1 Protein 2 Protein 1-Protein 2 Complex

After Binding

Cavity A blocked

A A
The Chemistry of Health I Actions and Reactions 7

Tucked away inside the DNA sequence of all of

your genes are the instructions for how to construct a unique individual. Our genetic identity 

is “coded” in the sense that four building blocks,

called nucleotides, string together to spell out 

a biochemical message—the manufacturing

instructions for a protein. DNA’s four nucleotides,

abbreviated A, T, G, and C, can only match up in

specific pairs: A links to T and G links to C. An

intermediate in this process, called mRNA (messenger ribonucleic acid), is made from the DNA

template and serves as a link to molecular

machines called ribosomes. Inside every cell,

ribosomes read mRNA sequences and hook

together protein building blocks called amino

acids in the order specified by the code: Groups

of three nucleotides in mRNA code for each of

20 amino acids. Connector molecules called

tRNA (transfer RNA) aid in this process.

Ultimately, the string of amino acids folds upon

itself, adopting the unique shape that is the signature of that particular protein.

Making a Protein From Scratch

2. On ribosomes, transfer

RNA (tRNA) helps convert mRNA into protein.

3. Amino acids link up 

to make a protein.

T A

G C

C

U

Amino Acids

tRNA

Ribosome

Thr Arg

A C G U A U C G U A C

C G

G C

A T

U A

C G

A T

G

A

T

C

A

C G

T

A

C

A

U

A

T

A T

C G

DNA mRNA

Tyr

1. Enzymes “copy” DNA

to make messenger

RNA (mRNA).
Building Blocks

So the case is made that enzymes, and all proteins,

are extremely important in the body. Where do

these important molecules come from? Do they 

last forever?

Proteins are synthesized continually throughout life. Stockpiles of proteins are not passed on

from generation to generation, but their molecular

instruction guides—our genetic material, DNA—

are. After reading the DNA “letters” in our genes,

specialized molecular machines (groups of enzymes

working side by side inside the cell) copy the DNA,

then other machines use this genetic template to

churn out proteins. To do this, enzymes mix and

match a set of 20 different amino acids, the building blocks of proteins. Hooking together these

amino acids, the body constructs thousands of

different protein types. Theoretically, millions of

proteins could be formed through all the possible

linkages between amino acids. It is not surprising,

then, that every one of these amino acids must be

readily available at all times for protein synthesis.

Dire consequences may result if one or more of

these amino acids is either absent or overabundant.

For instance, a genetic disorder called phenylketonuria (PKU) is caused by the body’s inability to

get rid of extra phenylalanine, an amino acid

abbreviated “Phe.” PKU is an “autosomal recessive”

disorder, meaning that the only way to get the

disease is if both of your parents carry a version of

a gene linked with this disease. If only one parent

has the gene linked to PKU, his or her children

cannot develop the disease. Children who have

PKU are born without the enzyme that breaks

down the Phe amino acid. Extremely high levels 

of Phe accumulate and are very toxic, especially 

to the brain. As a result, PKU causes mental 

retardation. Yet Phe is an essential amino acid—

your body cannot do without it. Both diet and

genes contribute to causing PKU, and so any

means to control the supply of Phe in the body 

can prevent the disease.

A thin silver lining to the PKU story is that the

disorder can be diagnosed simply—in fact, since

the 1960s, nearly every baby born in the United

States has received a tiny needle stick in his or her

heel to retrieve a droplet of blood to test for levels

of the Phe-chewing enzyme. If caught early

enough and treated in the first year of life, PKU

can be controlled. In 150 million infants tested

since the early 1970s, 10,000 cases of PKU have

been detected and treated. At present, doctors

treat children with PKU by prescribing a life-long

restrictive diet; certain foods, such as milk and

diet sodas containing the artificial sweetener

aspartame (NutraSweet®), are rich sources of Phe.

The diet is rigid, requiring children to avoid those

and many other foods, such as meat and fish, dairy

products, bread, nuts, and even some vegetables.

As a result, people with PKU have to take a special

Phe-free vitamin/mineral supplement to ensure

that they receive adequate amounts of all of the

other essential amino acids bountiful in those

foods. People used to think that once a child with

PKU reached the teens, he or she could go off

the diet, which can be expensive because of the

8 National Institute of General Medical Sciences
supplement. However, current guidelines recommend that people with PKU remain on the

restrictive diet throughout life.

To get around the difficulty and inconvenience of maintaining a highly specialized diet

and taking a dietary supplement for life, a better

solution might be to provide the Phe-digesting

enzyme to people whose bodies lack it. But while

replacing the missing enzyme that breaks down

Phe (abbreviated “PAH”) may seem a simple 

plan, this is much easier said than done. The PAH

enzyme has many parts and cofactors. What’s

more, delivering the enzyme requires a liver

transplant, a procedure that itself carries significant risks. An alternative approach would be to

supply people with PKU with an enzyme that will

get rid of Phe and that can be safely administered

by mouth. Such an enzyme, called “PAL,” abounds

in nature—plants, yeast, and a variety of other

organisms have it, and scientists can produce it 

in the lab using genetic engineering strategies.

Recently, researchers have succeeded in treating

an experimental strain of mice who develop 

a PKU-like syndrome with lab-made PAL.

Clinical studies in people will determine for

sure whether this strategy offers hope for 

people with the disease.

The Chemistry of Health I Actions and Reactions 9

z Three types of attractive forces hold atoms together to make molecules. Dots

represent electrons taking part in chemical bonding.

You may be surprised to learn that at the

heart of chemistry is physics—the study of

attracting and repelling forces that link up the

building blocks of life. Chemical bonds are those

physical forces that keep atoms together, and

they come in a few varieties (see drawing/

illustration above). Ionic bonds, in which positively charged atoms are attracted to negatively

charged atoms, are the strongest of the bond

types. Covalent bonds are more subtle, and

occur when neighboring atoms (such as 

hydrogen) share electrons from within their

respective halos of swirling particles. Chemists

refer to both ionic and covalent bonds as

“intramolecular” forces. Other important

forces are called “intermolecular” forces—

those holding different molecules together.

These types of forces form the basis for liquids

and solids, which are really just collections of

molecules arranged in a precise pattern in

space. Intermolecular forces are also called van

der Waals forces, named for the Dutch physicist

who first discovered them. Hydrogen bonds are

a type of van der Waals force, and represent 

an important bond in biochemistry.

A Special Bond

Ionic Bond (Sodium Chloride [table salt])

Hydrogen Bond (Water Molecules)

Covalent Bond (Chlorine Gas)

Sodium Chlorine Positive Negative

Charge Charge

Oxygen

Hydrogen

Na + Cl + Na Cl –
10 National Institute of General Medical Sciences

A type of bacteria called enterococci possess

enzymes that weave together alternating proteinsugar strands to create a tough cell wall—the

bacteria’s main defense against the outside world.

The antibiotic drug vancomycin interferes with 

production of the cell wall (see drawing/illustration

above). This kills the bacteria, which stops infection.

Some bacteria become resistant to vancomycin, and

thrive in the presence of the antibiotic.The developing cell wall of vancomycin-resistant bacteria has a

slightly different composition that the drug molecule

does not recognize. Specialized resistance genes 

provide the resistant bacteria with the ability to

reprogram the composition of the cell wall.

A Killer’s Strategy

From Mice to...Bacteria?

A favorite experimental tool of many scientists is

the laboratory mouse, which can be bred “to

order” with characteristics useful for addressing

specific research questions. While rodents differ

from people in important and obvious respects,

believe it or not mice and rats share many of the

same genes with humans. In some cases, upwards

of 80 percent of the nucleotides in a mouse gene

may be identical to a similar one —its “homologue”

—in humans. Nature is economical: Very important genes (those that code for key metabolic

enzymes, for instance) are conserved throughout

evolution, varying little between species. For

researchers, that’s a good thing. Mice and a slew of

other so-called model organisms—such as bacteria,

yeast, and even plants—are the workhorses of

many biochemical laboratories. But in addition to

these often striking similarities, there are significant differences in the biochemistry of model

organisms, especially in the most primitive of

species like bacteria. Scientists can exploit these

differences to fight disease, targeting enzymes or

other molecular parts that are common to

microorganisms but are absent from your body.

Legend

Vancomycin

Alanine-Alanine

Alanine-Lactate

z Drug-sensitive bacteria are killed when vancomycin attaches to an Alanine-Alanine

strand of the bacterium’s growing cell wall (top), preventing the protective cell wall

from forming at all. Vancomycin cannot attach to the slightly different, AlanineLactate strand of the drug-resistant bacteria (bottom). As a result, the resistant

bacteria are able to make their tough cell wall and survive in the presence of the

antibiotic drug.

VancomycinSensitive Bacterium

Cell Wall

Cell Wall

VancomycinResistant Bacterium

Vancomycin Cannot Bind,

Cell Wall Unaffected

Alanine-Alanine

Alanine-Lactate

Vancomycin Binds,

Cell Wall Does Not Form
The Chemistry of Health I Actions and Reactions 11

CHEMICAL BIOLOGY

in Action

Chemistry to the Rescue

Arguably many of the most important medical

advances this century relate to the development 

of powerful antibiotics and vaccines to treat

infectious diseases caused by bacteria, viruses,

and parasites. But those breakthroughs have come

with a cost—the microbes have learned how to

fight back, and with a vengeance. The misuse 

of antibiotics—these drugs are overprescribed 

by doctors and people often fail to finish a full 

prescription—is the most common reason why

antibiotic resistance is coming so rapidly to 

the fore.

When you take an antibiotic, the drug treats

infection by knocking out hundreds of strains of

“sensitive” bacteria in your body. But it also leaves

behind scores of “resistant” strains—slightly altered

versions of the sensitive variety. The resistant

microbes, with no stops in place, repopulate 

themselves rapidly. To make matters worse, these

lingering resistant organisms hang out not only in

your body, but they can spread to your family and

friends—worsening the problem for everyone.

Bacteria are not inherently malicious. In the

human body, many different types of bacteria

reside within the large intestine, where they

perform vital roles in processing food. Trillions 

of microorganisms break down undigested carbohydrates, common components of vegetables and

other foods like beans. In the wrong place, however, these normally innocuous bacteria—called

enterococci—can do the body great harm.

In disease, such microbes can seep from the

relatively safe harbor of the intestines into other

regions of the body, such as burned skin, the heart,

or the urinary tract. There, the bacteria can multiply rampantly, especially when the immune system

is already strained. Enterococci are stubbornly

resistant to most antibiotic drugs. Until recently,

an antibiotic called vancomycin fairly effectively

put the brakes on enterococcal infections.

However, in recent years the incidence of enterococcal resistance to vancomycin has been on a

disturbing rise.

Fortunately, chemists are hot on the heels 

of enterococci. Christopher T. Walsh and Daniel

Kahne, both of Harvard Medical School in Boston,

Massachusetts, have traced the roots of vancomycin resistance to a single, errant chemical link.

Vancomycin normally kills enterococci by getting

in the bacterium’s way while it tries to manufacture

a protective cell wall for itself. Vancomycin prevents

the molecular “bricks” of this cell wall from melding

together, leaving the bacterium susceptible to the

harsh environment and destructive enzymes in the

cells of its host’s body. Walsh, Kahne, and their

coworkers unearthed a set of just five genes that

enable enterococci to get past the antibiotic drug

vancomycin’s action by using a slightly different

method to build a cell wall. The researchers’ detective work points to promising avenues for future

antibiotic drug development, based on the strategy

of interrupting enzymes that rearrange the cell

wall precursors.
approaches, a supercomputer might be required.

We aren’t limited by our computational power 

at the moment, but rather by our lack of biological

knowledge and the scarcity of adequate modeling

approaches.

CH: What ingredients do you need to perform an 

in silico metabolism experiment?

Schilling: I start with a list of genes, then I look 

in textbooks and scientific articles to find out what

reactions they catalyze and what’s known about

them—this provides a “parts catalog” of sorts.

Then, I apply simple laws of physics and math 

principles—basically, describing networks of interacting enzymes as a set of mathematical equations.

Out of that comes a prediction of what kinds of

products the cell is capable of making under 

different environmental and genetic conditions.

CH: What don’t we already know about what goes

on inside living cells?

Schilling: Biologists are now forced to confront 

the issue of complexity in the cell—how a small

change in one component can affect hundreds of

things. The challenge facing the next generation of

scientists is to understand cells as systems...how all

the components interact and how the interactions

define cellular function.

CH: Do you need a really powerful computer to 

do in silico experiments?

Schilling: No, I just use my laptop—but I’m

working on relatively simple problems now using

basic linear algebra. In the future, as we try to build

models of more complex organisms—such as

humans—and apply more intensive mathematical

ioengineer Christophe Schilling works with computers, and he works in a

lab. But his is not a garden variety computer lab. Schilling, who earned his

Ph.D. in bioengineering from the University of California, San Diego, studies

bacterial cells—and the thousands of enzymatic reactions occurring inside

them—without ever putting on a pair of lab gloves or pouring bacterial broth

into a flask. Schilling’s in silico (literally, “within silicon,” a component of computer hardware) research relies on computers to study how enzymatic pathways

talk to each other and work together. But while the technique promises to be

inordinately powerful in predicting cellular performance under a vast set of

conditions, Schilling admits that he’d be out of a job if “wet” (laboratory-based)

biochemists didn’t keep busy in their labs figuring out what enzymes in the cell

actually do. The Chemistry of Health asked Schilling about the potential of

mapping a cell using computers.

B

QUESTION BOX

Computer Labs
CH: Will computers replace beakers and petri

dishes?

Schilling: No! Much of our knowledge of bacterial metabolism comes from biochemistry research

in the 1960s—I rely heavily on this information. In

the future, computer models will be used to design

experimental programs in research and industry—

yet at the same time the experimental results will be

required to improve the computer models. So, you

could say that they’re in a partnership of sorts.

CH: How would you attract young people to study

metabolism?

Schilling: I think you have to get people who 

are interdisciplinary—people who can gain 

appreciation for all aspects of the problem.

It won’t work with teams of different specialists 

just working together on their own subprojects in

genetics, biochemistry, or computational biology.

CH: How did you get interested in metabolism 

and bioengineering research?

Schilling: In my junior year at Duke University,

I was a biomedical/electrical engineering doublemajor and I saw a talk on automated DNA

sequencing by Leroy Hood, a genetics researcher 

at the University of Washington. It was the first

time I had seen engineering strategies of any sort

being applied to a molecular problem. The next

day, I dropped electrical engineering and picked 

up genetics.

In the future,

computer models will be used 

to design experimental programs 

in research and industry...

Describe one way 

bacteria become 

resistant to antibiotics.

What do biological 

motors use for fuel?

How does an enzyme speed

up a biochemical reaction?

What are the three 

phases of matter?

In 20 years, do you think

scientists will still study

biology in a laboratory—

or will they just do everything on a computer? Give 

a reason for your answer.

Got It?
Certain types of soil bacteria make the antibiotic

erythromycin—a complicated chemical structure

containing 37 atoms of carbon, 13 atoms of

oxygen, 67 atoms of hydrogen, and a single atom

of nitrogen—beginning with only a couple of

small and simple starting materials. The bacteria

make this widely used antibiotic through a pathway consisting of a series of enzyme “modules,”

or mini-factories, each of which is itself made up

of at least three different enzymes. In the case of

erythromycin production, the job of each module

is to progressively add two carbons to the growing chain of atoms destined to become

erythromycin.

Metabolic Factories Make Lots From Very Little

Harnessing Biology’s Magic

C HAPTER 2

C Erythromycin is made by enzyme modules, each of

which adds two carbons to the growing chain of atoms.

ADAPTED WITH PERMISSION FROM KOSAN BIOSCIENCES

ife scientists yearn to understand the natural

world. They persist in trying to unravel the 

mysteries of biology because these mysteries are

inherently intriguing. But more pressingly, scientists want to learn how biological systems work so

that they can control them. Such control yields

benefits to health and to the human enterprise in

countless ways. Harnessing biology’s magic underlies the extraordinary promise of biotechnology.

It’s Biology, It’s Chemistry...

It’s Engineering!

Metabolic engineering, that is. In this exciting 

field, biology and chemistry collide head-on.

The goal is to use the tools of biology to produce

chemical compounds that, in many cases, never

before existed in nature: “unnatural” natural

products. Metabolic engineers are in the business

of using living systems to turn simple sugars and

other small molecules into promising new antibiotic

drugs—even agricultural and veterinary products.

Some metabolic engineers aren’t even engineers, but rather biologists who picked up the

requisite chemistry knowledge or chemists who

learned the necessary biology. Many metabolic

engineers actually are engineers by training.

Whatever their background, the common thread

L

Module 2 Module 4 Module 6

S SS S S SS

O O O O

O

O

O

O

O

O

O

HO HO

HO HO

HO

HO

HO

HO HO

HO

HO

HO

HO

HO

Module 1 Module 3 Module 5
is that metabolic engineers think about metabolism with an unconventional pair of eyes. These

scientists see metabolic pathways as mini-chemical

laboratories, capable of carrying out multiple

chemical reactions in a single pot—the cell—

without the need for time- and labor-intensive

separation and purification steps.

Metabolic engineers work their magic by

altering the metabolism of a bacterium, plant,

or animal cell. To accomplish such a goal, the

researchers must first pick apart the biochemical

circuits these organisms routinely use to break

down food and produce energy from it (called

catabolic pathways), as well as those pathways 

that re-use the building blocks to make bigger

molecules (called anabolic pathways). Metabolic

pathways are those involved in the production 

or breakdown of aptly named molecules called

metabolites.

More than a hundred metabolites currently 

represent mainstay medicines for people, as well

as for animals. The antibiotics erythromycin and 

tetracycline, a cholesterol-lowering drug called

lovastatin (Mevacor®), and a flea-busting pet

medicine called avermectin are all “polyketides,” a

class of metabolites that soil bacteria manufacture

naturally and abundantly. Since polyketides are

made by a chain reaction of many enzymes,

metabolic engineers experiment with mixing and

matching the genes that encode these enzymes to

purposefully alter the ultimate outcome of the

series of reactions. By doing so, they can come up

with entirely new molecules. Companies have

been built upon this prospect, and they are mining

nature for the encrypted secrets that can enable

microbes to yield medicines that are more powerful

or have fewer side effects than those currently in

The Chemistry of Health I Harnessing Biology’s Magic 15

Drug companies large and small are in the business of locating new compounds, called leads,

to test for their usefulness in treating disease. In

general, the road to drug discovery involves two

sequential steps: lead discovery and lead optimization. One popular method some companies

use to discover could-be drugs is combinatorial

chemistry, a process in which chemists create

and then sift through immense collections of

compounds (“libraries”). Such screening libraries

consist of a diverse, randomly assembled array

of thousands of different molecules made from a

few starting chemical building blocks. While such

approaches can create a bewildering number of

possibilities, the lead molecules that are identified

through such a scheme may require extensive 

laboratory tinkering to transform them into bodyfriendly molecules that work well as drugs.

Combinations, Combinations
National Institute of General Medical Sciences

Tooling away in his microbiology lab studying

how the bacterium Escherichia coli (E. coli, a

common microbe) eats chemicals called hydrocarbons, David Gibson of the University of

Texas at Austin noticed a surprising thing: Some

of the bacterial spots in his petri dishes had

turned a brilliant blue. Looking in his notebook, Gibson realized that those particular

specimens were the very ones that he had just

spruced up with a new gene — one that coded

for an enzyme called toluene dioxygenase. He

carefully analyzed the blue pigment produced

by the new strain of bacteria and reasoned

that the color had been produced when the

enzyme converted a simple nutrient called

indole into indigo, the world’s largest-selling

dye and the one that makes blue jeans

blue. Coincidentally, the year was 1983,

exactly 100 years after 19th-century chemists

had devised a method to chemically synthesize

the dye, but one that relies on the use of hazardous starting materials (cyanide, for one)

and that also generates toxic byproducts.

Scientists at Amgen, a company in Thousand

Oaks, California, discovered that a very similar

enzyme, called napthalene dioxygenase, also

turns indole into indigo. Genencor International

of Palo Alto, California tried to introduce the

biological method to the $200 million indigo

market, but ran into trouble. Despite the

biotechnical innovation and environmentally

friendly nature of getting bacteria to make

indigo, as it turns out, the chemical synthesis

of this dye is far less expensive, quashing

commercial schemes to produce indigo

biologically.

Microbes Go Blue

16

use. Because these methods rely heavily on biology, they are in many cases considerably less toxic

than traditional commercial production schemes,

which often require the use of potentially hazardous chemicals to yield synthetic compounds.

Endless Possibilities

One of the most challenging aspects of the

search for new drugs is combing through reams

of possibilities—finding that perfect needle in 

a towering haystack. An enormous number of

new molecules can be generated by a variety of

means, but the tough part is finding the good

ones. A promising approach chemists are using 

to develop potential new drugs is combinatorial

chemistry, a sort of “needle-finding” technique 

in which chemists generate breathtaking numbers

(millions) of compounds and then attach each

one to a miniature plastic bead. The result is an

extensive collection, or a library, of many beads,

each with a unique molecule attached. Each bead,

then, holds a potentially good drug—a needle in

a huge haystack of possibilities. Scientists need to

be creative in finding ways to distinguish molecules that look very similar to each other but that

might act in very different ways. Often, chemists

do this by color-coding the process—the best

molecule advertises itself by turning red or blue,

for instance, when analyzed by a drug-target

chemical detection system.
The Chemistry of Health I Harnessing Biology’s Magic 17

to clear the air of methane, which is second only 

to carbon dioxide as a contributor to the

“greenhouse effect” that has been implicated as 

one source of global warming. In the United States,

the most significant sources of methane gas 

are landfills and agricultural livestock manure.

Chemistry for a Greener World

While strategies like metabolic engineering offer 

great promise for spawning new medicines, other

areas of chemistry aim to clean up the Earth,

improving people’s health by ridding the air and

waters of pollutants.

Terrence Collins of Carnegie Mellon University 

in Pittsburgh has developed a class of molecules,

called oxidation catalysts, that reduce the amount

of chlorine required for industrial bleaching

processes. The catalysts, crafted from nontoxic

components, may find use in the laundry and

paper industries and could also someday be used

to treat drinking water by cleansing it of harmful

parasites. Collins’ catalysts work by jump-starting 

a natural whitening agent (hydrogen peroxide) 

that is either present in, or can be easily added to,

water-based solutions. A key plus to these green

catalysts is that their shelf life can be pre-set.

This feature, something Collins calls “dial-a-lifetime,” permits scientists to control how long the

catalysts stick around before they self-destruct.

Innovative chemical strategies can help reduce

pollution from manufacturing processes, but they

might also help mop up after environmental damage has already occurred. To chemists, breaking

down small, stubbornly inert molecules such as

methane—a single carbon atom framed by four

hydrogens—is a technical tour de force. But to a

certain variety of bacteria that dwell in hot springs

in Bath, England, chewing up methane is a breeze.

As miniature apprentices, the hot springs bacteria

can provide a valuable service to scientists working

All chemical reactions involve the conversion of

starting materials (called substrates) into products.

Catalysts are molecules that make reactions go

much faster than they would on their own. By definition, catalysts are facilitators—they themselves

are not used up in the reaction and can be re-used.

In industrial reactions—say, the manufacture of

ammonia—catalysts can be a mix of simple molecules such as iron, potassium, oxygen, and

aluminum. Your body’s catalysts are enzymes.

Some enzymes make the reactions taking place

in your body occur up to a trillion times faster

than they would without any help! Enzymes are

therefore essential to life, since your body cannot

afford to wait days, weeks, or years to receive

the important products of biochemical reactions.

Speeding Along

Substrate Products

Enzyme Enzyme-Substrate

Complex

Enzyme

1.000 seconds 1.001 seconds 1.002 seconds

z Enzymes convert substrates into products very quickly.
18 National Institute of General Medical Sciences

Researchers and biotechnologists would love to

be able to use environmentally friendly biological

catalysts to convert methane into methanol.

Chemist Stephen Lippard of the Massachusetts

Institute of Technology in Cambridge has made

major strides in this area by intensively studying the

hot springs bacteria to find the magic ingredient—

an enzyme—that they use to eat methane.

Lippard and his collaborators figured out 

what this enzyme, called methane monooxygenase

(MMO), looks like and how it likely works. As it

turns out, MMO is a curiously complicated molecular machine made up of three separate parts.

Together, the three parts manage to transform the

tiny methane molecule into methanol in a reaction

with oxygen that replaces one hydrogen atom of

methane with an oxygen and a hydrogen. This

chemical reaction makes methanol, with water as 

a byproduct (see drawing/illustration above). The

fact that a bacterial enzyme can do this is important.

While methane is stubbornly difficult to break apart

in the laboratory, its chemical cousin methanol can

be processed rather easily. Moreover, methanol 

(a liquid) can be transported much more easily

than methane, which is a gas that is harder to 

keep contained.

Tiny Bits of Help

Many other scientists are finding ways to use the

bacterial work force. Some chemists are using

enzymes from bacteria to break down agents of

biological warfare. Sarin, the deadly nerve gas

sprayed in 1995 into the Tokyo subway system by

the cult Aum Shinrikyo, is one example. One of a

class of molecules called organophosphates, sarin

trips vital nerve circuitry in the bodies of people 

or animals who come in contact with it; very

small quantities can kill a sarin-exposed victim 

in as little as 5 minutes.

Fortunately, however, certain types of

bacteria manufacture an enzyme called phosphotriesterase (PTE) that inactivates sarin and other

organophosphate molecules like it, some of

which are found in certain insecticides but are

hundreds of times less toxic to people. Certain

organophosphates, such as the common insecticide malathion, kill insects because, unlike

animals, bugs lack an enzyme that breaks down

this chemical. For many years Frank Raushel 

of Texas A&M University in College Station has

studied the PTE enzyme, and recently he and 

his colleague Hazel Holden of the University of

Wisconsin–Madison cleared a substantial hurdle:

They identified the three-dimensional structure—

a “molecular snapshot”—of what this enzyme

looks like. This information will help scientists

understand how the enzyme works—and could

reveal how to engineer one that works even better.

H

C

H

H H

H

C

H

H OH

2H O2

H2O

2 Hydrogens

Methane

(Gas)

Water

Methanol

(Liquid)

1 Oxygen

z The enzyme methane monooxygenase converts methane into methanol,

producing water as a byproduct.

Enzyme Reaction
The Chemistry of Health I Harnessing Biology’s Magic 19

Evanston, Illinois, deciphered the three-dimensional

structure of a yeast copper “chaperone” protein.

This protein transports copper to the SOD enzyme

and protects the metal from unwanted cellular

interactions along the way. In ALS, researchers suspect, defective SOD—when energized with the

copper it needs to function—runs amuck and

causes cellular damage. Understanding more about

how the copper chaperone-SOD duo trades copper

will offer drug designers a crystal-clear glimpse of

how to cripple this molecular embrace in patients

with Lou Gehrig’s disease.

Metals Can Be Good for You...

Enzymes like PTE rely upon a special kind of

molecular assistance to do their jobs efficiently.

Metals such as iron, zinc, and copper all perform

vital roles in some of the enzymatic reactions that

fuel the body’s metabolism. Iron, for instance,

helps the protein hemoglobin transport oxygen 

to organs in the body. Many metals act to stabilize

the shapes of enzymes. But the body’s handling of

metals—some of which can be highly toxic in

excessive amounts—is a tricky business. In some

cases, cells exert exquisitely tight control, assuring

that only one or two free metal atoms are present

inside an individual cell.

Copper is a case in point. Crab and lobster are

more than perennial summer favorites—they are

also a good dietary source of this metal. Yes, the

stuff of pennies is crucial for life—copper is an

important helper to many cellular enzymes,

including one called superoxide dismutase (SOD),

which sops up dangerous “free radicals” that accumulate inside cells. Defects in SOD have been

linked to some inherited forms of amyotrophic

lateral sclerosis (ALS), also known as Lou Gehrig’s

disease. Although copper is necessary for life, it 

is a potentially toxic substance that—in the wrong

cellular locale—can damage other molecules, and

in some cases even cause disease. A team of

scientists including Valeria Culotta of the Johns

Hopkins Bloomberg School of Public Health in

Baltimore and Thomas O’Halloran and Amy

Rosenzweig, both of Northwestern University in

It’s a far cry from the real thing, but a

new artificial tongue promises to do a

lot more than taste hamburgers and

lick stamps. Chemist Eric Anslyn of the

University of Texas at Austin and his

coworkers have developed a prototype “tongue” biosensor for sampling

liquids: a tiny silicon wafer embedded

with detection beads that turn color in

the presence of specific chemicals.

Anslyn’s original electronic tongue

could only differentiate between acids,

simple sugars, and certain electrically

charged molecules. In theory, though,

many more chemical micro-detectors

could be added to the chip, enabling the device

to pick out several different components of a

solution poured over it. Indeed, an electronic

tongue might be a really good thing, considering some of the solutions it might be used to

“taste”— blood, urine, and polluted water, for

instance. Of course, the system might also be

used to assure quality control in much more

palatable substances, such as soft drinks.

An Electronic Tongue

MARSHA MILLER

z An artificial tongue can be used 

to “taste” chemicals.
20 National Institute of General Medical Sciences

...or Metals Can Be Bad for You

While it’s clear that the body would not work properly without a prescribed amount of a select group

of metals, some metals are indeed toxic to the

body. Even for the metals your body needs, too

much is not a good thing. Since metals are elements (the building blocks of all chemical

compounds), as basic components of the Earth

they cannot be broken down (like proteins and fats

can, for instance). Thus your body takes great care

to shepherd these potentially toxic materials to

their proper destinations inside cells. As with

copper, many other metals are escorted around 

by protective, chaperone-like molecules.

MET ALS IN HEAL TH AND DISEASE

WHERE IS IT?

Binds to enzymes throughout the

body (e.g., hemoglobin, nitric

oxide synthase) 

Binds to enzymes throughout the

body (e.g., superoxide dismutase)

Binds to enzymes throughout the

body, to DNA, and to some hormones (e.g., insulin)

Throughout the body (Na outside

cells, K inside cells)

Bones, muscle 

Forms the core of vitamin B12

Rocks, soil

Old paint (before 1973)

Contaminated fish (especially 

from the Great Lakes region 

of the United States)

HOW DO I GET IT?

Meats (highest in beef, pork, liver), baked

or lima beans, molasses, spinach 

Shellfish (crab, lobster), dried beans, nuts 

Shellfish (oysters), chick peas, baked

beans, whole grains, nuts 

Na: Table salt and baking soda

K: bananas, oranges, avocados 

Dairy products, broccoli, figs, sardines 

Meats, dairy products, leafy green 

vegetables

Toxic 

Toxic 

Toxic 

Some toxic metals, in contrast, aren’t good in 

any amount. They can hinder important enzymes,

preventing them from doing their jobs. Lead from 

the environment, for instance, can trip up the

body’s synthesis of a vital component of hemoglobin called heme, disabling the blood’s oxygen

transport system. Some metals can get trapped

inside cellular compartments called organelles 

and pose trouble for normal cell functioning.

Certain forms of mercury can be deadly, causing

irreversible damage in the brain. Scientists think

that some highly toxic metals, such as arsenic, can

also cause cancer in the skin and lungs.

METAL(Chemical Symbol)

“Healthy” Metals 

Iron (Fe) 

Copper (Cu) 

Zinc (Zn)

Sodium (Na) 

Potassium (K) 

Calcium (Ca) 

Cobalt (Co)

“Unhealthy” Metals

Arsenic (As) 

Lead (Pb)

Mercury (Hg)

WHAT DOES IT DO?

Helps body transport oxygen and

certain chemical messengers 

Defends body against damage from

free radicals

Plays role in sexual maturation and

regulation of hormones, helps some 

proteins stick tightly to DNA 

Helps communicate electrical signals

in nerves, heart 

Muscle and nerve function; blood

clotting 

Necessary ingredient for making red

blood cells

Can cause cancer, death 

Can cause cancer, neurological 

damage, death 

Binds to sulfur-containing molecules

in organelles; can cause neurological

damage, death
CH: What turned you on to science?

Lidstrom: I grew up on a cattle ranch in

Oregon, where I was around biology all the time.

I have always been fascinated with how things

work and why—how does light shining on a leaf

open it up? And I had great science teachers to

nurture my interests.

CH: Why microbiology?

Lidstrom: There’s no blood! And bacteria—

they have such amazing metabolism. They can

do almost anything.

he Chemistry of Health asked Mary Lidstrom, Professor of Chemical Engineering and Microbiology

at the University of Washington in Seattle, “What’s new for you on the biotechnology horizon?”

Bioremediation isn’t necessarily her pressing interest, says Lidstrom, explaining that engineers at companies are well on their way to getting bacteria—especially the kind she studies—to clean up the

environment. To her, the real excitement is in getting bacteria

to manufacture novel materials cheaply and efficiently, using

nontoxic starting materials and generating nontoxic waste products. In her own lab, Lidstrom spends much of her time trying

to convince bacteria to do things they weren’t meant to do.

CH: What does the future hold for the kind of

biotechnology you’re working on?

Lidstrom: The greatest challenge is for the chemical industry to move away from petrochemicals.

Our goal is to turn bacteria into chemical factories.

CH: How would that help matters?

Lidstrom: You could use simple sugars like

glucose, or other potentially renewable resources—

such as methanol—as starting materials.

CH: What challenges do biotechnologists working 

in this area face?

Lidstrom: The problem is that we can’t do this 

economically right now—the challenge is how 

to redesign these bacteria. Nature didn’t make 

them to do this.

Future Factories

What are the substrates

used by the enzyme

methane monooxygenase?

What products does this

enzyme make?

What advantages do 

combinatorial chemistry

methods have over the

more traditional ways

chemists have used to

screen for new drugs?

Name an antibiotic manufactured by soil bacteria.

Describe two ways your

body uses metals to

function properly.

Discuss some of the

plusses to using living

organisms to produce

medicines or other

consumer products.

Got It?

QUESTION BOX

T

And bacteria—

they have such amazing metabolism.

They can do almost anything.
o a great degree, the old saying is true: We 

are what we eat. Our diets—everything from

broccoli to butter to bread (a mix of proteins, fats,

and sugars)—contain the biochemical ingredients

for life. Ultimately, sugars (called carbohydrates)

and fats (called lipids) are your body’s chief

sources of fuel.

But wait—tempting culinary concoctions like

velvety caramel or cookie-dough ice cream aren’t

exactly what scientists are talking about when they

refer to sugars or fats. The proteins, fats, and sugars

you eat actually contain varying mixtures of all

three of these types of molecules, plus water.

Your digestive system teases apart a towering swirl

of frozen yogurt, for instance, into its constituent

“biopolymer” parts (proteins, lipids, and carbohydrates). These biopolymers are further digested 

into even smaller pieces: proteins into amino acids;

carbohydrates into smaller sugars called simple

sugars (like glucose); and fats into two breakdown

products, called glycerol and fatty acids. Your body

then transforms most of these breakdown products

into just a few common biochemical intermediates.

These are the simple molecules fueling the metabolic engines that produce the energy you need 

to eat and breathe.

T

Sugars and Fats: Are We What We Eat?

CHAPTER 3
The Chemistry of Health I Sugars and Fats: Are We What We Eat? 23

engineering, orchestrated by the orderly arrangement of ball-and-stick molecules called glycolipids 

(lipid chains adorned with sugars) and phospholipids (lipids marked with charged cellular tags

called phosphate groups). When aligned, these fatcontaining molecular creations resemble a double

array of matchsticks lined up perfectly end-to-end.

The components can line up so flawlessly due to

the simple chemical rule that oil and water don’t

mix. A double-thickness plasma membrane more

or less automatically forms when the matchstick

end (the lipid part) of each glycolipid or phospholipid gravitates toward oil (other, similar lipid

matchstick ends) and the matchstick head (the

sugar or phosphate part) drifts naturally toward

the watery environment typical of the areas inside

and between cells. Varying amounts of cholesterol,

Form and Function

Sugars and fats are also key structural components

in cells. It is true that fat has gained a certain notoriety, signifying the consequence of too many

French fries that end up in extra pounds. But fats

are essential ingredients that are constantly being

produced, recycled, and incorporated into crucial

fixtures such as the cell’s lining and protective barrier, the plasma membrane. Fat and a fat-derived

substance called cholesterol constitute important

structural components of the plasma membrane—

a greasy envelope of lipids and sugars with proteins

threaded through—that encases and protects the

DNA and myriad signaling and structural proteins

nestled inside. Yet the plasma membrane is not just

a simple barricade; rather, the construction of

this interactive sheath is a true feat of cellular

By far, the majority of molecules people taste as

sweet are carbohydrates. Besides table sugar

(sucrose), many other sweet molecules do exist.

Surely everyone is familiar, for instance, with the

pink or blue artificial sweetener packets joining

sugar as staples on restaurant and coffee shop

tabletops. Sweet ‘N Low® and Equal®, which 

contain the chemicals saccharin and aspartame,

respectively, are roughly 200 times as sweet as

table sugar. Saccharin, believe it or not, is a

chemical derived from petroleum. Aspartame 

is a tiny molecule constructed from two of the

body’s natural amino acids, phenylalanine and

aspartate. But drawbacks such as aftertaste and

lack of heat stability have prompted food scientists

to pursue alternative sugar substitutes. Among

these is a protein, called brazzein, extracted from 

a fruit native to Africa. To date, scientists have discovered only seven proteins—not sugars—that

our tongues perceive as sweet. Of these, brazzein

is the smallest and among the sweetest—more

than a thousand times sweeter than sucrose. Food

industry researchers are hot on brazzein’s trail, as

the protein seems to leave no unpleasant aftertaste

and can withstand unusually high temperatures.

The molecule is amazingly stable to heat: It retains

its sweetness even after being “cooked” for 2

hours at temperatures greater than 200 degrees

Fahrenheit. In a surprising twist, scientists who

recently unscrambled the three-dimensional structure of the brazzein molecule say it resembles

plant proteins involved in defense against microbial pathogens and some arthropod toxins, such

as those secreted by scorpions.

How Much Sweeter It Is
out to be. This, in turn, affects the shape of the cell

structures they form.

In many cases, lipids are much more than

passive molecular bystanders—they serve as active

participants in cell function. Besides influencing

the physical state—the fluidity, shape, and

structure—of the membranes of all types of cells,

lipids perform other important cellular tasks, such

as carrying messages. Sugar and phosphate chemical tags target glycolipids and phospholipids for a

journey throughout the cell interior, where they

participate in the relay of cell signals—including

those that tell a cell to grow and divide, or not.

also a matchstick-shaped molecule, account for 

the fluidity, or flexibility, of any given plasma

membrane. “Sticks” of cholesterol slide in between

phospholipids and glycolipids and influence

interactions between them—making the entire

membrane more liquid or solid, depending on 

the exact location and amount of the cholesterol

molecules present.

Long chains of water-insoluble lipids are constructed from building blocks called fatty acids,

which are also stowed away as a source of fuel in 

fat cells. The chemical bonds linking fatty acid units

together in glycolipids and phospholipids determine how rigid or floppy the lipid chains will turn

24 National Institute of General Medical Sciences

Outside the Cell

Inside the Cell

Carbohydrate

Plasma

Membrane

Glycoprotein

Glycolipid

Cholesterol

Phospholipid

Protein

z The plasma membrane is a cell’s

protective barrier.
The Chemistry of Health I Sugars and Fats: Are We What We Eat? 25

Scientists have already determined that depriving

bacteria of lipid A—either by taking away the

cells’ ability to make it or by wiping it out with a

drug—kills the bacteria that produce it. Biochemist

Christian Raetz of Duke University in Durham,

North Carolina, has extensively studied the pathways

that bacteria use to make lipid A. In the process,

Raetz and his colleagues have identified certain

compounds that stifle the production of lipid A,

some of which may lead to the discovery of new

antibiotic drugs. Ironically enough, Raetz has

found some precursors to the synthesis of lipid A,

as well as some lipid A look-alike molecules, that

block the lipid A-provoked inflammation that leads

to septic shock. One of these compounds is currently undergoing testing in Phase II clinical trials,

the stage in the testing of potential new drugs in

which researchers determine if the compound is

effective. (To progress to Phase II clinical testing,

researchers have to first prove, in Phase I trials,

that the compound is safe for use in people.)

Fats That Protect Bacteria 

Can Harm People

The outer surfaces of the cells of some types of

bacteria, such as E. coli or Salmonella, are coated

with fat. This lipid-rich shield, a component common to all bacteria of one particular class called

gram-negative bacteria, serves a barrier function

and prevents the escape of important microbial

enzymes. An integral part of this bacterial barrier 

is a lipid-and-sugar-containing substance called

lipopolysaccharide (LPS). A key constituent of LPS

is a molecule called lipid A, which scientists also

call endotoxin. This molecule can be very toxic 

to humans who encounter it. During severe

infections, large amounts of lipid A shed by gramnegative bacteria trigger the body’s immune system

to overreact, commanding an army of immune

cells to mount an attack. The resulting overproduction of immune chemicals can damage

blood vessels and lead to a deadly condition called

septic shock, in which blood pressure plunges to

dangerously low levels and key organs such as the

heart and kidney quickly become starved of oxygen

from the blood. For obvious reasons, lipid A is an

important target for chemists interested in

developing antibiotic drugs.
In medical research studies, the “sugar pill” 

is usually the so-called placebo: a “dummy”

pill that scientists administer to half of a test

group of patients to evaluate how well the real

pill works. In an interesting twist, biochemist

Hudson Freeze of the Burnham Institute in La

Jolla, California, and his colleagues are using

sugar pills themselves to combat a rare, inherited childhood disease. Given the many crucial

roles sugars play in the body, it is not surprising

that when the body doesn’t manufacture sugars

properly, dire consequences follow. Usually,

diseases caused by a body-wide lack of certain

carbohydrate-containing proteins damage the

central nervous system (often, the brain) and

result in severe mental retardation, but other

very serious symptoms, such as bleeding

problems caused by defective blood proteins,

are also a hallmark of some carbohydrate 

deficiencies. Upon analyzing the cells of a child

with CDG (a group of diseases collectively called

Congenital Disorders of Glycosylation), Freeze,

who for years had studied sugar metabolism

in a primitive organism called a slime mold,

quickly noted a conspicuous shortage of one

sugar in particular, called mannose. He worked

out a plan to try supplementing the child’s

diet with the missing sugar. As a result of

receiving this inexpensive treatment, the

child—who, it turns out, lacks the enzyme

that converts another sugar, glucose, into

mannose—has been able to resume a normal

life. Since then, approximately 20 children

have had similar success with this treatment.

Sugar-Coated Proteins

Sugars attached to proteins (glycoproteins) are

another key ingredient of cell membranes. Just as

the sugar portions of glycolipids are oriented

toward the watery cell exterior, so too are the

sugar components of glycoproteins. Jutting out

from the cell, these sugary “decorations” serve an

identifying role, sort of like cellular address

labels. Signaling molecules coursing through

body fluids encounter specific patterns of sugars,

which either grant them entry or refuse access.

In this way, glycoproteins play a gatekeeper role

in human cells. By virtue of marking cell surfaces,

glycoproteins also help organs and tissues form,

by directing “like” cells to meld together properly.

Sugar coatings also help roving cells move along

blood vessels and other cellular surfaces inside

the body, providing traction via their ability to

latch on to cell surface receptors.

26 National Institute of General Medical Sciences

Sweet Therapy

z The chemical structures of the sugars 

glucose and mannose are very similar.

CH2OH

H

H

H

H

Glucose Mannose

O O

OH

OH

OH

OH

H

CH2OH

H

H

H

H

OH

OH

OH

H

OH
signaling molecules inside the cell, neoglycopolymers

prevent cells from touching each other in the first

place. Kiessling’s research is yielding valuable insights

into cellular processes that hinge upon cell migration—not only inflammation, but also the spread 

of cancer throughout the body, and perhaps even 

the way in which bacteria infect humans.

In addition to blocking the sticky interactions 

that draw cell surfaces together, scientists are also

interested in changing cellular landscapes altogether.

To that end, Carolyn Bertozzi of the University of

California, Berkeley, has gotten into the business of

“remodeling” cell surfaces. Like Kiessling, Bertozzi is 

a chemist interested in intercepting biological maneuvers that underlie human disease processes such as

infection, inflammation, and the unchecked spread 

of cancer cells. Bertozzi set about her goal by figuring

out a way to trick a cell’s own metabolic machinery

into redecorating its surface with unnatural molecules—such as ones on cancer cells that might be

especially attractive to cell-killing agents, or ones on

heart cells that might be attractive to artificial materials like pacemakers and other medical implants. The

method Bertozzi dreamed up is beautifully simple 

in design. Her experiments have shown that she can

feed cells a novel synthetic sugar that is just a little bit

different from a natural cell surface sugar and get the

cell to build a chain of such sugars and send it to the

surface for display. Bertozzi can coax different cell

types to ingest and display varying amounts of the

unnatural sugars, providing the cell with brand-new

surface features. In many instances the cells don’t even

seem to notice!

Sticky Situations

A class of immune system cells called white blood

cells are a case in point. Studding the exterior of

these cells are protein molecules called L-selectins.

These sugar-grabbing proteins help white blood

cells perform their tasks, such as to travel to the site

of an impending infection to fend off microorganisms. The body’s process of recruiting immune cells

to combat injury or infection, however, has its own

shortcomings—in the act of responding to such

crises, immune cells spill their toxic contents and

inevitably damage normal cells in the process. The

result can be inflammation and pain.

Developing means to quash inflammation is

therefore an important goal, and indeed is the target

of an ongoing, multibillion-dollar pharmaceutical

effort. Chemist Laura Kiessling of the University 

of Wisconsin–Madison had a hunch that forcing 

L-selectin molecules on immune cells to cluster

together might send a signal to the cells’ clean-up

crews to clip the molecules from the cell surface.

By doing so, the cells would lose critical docking

sites that normally render the cells capable of sticking to each other—a key step in setting off an

inflammatory response. Her hunch was correct:

A few members of a new class of synthetic sugar

molecules called neoglycopolymers can perform this

trick, causing L-selectin molecules on meandering

cells first to cluster and then to fall off cell surfaces.

Neoglycopolymers are simple to make and halt

inflammatory processes in a distinctly different way

than do existing anti-inflammatory drugs, such as

aspirin or ibuprofen. While these medicines block

CHEMICAL BIOLOGY

in Action
A Complicated Recipe

Many drugs currently in the development pipeline

are proteins. Genetic engineering has enabled 

scientists to make proteins from DNA in just a

few easy steps. But the going hasn’t been so easy

with sugars. Chemists have long struggled with

the problem of being able to tailor-make sugar

molecules in the laboratory, and finally some scientists are nearing the light at the end of the

tunnel. An ability to make all types of sugars on

demand will undoubtedly tap the innumerable

resources these molecules harbor— as drugs, as

cellular “handles” for drugs to hang onto, and as

basic research tools to probe hidden facets of

cells. In practical terms, the ability to make sugars and sugar-derived molecules in the lab will

allow chemists to spend less time agonizing over

how to make the sugars and more time on studying the many roles these complicated molecules

play in the body.

28 National Institute of General Medical Sciences

Throughout your body, sugars help communicate

messages by serving as molecular routing slips

like the ones that direct pieces of mail to their

correct destination. Sugars also play important

structural roles within and between cells. Sugars

form the scaffolding for the alphabet of life, DNA.

The two threadlike strands of DNA “zip” together

by virtue of a biochemical concept called complementarity. The four letters of the DNA alphabet—

the bases A, T, G, and C —spell out the sequence

of your genes, sort of like words. Because of each

base’s shape, Gs stick only to Cs and As attach

only to Ts. The double helix of DNA, therefore, 

is a consequence of these base-specific chemical

attractions. Bolstering the bases in place is a scaffolding of sugars that is “glued” together via

molecules called phosphates. In plants, bacteria,

fungi, and some arthropods, the supportive structural role played by carbohydrates is dramatic:

Sugars literally hold the cell together by helping

to form and maintain a tough cell wall.

A Supporting Role

z Sugars are part of the DNA 

double helix.

Sugars

Phosphate

Groups

Bases
The Chemistry of Health I Sugars and Fats: Are We What We Eat? 29

One especially exciting avenue is the potential

for scientists to make from scratch the various sugars that reside on the surfaces of bacteria and

viruses. The ability to mimic such sugars will grant

scientists the capacity to design new vaccines to

control these disease-causing microorganisms.

Why is making proteins so easy and making

sugars so hard? The answer lies in the fundamental

structure of each (see drawing/illustration, p.30).

Proteins are chains of amino acids that can only fit

together one way: head-to-tail, sort of like beads on

a string. On the other hand, oligosaccharides—long,

and often branched, chains of sugars—can fit

together in many different ways, and chemists have

a tough time forcing the construction one way

instead of another.

Just two of the building blocks of an oligosaccharide chain can chemically snap together 

in dozens of ways. Another constraint is the fact 

that chemists often want to make branched structures, as opposed to linear “beads on a string.”

Traditionally, chemists attach chemical masks 

(protecting groups) to prevent the simple-sugar

building blocks from forming unwanted linkages.

This way, by blocking every potential attachment

site but one—the wanted one—a chemist can

ensure that only that particular link will be made.

Afterward, the protecting groups can be removed,

leaving only the sugar. This process of carefully 

separating chemical mixtures and applying and

removing protecting groups can be very 

time-consuming.

c So-called “protecting groups ”( ) help chemists 

prevent unwanted chemical reactions.

H H

H

H

O

OH

OH

OH

OH

CH2

OH
30 National Institute of General Medical Sciences

z (top) Amino acids (aas) link head-to-tail to make proteins. (bottom) Simple sugars link in many orientations to make oligosaccharides.

aa aa aa aa

Simple 

Sugar
The Chemistry of Health I Sugars and Fats: Are We What We Eat? 31

structures and reactivities into his computer will

ultimately allow for the process to be completely

automated by robots.

Wong’s strategy is but one of many aimed at

synthesizing sugars on demand. Other chemists 

are using a variety of techniques— virtually all of

which rely upon the use of protecting groups.

(The ones that don’t rely on the use of protecting

groups use enzymes, which are uniquely capable 

of selecting one, and only one, particular attachment site.) Some chemists, such as Daniel Kahne

of Harvard University are perfecting a technique to

build sugar chains atop a solid support. The rationale for such an approach is that sugars exhibit

unique shapes and properties when stuck to a 

surface compared to floating around in a solution.

Studying some of those unique properties has

obvious relevance to how sugars behave in real cells

in real bodies, where they mostly exist on surfaces.

Another plus to making, and studying, sugars on 

a solid surface is that the method is efficient and

easily permits the use of combinatorial chemistry

techniques that can randomly generate huge collections of surface-bound sugar arrays that are

potentially useful as drug targets.

One-Pot Synthesis

Chi-Huey Wong of the Scripps Research Institute in

La Jolla, California, devised an inventive strategy to

make some types of sugars in his lab—in a fraction

of the time required by most other approaches.

Wong’s recipe for making oligosaccharides takes

little time because it can all be done in one pot. The

ingredients for one-pot oligosaccharide synthesis

(as he calls it) are individual sugar building blocks

with masking groups attached, plus a computer. At

present, the process isn’t simple—a considerable

amount of groundwork is required to get his

computer to guide the assembly of sugar pieces in 

a pre-defined order. Just as cooking a meal requires

the chef to cut up all the vegetable and meat

ingredients before cooking, before Wong added

components to the “pot,” he had to prepare all his

chemical ingredients. To do so, he first conducted

a series of chemical reactions and assigned a computer to monitor these reactions, rank how fast each

occurred, and keep track of all those reaction rates.

Wong then instructed the computer to choose individual chain-building linkages by virtue of how fast,

or reactive, they were. At the moment, he has only a

limited set of building blocks and reactions to start

with, but Wong predicts that entering even more
am Sasisekharan, a biochemist at the Massachusetts Institute of

Technology, constantly finds himself caught up in sticky situations.

In fact, it’s his choice to do so. As a scientist who ponders the scores of roles

sugars act out in physiological systems, he spends much of his time devising

ways to figure out how long, complicated tangles of carbohydrates are hooked

together. Sasisekharan uses a brew of chemistry, physics, and math to determine

the letter-by-letter sequence of sugary molecular chains called polysaccharides.

Historically, Sasisekharan says, biologists have tried to “get rid of sugars” in 

the samples of proteins and DNA they analyze, because “they got in the way

and were a nuisance.” This is hardly the truth, he says, extolling the virtue

inherent in studying sugar molecules—in his words, “the most informationdense molecules Mother Nature makes.” According to Sasisekharan, sugars 

are orders of magnitude more complex than proteins or nucleic acids, which 

is a likely reason they’ve been the molecule scientists left behind. With a 

recent explosion of research on sugars and the important things they do in 

the body, that’s unlikely to be the case for long. The Chemistry of Health

asked Sasisekharan to fill in some of the exciting details.

CH: What are some of the things sugars do that

make them so interesting to study?

Sasisekharan: Sugars are like clothes cells wear.

Which sugar coat a cell wears —for example a wool

coat or a T-shirt—affects how that cell perceives

and responds to its environment. The sequence of

a sugar chain can influence the job a cell performs.

I hope the day will come that we can tell cells what

to wear—so that by having cells wear the right

clothes at the right time, we can influence what

cells do!

CH: You’ve recently discovered a way to decipher

the sequence of long chains of sugars —how do

you do it?

Sasisekharan: The sequencing method we

developed really hinges on two key principles:

mathematical coding and atomic-scale measurements of the weights of sugars. First, we start with

R

QUESTION BOX

Putting Things In Order
Why is it difficult for

chemists to make

carbohydrates from

scratch?

Cholesterol has an essential function in every cell 

in your body—what is it?

Describe two roles carbohydrates play in your body.

Can you think of some

possible ways that 

carbohydrate chemistry

research might lead 

to improvements in

treating disease?

Got It?

garage. I see math as a form of communication

cutting up a problem into smaller, more manageable pieces so you can put them all back

together in a logical way and solve the problem.

CH: How do you see advances in carbohydrate

chemistry advancing human health?

Sasisekharan: I think the greatest gains will

be in diagnosis, in getting a handle on correlating disease states. The ability to study sugars in

detail will enable scientists to be able to find all

the possible cellular landscapes, and possibly

what alters them. Said simply—why do cells

wear different sugar coats at different times?

Pinpointing exactly which sugars appear on the

surface of cells is going to play an important

role in how we understand development—

the very fundamental principles of how cells

position themselves to form tissues and organs.

CH: Why do you find studying science exciting?

Sasisekharan: Besides basic survival, I think

a fundamental human instinct is curiosity.

Innovation and invention have been instrumental for the survival of humankind...like Isaac

Asimov said, “No way but onwards.”

cellular material that contains not only sugars, but

also proteins and lots of other stuff. We’re starting

with a sugar chain called a glycosaminoglycan

(GAG, for short). We know that there are 32 subtly

different sugar building blocks to make this

particular kind of sugar. In order to be able to

distinguish the building blocks—and all their

chemical markings—from one another, each has

to be uniquely coded by a computer.

Next, we chop up the sugar several different ways,

with enzymes and chemicals, producing a huge

number of overlapping pieces. Then we weigh the

tiny pieces with atomic-level accuracy, using a

powerful technology called mass spectrometry.

Finally, we feed all this information to a computer,

and using the mathematical code we developed,

the computer helps us figure out the solution.

A lot like a jigsaw puzzle, there’s only one way this

puzzle can be properly assembled. We had a real

“wow” moment when we saw that our computer

program could generate a database of all the input

material and just pop out the answer!

CH: Using math seems very important to the type

of research you do—is that true?

Sasisekharan: Yes. Math is everywhere—it’s just

another system of logic we use to solve problems.

Everybody thinks about problems in some logical

way—like how to get from the kitchen to the

I see math as a form of communication 

cutting up a problem into smaller, more manageable pieces 

so you can put them all back together 

in a logical way and solve the problem.
o many, the word chemist conjures up images

of wafts of steam spiraling out of glass laboratory beakers bubbling with scorching, brightly

colored liquids. A vivid scene, perhaps, but a more

accurate image of the toolbox of today’s chemist

might include equipment such as computers,

microscopes, and large vats of fermenting bacteria.

The chemistry of yesteryear bears only a slight

resemblance to today’s endeavor. To be sure, the

quest for knowledge—to understand how and why

molecules combine and recombine in wondrous

ways—remains the same. Yet chemistry, biology,

and even physics are all fields of study that are

becoming much less self-contained. Biologists use

physics trickery with lasers to watch molecules

move one at a time. Physicists craft unique

radioisotopes that exist for only minutes or hours

(as opposed to many that stick around for centuries) and that serve as perfect tools for researchers

to track molecules in the bodies of animals and

people. Biologists and an increasing number of

chemists use living organisms—model systems

such as bacteria and yeast—to probe the molecular

mysteries of health and disease.

Basic biomedical scientists—chemists, biologists,

biochemists, and many others—study health-related

problems that may not, at the outset, have a clear

connection to a specific disease. Drafting hypotheses and testing them, over and over again, is a lot 

of hard work. Many experiments “fail” in the sense

that the scientist’s hunch turns out to be wrong.

But every failure is in itself a success: a key tidbit 

of information pointing the scientist’s trained eye

in a slightly new direction, where he or she can 

re-test an idea under a slightly different set of

conditions. For most scientists, this ongoing 

process is addictive!

By using models, researchers can perform all

this testing and re-testing with systems (such as

microorganisms, plants, animals, or computers)

that have a set of defined characteristics that don’t

change much from day to day, or from experiment

to experiment. Remarkably, many creatures that are

less highly evolved than humans use similar molecules and pathways to carry out their everyday lives.

One example is amylase, an enzyme in your saliva

that breaks down starch into smaller sugars. In

breadmaking, amylase is “food” for yeast, which 

use this enzyme to help them produce carbon

dioxide, the gas that makes dough rise. In many

cases, if a particular enzyme or pathway is very

similar in diverse organisms, there is a good 

chance that it’s a very important molecule—

often indispensable for life.

T

 Traditional chemistry lab equipment consisted of

glass beakers, clamps, and tubing.

A Chemist’s Toolbox

CHAPTER 4
The Chemistry of Health I A Chemist’s Toolbox 35

When it comes to using model organisms, chemist

Jerrold Meinwald of Cornell University in Ithaca,

New York, goes one step further than many scientists: He looks for critters that run their own

chemical laboratories. Insects do virtually all of

their communicating—with other insects, plants,

and their environment in general—by chemical

means, exuding a host of different materials,

such as toxic venoms and sexual attractants, in

the process. Meinwald and long-time Cornell

collaborator Thomas Eisner discovered that one

variety of insect, the squash beetle, undertakes

the constant production of a bewildering array 

of chemical compounds—some with enormous

molecular rings—starting with just a few small

chemical building blocks. Even more amazing,

these chemical secretions—which appear as

“defensive droplets” on tiny hairs on the surface 

of the non-moving, immature form of the beetle—

continually change themselves (by slight shifts 

of pliable bonds between connected atoms) to

create still more molecules. In general, Meinwald

suspects, many such insect-made concoctions

serve as defense against predators, but most

haven’t been analyzed yet in the lab.

A Model Cell

A protective barrier called the plasma membrane

(see p.24) is one of the most important regulatory

locales in a cell, serving as the point of entry and exit

for a bounty of large and small molecules that are

carried to a cell via the bloodstream. To function

properly, cells need a constant supply of nutrients,

electrolytes, and structural materials. While some of

these necessary components are manufactured inhouse, many are obtained from outside the cell. The

plasma membrane is also an important communications hub, filtering messages sent by other cells and

the outside environment. Membranes are studded

with proteins called channels and pores that thread

their way from the outside to the inside of the cell,

or the other way around. Scientists often study these

proteins because they are a key target for drugs.

Scientists have devised molecules “smart”

enough to self-assemble into miniature cells 

or cell parts—such as the plasma membrane.

And some researchers are creating teeny,

laboratory-made reaction vessels.

M. Reza Ghadiri of the Scripps Research Institute

has invented a way to get laboratory-made rings and

strings of amino acids to assemble themselves into

tube-shaped channels and pores. To create the tubes,

Ghadiri constructs rings of eight to ten amino acids.

By altering the reaction conditions a little, such as

fine-tuning the pH of the test-tube liquid, Ghadiri

can get the rings to stack on top of each other,

forming a tube. Such artificial versions of naturally

occurring molecules might be an extraordinarily

useful tool for scientists to use to design—and ultimately deliver—drugs to the right spot in the body.

Bug Labs

z Squash beetles are sophisticated chemistry labs.

THOMAS EISNER
National Institute of General Medical Sciences

By tweaking the dimensions of the amino acid

ring-building blocks, for instance, Ghadiri can

design channels to transport substances of

varying sizes, ranging from three-atom water 

molecules to considerably larger molecules of

sugars, like glucose. The designer molecules could

also be used as antibiotic medicines, by virtue of

the artificial channels’ ability to poke holes in 

bacterial membranes—making them too leaky to

hold their contents.

This Is Organic Chemistry?

A similar approach, being pursued by Fredric

Menger of Emory University in Atlanta, is the

design and production of “giant vesicles,” which

are sort of like artificial cells. Menger can make 

the vesicles—basically large, membrane-encased

bubbles—about the same size as a cell, and with

custom-made cellular properties. His innovative

work is yet another example of how blurred the

classic lines have become between chemistry and

biology. Before Menger’s graduate students can

begin to study cell function—traditionally a biological pursuit—they must pass muster as expert

synthetic organic chemists. Menger asserts that

such a skill—the mastery of using chemistry to

make from scratch a multitude of biological

mimics—comes in very handy when asking

questions about fundamental cellular processes.

For most of his vesicle experiments, Menger

drops into water a greasy material (a lipid called

DDAB, didodecyldimethylammonium bromide).

Almost instantaneously, the oily liquid balls up,

36

z Two giant vesicles are about to fuse.

JASON KEIPER
The Chemistry of Health I A Chemist’s Toolbox 37

Eons of natural selection have arranged perfect

fits for biological teammates such as receptors 

and the proteins they recognize: enzymes and

their substrates, for instance, or two twists of

matching DNA strands. Starting from scratch 

in the laboratory, however, chemists must work

hard to create an appropriate suitor for a known

molecule or for a brand-new one that doesn’t

even exist in nature. A field of research called

host-guest chemistry aims to devise ways to

study—and even create—interactions between

two molecules (the host and the guest), mimicking or blocking some naturally occurring

function. Often, the guests are known biological

entities. One example might be a receptor for a

hormone. In your body, such receptors are

linked to other receptors through biochemical

pathways, so activating one sets off an unstoppable cascade of reactions causing some

physiological response, such as a change 

in your blood pressure. To interrupt such

pathways—those revved up in heart disease 

or cancer, for instance—scientists are trying to

develop synthetic hosts that can attach themselves tightly to their guest molecule and keep

them from talking to other proteins (their real-life

hosts). Such a strategy has the potential to trip

up an entire signaling pathway. Chemists use

computer models along with as much detailed

knowledge as they can find about molecules’

behaviors and shapes to custom-manufacture

new molecular mimics.

pinching itself off into spheres. Though seemingly tiny, by a chemist’s standards they are

gargantuan—nearly the size of a cell (something

easily seen with a standard light microscope). If

you’re going to use the vesicles to ask cellular

questions, says Menger, it is essential to make the

spheres approximately that size (so the angle of

curvature of the “membrane” most closely resembles that of a cell). But the real advantage of

making the lipid balls so big is that Menger can

peer into a microscope and watch what they’re

doing—in real time—as he dumps other chemicals or hormones on them or subjects them to

quick shifts in temperature. Menger hopes these

unusual chemistry experiments will shed light on

very biological problems, such as how tumor cells

stick together, how severely disrupted membranes

(such as in burns or wounds) heal themselves,

and even how sperm fertilize eggs. And, since cell

membranes are a common port of entry for a

variety of drugs, the work may also lead to better

drug delivery schemes.

Who’s Hosting This Party?

Pathway “On”

Hormone

Receptor

Pathway “Off”

Plasma

Membrane
National Institute of General Medical Sciences

A Room Without Much View

Mimicking cell parts to study chemical reactions in

biological places is an important area of chemistry

research today. In so doing, scientists can easily

make ever-so-slight alterations that may not even

exist in nature and then test the physiological

outcome of such changes. In addition to manufacturing cell-like components, some chemists have

gotten into the business of creating tailor-made,

sub-microscopic spaces for reactions to take place.

Such spaces aren’t very roomy, but they do provide

a really snug fit for just a couple of molecules of a

defined shape. Julius Rebek of the Scripps Research

Institute is an expert at making such molecular

cages, which in some cases could make it easier for

scientists to study biochemical reactions in the lab.

The clever thing is that Rebek spends little time

constructing these molecular cages—they do it

themselves. Rebek supplies the scaffolding—

enjoined rings of atoms that can be prepared from

fairly uncomplicated chemical recipes. Then,

chemical attractive forces glue the pieces of the

cage together, in much the same way as the seams

of a softball are stitched together. The cages are

ideal reaction centers. Rebek traps other chemicals

inside the cages, so these molecules are forced to

touch each other and then react. As the reaction

proceeds, the products are also trapped inside, and

they can be extracted later. The process is a lot like

what happens with enzyme-catalyzed reactions, in

which the key job of the enzyme is in positioning

the reacting chemicals side by side in close proximity. In addition to acting like enzymes, molecular

cages —which can be formed repeatedly and

reversibly—may find use as biological sensing

devices, designed to detect only molecules that

have a certain unique shape.

38

z Two flaps of this “softball” molecular cage open up to expose a molecule

called adamantane (in center) to other incoming reactants.

REPRODUCED WITH PERMISSION FROM JULIUS REBEK, JAVIER SANTAMARIA, AND MICHAEL PIQUE 

(SCRIPPS RESEARCH INSTITUTE)
The Chemistry of Health I A Chemist’s Toolbox 39

Pass the Chip, Please

But don’t bother with the sour cream and onion

dip. Because this isn’t the potato kind, but rather a

variety of chip that’s made from silicon, plastic,

and glass...the kind that fits easily between the tips

of two fingers...the kind that contains a laboratory 

full of instruments! It’s true—Purdue University

chemist Fred Regnier has succeeded in creating

such a “laboratory-on-a-chip” that contains expansive networks of miniature tubes and Lilliputian 

separation columns, all etched onto a dime-sized 

silicon wafer, via the same techniques used routinely to manufacture computer chips. Voltage

applied to alternate ends of the chip channels a

liquid sample throughout the tubing, where it then

encounters various mini-instruments, such as dust

particle-sized reaction vessels and single, hair-thin

chromatography columns (chambers that separate

components of a mixture). The tiny chip-labs use

far less starting material, requiring a millionth the

amount of liquid compared to typically sized

instruments—a quantity that equates to just a

fraction of a drop. And besides conserving workspace, the chips also save time by permitting

several experiments to be conducted at once rather

than separately. Such properties could someday

also make this technology ideal for measuring

multiple components of a solution—cholesterol,

sugar, and electrolytes in blood, for instance—

in a doctor’s office.

z This lab-on-a-chip contains an expansive network of miniature tubes

and columns, each the size of a tiny fraction of a drop of water.

COURTESY OF FRED REGNIER
40 National Institute of General Medical Sciences

The first thing most people think of when they

hear the word antibody is “something that floats

around in my body and helps me fend off a cold

or the flu.” In your body, that’s indeed the main

task for antibodies. Tailor-made by your immune

system, antibodies heal you by first identifying—

then supervising the destruction of—the

microbes that make you sick. Even better, the

next time the same molecule or organism comes

around, you have the antibodies on hand, just

waiting to do away with it. Perhaps the most

remarkable thing about antibodies is how versatile

they are. Any foreign molecule, really, can touch

off the production of a specific antibody that will

match it. Tree pollen. Bacterially produced toxins.

DNA. Stop for a minute and think how clever the

immune system must be to have the capacity to

whip up a perfectly targeted antibody for such a

wide variety of different molecules with which we

come into contact! Chemists have harnessed the

extraordinary power of our antibody-producing

immune systems to probe fundamental problems

in chemistry. Antibodies, for example, have been

prepared against molecular complexes that occur

in the middle of a chemical reaction. Such

complexes—what chemists call transition states

are like a molecular snapshot of what happens

during the most important part of a chemical

reaction. So-called catalytic antibodies can be

prepared that actually influence—by speeding up

or even freezing in time—an interesting chemical

reaction that a scientist wants to study.

Catalytic Antibody

Reactant Product

Hard-Working Antibodies

Other scientists are developing similar chips to

be used as drug delivery devices. Such a “pharmacy-on-a-chip,” dreamed up by chemist/engineer

Robert Langer of the Massachusetts Institute of

Technology is still in the development stages.

Langer’s chip—also a dime-sized wafer of silicon—has a few dozen tiny reservoirs carved into

it. The sample wells, as such reservoirs are called,

hold a volume smaller than that of a salt grain.

The wells are lined with a gold membrane and

filled with various solutions (in the testing phase,

the researchers poured in fluorescent compounds

that would be easily detectable upon release).

The reservoirs are then sealed off with glass.

Langer and his co-workers formulate a solution

that mimics body fluid (in terms of pH and electrolyte content), submerse the chip in this liquid,

and rush electrical current across electrodes

laced atop the wells. Then, chemistry happens!

Gold particles team up with chloride molecules 

in the solution and form what chemists call a salt:

a duo of alternately charged molecules. Result:

The gold membrane well covering collapses and

the well’s contents—say, a drug—spill out into

the solution.

H H

H

M

H M

H H

H H

c Catalytic antibodies can act like enzymes, converting

reactants into products.

ADAPTED WITH PERMISSION FROM TRENDS IN CELL BIOLOGY 1999, 9, M24-M28. COPYRIGHT 1999

ELSEVIER SCIENCE.
The Chemistry of Health I A Chemist’s Toolbox 41

DNA Electrical Mini-Wires

Scientists have known for half a century that the

DNA in our bodies—and in microbes, plants, and

animals—has a special structure (called a double

helix) that looks a lot like an upward spiraling

staircase. The two halves of the staircase are complementary—they stick to each other much like

the opposite strands of VELCRO®. Each banister

of the staircase consists of ringed sugar molecules

held together by chemical units called phosphate

groups, and the steps in between are also flat—

they are stacks of ringed molecules called

nucleotides. These steps are the letters in the code

of life, and make up each gene’s alphabetical

sequence. Because of the orderly arrangement of

the whole thing, strands of DNA have defined

electrical properties. Stacks of ringed molecules

exhibit orderly displays of electrons and form 

what scientists have creatively dubbed “pi-ways.”

(So-called pi-orbitals are electron-occupied shells

that hover above atoms and are particularly common surrounding the types of bonds in ringed

molecules.) Scientists have found that electrons 

can literally hop along these routes. Why would

anybody care that DNA can conduct electricity?

Damage to DNA, suspect scientists such as

Jacqueline Barton of the California Institute of

Technology, might be caused—or perhaps even

fixed—by electron transfer through DNA. More

practically speaking, DNA wires could be very

useful components of miniature machines.

DNA— it’s not just for heredity anymore.

Deoxyribonucleic acid, whose primary function 

is passing on genes from parents to offspring, is 

at heart a collection of molecules—a chemical.

Scientists are capitalizing on some of the unique

features of this versatile substance, and in this way,

DNA is acquiring a host of new uses. In the future,

electronic devices wired with DNA have the potential to work faster and to fit into a tiny fraction of

the space today’s larger machines require. DNAbased mini-machines also promise to be extremely

efficient, consuming less power and producing less

heat than the equipment currently in routine use.

Many properties of DNA—its size, structure, and

the rules that govern how it is copied—may make

it superior to current materials for a variety of

purposes. Here’s a sampling:

The Many Faces of DNA

Light

DNA can conduct electricity. v 

COURTESY OF JACQUELINE BARTON

Electrical

Conduction
DNA Mini-Robots

Some of the factories of the future will be far

smaller than those of today. That’s because such

manufacturing plants will have on staff tiny robots,

not humans, to perform routine and repetitive

tasks. Nadrian Seeman of New York University 

in New York City has used laboratory-prepared

strands of DNA to construct the first DNA-based

nanomechanical device. (The prefix nano signifies

one-billionth, so that an object that is 1 nanometer

is one-billionth of a meter long). Seeman started

with a synthetic DNA molecule he calls DX DNA,

whose shape is very rigid. This property makes it 

an ideal robotic arm. Seeman used enzymes that

link up the building blocks of DNA to fit together

three different DNA pieces, each looped off at the

end. The junctions of the mini-machine’s parts 

are twists and turns that naturally occur in DNA.

Seeman’s tiny nanodevice is much too small to see,

even with a microscope. So, as a means to measure

the distances between the connecting DNA parts,

and to be sure that the entire device is constructed

as planned, Seeman labels each of the parts with 

a fluorescent tag and looks for telltale glows that

occur when molecules are close together (or that

don’t occur when they are farther apart).

DNA Biosensors

In the very near future, DNA will find use as a 

versatile material from which scientists can craft

biosensors, devices that detect the presence of

something biological —say, a minute amount of

DNA in a virus—and then output a signal. DNA

biosensors can theoretically be used for medical

diagnostics (for instance, detecting a misspelling 

in a disease-causing gene), forensic science, agriculture, or even environmental clean-up efforts.

A significant advantage of DNA-based sensing

devices is that no external monitoring is needed.

How do they work? DNA biosensors are complicated mini-machines—consisting of sensing

elements (“probes” that match up in sequence with

the DNA to be detected), microlasers, and a signal

generator, all in one. At the heart of DNA biosensor

function is the fact that two strands of DNA stick to

each other by virtue of chemical attractive forces.

On such a sensor, only an exact fit—that is, two

strands that match up at every nucleotide position—

gives rise to a fluorescent signal (a glow) that 

is then transmitted to a signal generator. Ideally,

the sensor would be a tiny square of a chip that

could be immersed in a test fluid—blood, for

instance—to pick up traces of disease-causing

bacteria or viruses.

42 National Institute of General Medical Sciences

Z–B B–Z

z Rotation between two naturally occurring shapes of DNA (B and Z)

causes this tiny robotic arm to move back and forth.

COURTESY OF NADRIAN SEEMAN
The Chemistry of Health I A Chemist’s Toolbox 43

finding the answer, because the only way they

know how to solve the problem is to try all the

possibilities, one by one. In fact, with 100 or so

cities, a supercomputer is needed, and with 1,000

cities, no existing computer can solve this problem!

DNA-based computers, on the other hand, would

find such a problem a breeze, since they could test

all the possibilities at once, in parallel. How might

they do that? Scientists made “cities” out of synthetic strands of DNA that they made in the lab

(much like a gene, each DNA-city had a different

combination of the four different nucleotides).

Next, the researchers made connector strands. The

lengths of these connectors, which linked the end

of each DNA-city with the start of another (several

cities could be hooked together in this way), were

sized according to the distance between the cities.

The scientists then mixed everything together, and

all of the matching DNA-cities came together in all

possible combinations. Voilà! The shortest string 

of DNA to come out is the answer to the problem.

DNA Computers 

Scientists crafted the first prototype DNA computer in 1994. These tiny PC-wannabees aren’t

mainstream yet, but they may present technologists

and biologists alike with a powerful tool for solving

bewilderingly complicated problems. If you think

about it, computers made of DNA make sense.

Mother Nature picked DNA as the carrier of life

for good reason. DNA is both stable and predictable—intact strands of the genetic material

have been unearthed in specimens thousands of

years old. A set of mathematical rules defines how

DNA is transmitted across generations. And to top

it off, DNA is self-replicating—it can copy itself!

Take a famously hard-to-solve math problem

called the Hamiltonian Path Problem, in which

given several points—cities, for instance—the goal

is to find the shortest trip from the start city to the

end city, but the rules state that you can only travel

through each intervening city once. Seems easy,

but conventional computers have a miserable time

z A DNA computer can solve extremely difficult math problems.

ADAPTED WITH PERMISSION FROM TOMO NARASHIMA

Atlanta to Boston Boston to Chicago Chicago to Detroit 

Complement of Boston Complement of Chicago
ife on the edge can be most interesting. To chemist Barbara Imperiali of the

Massachusetts Institute of Technology, the borderline between chemistry

and biology is indeed an intellectually challenging frontier, and one likely to

deliver significant gains in human health. Using a chemistry toolkit, Imperiali is

one of many of today’s chemists seeking to solve biological mysteries. One

problem Imperiali has chosen to tackle is how certain sugar-studded proteins

get around compartmentalized cells (those—like human cells—that contain a

nucleus and other organelles) which, she describes, “have a need for serious

traffic control!” Imperiali focuses on cell pathways responsible for tacking sugars onto proteins, and on those proteins themselves. Using innovative design

strategies, she’s developing artificial proteins from building blocks not used by

Mother Nature. She’s also pushing the limits of technology in developing

exquisitely sensitive biosensors that can detect trace amounts of metals in biological fluids. The Chemistry of Health asked her what kinds of tools she needs

to make these sorts of experiments possible.

CH: What are some of the most exciting technologies at the chemistry-biology interface?

Imperiali: There isn’t really any single technique

that stands out. Technology has been making

enormous leaps and bounds in the last two to three

decades. We’re in a position now to bring all the

tools together to investigate complex biological

systems in great detail.

CH: What technologies are indispensable for the

kind of work you do?

Imperiali: NMR (nuclear magnetic resonance) 

spectroscopy, for sure. This is a technique for looking at the structure and movement of molecules in

a water-based solution. It’s one way we test if the 

proteins we’ve designed actually do what we think

they do. NMR is also very valuable in medicine

these days, where it’s known as MRI and is being

used to image whole people.

L

Life on the Edge

QUESTION BOX
How do molecular cages

resemble enzymes?

Give three examples of

how scientists are using

miniature biological chips

in research today.

List a few examples of

model organisms.

How do researchers use

host-guest chemistry to

study biology?

Discuss why it is important for chemists to work

together with biologists,

physicists, and other

types of scientists.

Got It?

CH: What got you interested in science to 

begin with?

Imperiali: No one in my family was a scientist.

I just found it fascinating. I liked biology, but 

I loved the precision that chemistry can offer.

I was excited about looking at individual molecules and understanding biological function,

molecule by molecule.

CH: Would you advise a young person

interested in science to pursue a chemistry

research career?

Imperiali: Absolutely, but I also tell them that

they should choose something that they really

enjoy. Otherwise, it won’t be worth it. I try to

tell them to learn how to think rather than to

learn a specific skill.

Another great method is fluorescence, a technology that’s extremely sensitive in detecting

vanishingly small amounts of biological samples

and can even be used to follow proteins around

inside living cells! 

Another fantastic technique is mass spectrometry. With “mass spec,” as it’s called, we can

instantly determine the composition of tiny

amounts of sample—with other methods,

10,000 times as much material might be required

to analyze some samples.

CH: How are chemistry labs different today from

10 or 20 years ago?

Imperiali: When I was a graduate student, a desk, a

bench, and a chemical hood was “my territory.”

Now, students have a desk, but they move around

the lab to different stations to do their experiments.

There’s also a lot more intermixing of labs. That

happens a lot—it’s absolutely the thing to do when

you’re trying to tackle interdisciplinary problems.

No one in my family was a scientist.

I just found it fascinating.

I liked biology,

but I loved the precision 

that chemistry can offer.
hat medicine came from where? Scientists are

hunting in some very unusual—indeed, some

even downright unpleasant—places for new drugs.

Take chemist Jim Gloer of the University of Iowa 

in Iowa City who is on the prowl for new antibiotics

produced by a type of fungus that thrives in animal

dung. Yes, you heard it right: animal poop. These

unenviable organisms, called coprophiles—literally,

feces-loving—are a rarely studied microbial

breed, but offer tremendous promise for finding

useful drugs. Oddly enough, such fungi are fiercely

territorial, spitting out chemicals that are toxic to

neighboring (and thereby competing) species of

fungi. That is precisely what biomedical researchers

look for—chemicals that will poison bothersome

types of fungi that can be dangerous to people

infected with them.

That’s an important goal. Due in part to the 

disease and part to the treatment, illnesses like

AIDS and cancer often set the stage for the body 

to become overwhelmingly infected by microbes

that otherwise would be rejected at the door. Such

opportunistic infections are most often caused by

just a few notorious types of fungi. Unfortunately,

not many drugs are currently available to thwart

these microbial menaces without causing severe

side effects. A key advantage of Gloer’s strategy 

is that his approach to finding anti-fungus compounds isn’t a random one (as many antimicrobial

drug screens typically are). By selecting compounds

that he already knows can eradicate other fungi,

Gloer is starting with a batch of molecules that

all possess exactly the type of cell-killing activity

he’s looking for.

T

The Healing Power of Chemistry

CHAPTER 5

 Fungus thrives in possum dung.

RUSSELL BARROW
The Chemistry of Health I The Healing Power of Chemistry 47

Looking to Sea

The vast, largely unexplored seas are another

promising source for medicines. Scientists are

plumbing the oceans’ depths to discover novel

molecules in organisms such as marine sponges,

snails, and a wealth of other sea-worthy creatures.

It may seem surprising that, in general, fast swimmers and successful predators are not what the

researchers are after. On the contrary, scientists

have come to appreciate the extraordinary chemical richness lying in wait inside the tastiest,

most brightly colored “couch potatoes” of the

seas—the so-called filter feeders that stick to rocks and

coral. Precisely because they

can’t move—or because they

stand out in a crowd due to

their surface coloring—these animals are sophisticated chemistry labs. For protection, and to

compete for food and other resources, such animals engage in chemical warfare day in and day

out. Scientists have discovered that some of these

potent chemicals show tremendous promise for

treating cancer and other diseases. Certain compounds have passed initial muster—showing

promise in test-tube and animal studies—and

have now progressed to clinical trials in humans.

But while there are many promising could-be

medicines out yonder in the world’s oceans, an
National Institute of General Medical Sciences

imposing obstacle is getting enough of them.

Researchers are finding one way around this

dilemma by devising ways to make the compounds

in their labs, but there are significant obstacles to

efficiently synthesizing usable quantities of many of

these chemicals. Aquaculture (water “farming”) is

an innovative strategy coming into practice, in

which researchers cultivate in small, specialized

ponds large amounts of the organisms that produce

compounds that exist in vanishingly small quantities in nature.

It so happens that marine organisms harbor

another hidden resource when it comes to finding

potential drugs. Looking more closely, chemists are

discovering that tiny, one-celled sea plants called

microalgae that hitch a ride on larger marine 

organisms are also great producers of interesting

chemicals. Terrestrial plants have been a source 

for drugs for thousands of years, so perhaps it

shouldn’t come as a big surprise that sea plants 

are turning up compounds with exciting potential

uses as drugs to fight cancer, heart disease, and

many types of infections. Miniature plant-like

organisms called cyanobacteria that live in a variety

of wet environments—fresh or salt water, or even

damp soil—are also surfacing as excellent sources

of powerful cancer and bacterial cell killers.

Dick Moore of the University of Hawaii at Manoa

successfully used a strategy to find compounds

specifically effective against slow-growing and hardto-treat solid tumors (those that accumulate as

lumps of tumor cells in various organs and account

for most cancer deaths in the United States). One

such compound he found, called cryptophycin-8,

can tear apart the cellular scaffolding in a broad

spectrum of solid tumors implanted in mice,

including multidrug-resistant ones that are no

longer susceptible to standard cancer drugs. Moore

found another cyanobacteria-derived molecule,

called majusculamide C, that works in a similar

fashion but hones in on fungus cells, making it

potentially useful for treating fungus-provoked diseases in humans as well as in agricultural crops.

48
The Chemistry of Health I The Healing Power of Chemistry 49

Everyone knows that frogs don’t really turn into

princes, but scientists suspect that frog skin

might turn into useful medicines. In the late

1980s, while working in a lab at the National

Institutes of Health in Bethesda, Maryland, biologist Michael Zasloff wondered why frogs with

surgical wounds usually healed perfectly without

getting infections, despite living in a relatively

dirty lab aquarium. Zasloff turned his attention to

this quizzical observation and went on to isolate

a peptide—a string of amino acids—called magainin (coined after the Hebrew word for shield)

that frogs produce in response to skin injury. 

Zasloff is quick to note that nobody has a

clue how a giant squid or an octopus—which

have neither antibodies nor white blood cells

called lymphocytes—avoids becoming consumed by microbes! Over the years, he and his

colleagues have uncovered many frog-made

peptides that possess potent microbe-killing

properties. Such a chemical defense system

operates by virtue of the peptides’ ability to

poke holes in the cell membranes that serve 

to protect bacteria from the outside world. In

addition to the peptides, scientists including

Zasloff have found hundreds of other types of

molecules called alkaloids in amphibian skin.

When inside cells, many alkaloids home in on

structures called ion channels—tunnel-like

assemblies through which important electrolytes pass. These are key cellular fixtures,

as they police the entry and exit of charged

molecules across cellular membranes. As such,

they also happen to be important drug targets.

Some channels, for instance, initiate a cascade

of molecular events that tell the cell to “feel”

pain. Researchers have discovered that one

particular molecule isolated from frog skin,

called epibatidine, shows powerful painkilling

activity possibly due to the compound’s ability

to latch onto such channels. After studying it,

scientists realized epibatidine was too toxic to

be used as a pain-relieving drug. Researchers

learned how to make the molecule in the lab

and have continued to tinker with its chemical

structure with the goal of making a drug

that could ease pain without producing

unwanted side effects.

Interestingly, scientists think 

that many of the alkaloid

“drugs” in frog skin come

from the bug meals 

they eat—spiders and

other arthropods 

in particular.

By land or by sea, tradition has it that

chemists first find interesting nature-made chemicals that show promise in fighting disease, then

the scientists learn how to make them synthetically. Ultimately, many of the best drugs have been

born of medicinal chemists’ fiddling with natural

compounds in order to retain useful, therapeutic

portions of the molecules, while stripping away

parts that cause unwanted side effects.

A Princely Role
National Institute of General Medical Sciences

Designing drugs is a tricky business. Lots of

could-be medicines look good on paper, but 

a drug can only do its intended job of treating

a symptom or fighting a disease if it gets to

the right place in the body to do its job. That’s

tough, since many modern medicines are lookalike versions of the body’s natural molecules—

small pieces of proteins called peptides that

are meant to nestle into other protein targets

like receptors. The problem is that the body’s

digestive tract chews up proteins, and peptides,

as a normal part of metabolism (getting energy

from food). So what’s a medicine designer to do?

Many have opted to seek out molecules called

peptidomimetics, which possess many of the

useful properties of peptides (in that they mimic

important biologic targets) but differ from 

peptides in other significant ways. Medicinal

chemists in the business of designing drugs try

to make mimics that are absorbed into the body,

stand up to digestive enzymes, and stick around

long enough in the bloodstream to get to the

tissues and organs where they need to go.

Drugs such as these are already used in clinical

practice to treat infections, heart disease, and

cancer. A key factor in making the look-alikes

useful, however, is tricking the body into thinking

they’re natural molecules, and not drugs. That’s

important, because to get to their molecular

job sites, peptidomimetic drugs often hitch a

ride via the body’s natural molecular transportation systems.

Making Medicines

A key role played by chemists is learning how 

to mimic effectively nature’s bountiful manufacturing processes. Once in a while, such 

a strategy—when it pans out—can tell a story 

of “research-to-riches.” Robert Holton, an

organic chemist at Florida State University in

Tallahassee, discovered a way to produce commercially useful amounts of Taxol®, a top-selling

cancer drug worldwide. This drug, which doctors

use (often in combination with other cancer

drugs) to treat ovarian and breast cancer, was

50

Peptidomimetics (top) are chemical substitutes

for hormones, such as the 14-amino acid 

peptide hormone somatostatin (bottom). Somatostatin Peptide (Hormone)

Somatostatin Peptidomimetic (Chemical)

Acts Like a Protein, But It’s Not

1 2 3 4 5 6 7 8 9 10 11 12 13 14

O

O

H2N

N

H

N

H

Ala – Gly – Cys – Lys – Asn – Phe– Phe– Trp – Lys – Thr – Phe – Thr – Ser – Cys

S

N
first discovered in the 1960s. Scientists found Taxol

in the bark of the Pacific yew tree, which grows in

the northwestern United States. But there was a

problem. The Pacific yew is a slow-growing, environmentally threatened species. Holton helped

pave the way to Taxol’s current success with a practical approach: He figured out a way to make the

drug from a more readily available ingredient that

is abundant in the more plentiful European yew

tree. Holton licensed his semi-synthetic technology to the pharmaceutical company Bristol-Myers

Squibb, and since 1992, when the FDA approved

the lab-made form of Taxol, Holton has earned

millions of dollars in royalties. A few years later, he

went on to lead the first group of scientists to

make Taxol completely from scratch. Rather than

resting on his laurels, Holton poured many of his

rewards straight back into research by founding

the MDS Research Foundation in 1995. In turn,

this nonprofit organization licensed Holton’s technology from Florida State University and started a

company called Taxolog to create new Taxol-like

molecules (called taxanes) that are more effective

at treating cancer. Through such an arrangement,

profits from new anti-tumor agents are recycled

back into basic research in synthetic chemistry.

CHEMICAL BIOLOGY

in Action

Library Research Pays Off

Chemists Gary Glick and Jonathan Ellman never

intended to work on the same problem, but now

they do, and the collaboration is paying off impressively. Two clever minds can be better

than one—out of these scientists’

partnership has emerged at least one

promising new drug to treat a devastating autoimmune disease called 

systemic lupus erythematosus, often

called lupus for short. According 

to the Lupus Foundation of America,

this disease affects 1.5 million Americans,

some of whom bear a characteristic rash across

the bridge of their nose dubbed the “butterfly

rash,” because of its shape. Lupus ravages the

body’s immune system by coaxing the kidneys to

attack their own DNA. Current treatments are

ineffective and have serious, use-limiting side

effects. Glick, of the University of Michigan–

Ann Arbor, and Ellman, of the University of

California, Berkeley, sought to identify a drug to

treat lupus by harnessing the power of combinatorial chemistry to rapidly leaf through thousands

of molecules. The team started with a huge catalog

of molecular structures and searched for compounds

that could kill the cells responsible for causing

lupus (autoimmune lymphocytes), while sparing

normal immune cells. This type of drug discovery

effort is only possible with the advent of combinatorial chemistry, because very large numbers of

compounds (libraries) have to be tested before

scientists can pluck out molecules with the

The Chemistry of Health I The Healing Power of Chemistry 51
National Institute of General Medical Sciences

Getting It Left or Getting It Right?

Making chemicals in the lab isn’t quite the same

thing as cooking up a pot of spaghetti, in which

you simply boil the pasta, heat up the sauce, and

voilà! It’s not so easy to make molecules from a

laboratory recipe. The thing is, many small molecules—created by scientists or by nature—come 

in two, mirror-image forms, a “left” and a “right.”

The molecules that make up sugars and DNA 

conform to this principle, called chirality, which is

actually rooted in the laws of physics. Chemical

bonds—the physical forces that attract or repel

atoms in molecules—rotate in space two ways,

giving rise to two complementary, mirror-image

molecular forms. These are sort of like a left hand

and a right hand—put them together and they

match up, but they’ll never align when placed 

atop each other. Put another way, a right hand 

will never fit into a left-handed glove.

Why should any of this matter when it comes

to drugs? Well—take the case of a small-molecule

drug that does its job in the body by nestling

snugly into a particular cavity of a certain protein

receptor. The left-handed version of this drug might

fit perfectly into the correct space inside the

receptor, whereas its right-handed counterpart

desired properties. Glick and Ellman’s search led

them to one interesting candidate molecule that

stops lupus in mice prone to developing the

disease. An especially exciting feature of the

newfound molecule is that after the lupus-prone

mice take it, they suffer none of the serious side

effects common to all current anti-lupus drugs 

on the market. Glick and Ellman are setting out 

to test the compound in humans.

52
The Chemistry of Health I The Healing Power of Chemistry 53

couldn’t squeeze in, no matter what. And in

some instances, both hands of a drug (each

called an enantiomer) fit into a biological spot,

but one might help treat a symptom while the

other causes the body harm! 

A terrible tragedy occurred when this happened with a drug called thalidomide, which was

used in the 1960s to treat morning sickness in 

pregnant women. Scientists found out too late 

that one of thalidomide’s two hands caused horrific birth defects. What’s more, researchers

discovered that removing the “bad” hand from a

dose of thalidomide didn’t take care of the problem—the body can itself make the harmful hand

from the “good” one.

Another two-faced drug in this regard was 

a popular allergy medicine called Seldane®, which

the Food and Drug Administration removed from

the market in 1997 because in combination with 

a certain antibiotic it caused life-threatening

heart rhythm problems. Scientists determined

that neither enantiomer of a breakdown product of Seldane—now marketed as a medicine

called Allegra®—interacts the same way with

the antibiotic, and Allegra is now used safely 

by millions of Americans.

When thinking about chemical reactions, it’s

tempting to focus on two things only: what

goes in (the starting materials, or reactants) 

and what comes out (the product or products).

Sometimes left out is all the exciting stuff that

happens in the middle. Think of a chemical

reaction as being like two valleys with a mountain in the middle. To become products (one

valley), reactants (the other valley) must overcome something chemists call the energy 

of activation, or energy hill. In this mountain

range analogy, the energy hill is the highest

point of the peak between the two valleys. 

In molecular terms, this point in space and time 

is called the transition state, and it represents

a freeze-frame arrangement of bonds broken

or enjoined, which only lasts one thousand-billionth of a second. In a sense, the transition

state is the precise point at which a seesaw tips

over to the other side. Despite their fleeting

existence, transition states are highly sought

after by chemists who wish to purposefully

alter reactions one way or another by knowing

the details of this pivotal micro-moment.

In the Middle

Transition

State

Products

Reactants

Activation

Energy

 To become products, reactants must

overcome an energy hill.
National Institute of General Medical Sciences

To manufacture products quickly and costeffectively, traditionally pharmaceutical companies

have chemically cooked up medicines that contain

equal portions of the left and right hands. That is

because it is usually much less efficient and more

expensive to produce only one hand of a drug.

Over time, however, chemists in industry and

elsewhere have come to realize the importance

of making single-handed compounds. There are

those especially troubling cases in which one

enantiomer is toxic. But in the vast majority of

cases, most drugs produced as left- and righthanded mixtures are only half as strong as they

could be, because one hand does nothing more

than dilute the medicine produced. Chemist Eric

Jacobsen of Harvard University spent years 

54

A Dead-End Job

For many years, chemist JoAnne Stubbe of

the Massachusetts Institute of Technology 

has been picking apart every step of one biochemical pathway vital to synthesizing the

building blocks of DNA. In particular, she has

focused her energies on an important enzyme

in this pathway, called ribonucleotide reductase, or RNR. In the course of her studies,

Stubbe has sleuthed the way RNR grabs its

substrate—arming her with strategic knowledge

she has used to design look-alike molecules

that fit into the enzyme’s shape, but don’t

make it work. Compounds such as these,

called suicide substrates, completely freeze

up the enzyme they’re targeting. They trick

the enzyme into thinking that it is doing its

job, but in fact no job gets done. Cancer

cells—which divide as fast as they can—are

super-synthesizers of DNA, and are crippled

by any drug that interferes with this process.

Stubbe and her industry coworkers have

shepherded one such RNR suicide substrate

through test-tube and animal studies, and 

into testing in people. Clinical trials with this

potential cancer drug are currently under way.

O O R R

H

H H

H

OH H

H H

H H

OH OH

Base Base

 By removing an oxygen (O), the enzyme 

ribonucleotide reductase creates deoxyribonucleosides, the building blocks of DNA.

Ribonucleoside Deoxyribonucleoside
The Chemistry of Health I The Healing Power of Chemistry 55

Losing Medicines

Finding or making effective new drugs is a challenge in and of itself. But complicating matters

further, sometimes perfectly good drugs simply

stop working. More often than not, these are antibiotics—drugs used to treat bacterial or fungal

infections. It is true that major strides have been

made in the past century in scientists’ quest to treat

infectious diseases caused by bacteria, viruses,

and other microbes such as parasites. Humans’

increased lifespan during the past hundred years 

is due largely to the fact that we succumb to infection far less frequently today than people did 50 

or 100 years ago. But this success has come with a

price—many antibiotic drugs that once stamped

out bacteria effortlessly now work much less effectively, if at all. In the blip of evolutionary time in

which such advances have been made and put into

routine medical practice, microbes are making 

a comeback. They are getting “smart” and devising

ways to evade poisons (our drugs). Drug-resistant

organisms pose a serious health threat.

Fortunately, many chemists and biologists have

risen to the occasion and are working hard to outwit microbes that develop resistance. Many new

forms of antibiotic drugs are currently in the

pipeline; most are being specifically tailored to

minimize the chance that bacteria will become

resistant to them.

perfecting a laboratory tool—a chiral catalyst—

that can purposefully produce one and only one

enantiomer of a particular type of molecule. This

eliminates the waste inherent in the process of

making a left- and right-handed mix, or in separating the two enantiomers from each other after

manufacturing. The pharmaceutical company

Merck recognized the value of Jacobsen’s tool and

has used it successfully for the production of a

widely used AIDS drug called Crixivan.® Other scientists, such as K. Barry Sharpless of the Scripps

Research Institute, have tailor-made chemical

reactions that produce a single enantiomer. The

method is sort of like stripping the random part

out of a coin toss so that the quarter always comes

up heads. Sharpless’ reactions, which give rise to

one-handed chemical intermediates, have been

important for the production of a variety of medically useful chemicals, including certain antibiotics,

heart medicines, and antidepressants. Sharpless

won the 2001 Nobel Prize in chemistry for his

discovery of chiral catalysts.

By paying more attention to getting it right 

(or left, as the case may be) today’s chemists 

have enormous opportunity for improving

existing medicines—by eliminating dose-related

side effects, for instance—as well as for streamlining the process of making the most effective 

new medicines.
CHEMICAL BIOLOGY

in Action

The Shape of 

Things to Come

One of the beauties of science 

is sharing the wealth. Sometimes

a collision of discoveries in completely different areas of science

brings important breakthroughs.

By blending advances from the

worlds of chiral (so-called

handed) chemistry and structural

biology (in which scientists determine the threedimensional shape of biological molecules), Arun

Ghosh of the University of Illinois at Chicago has

unearthed some promising potential drugs to fight

AIDS. Ghosh and his colleagues pored over the

results of other scientists studying the threedimensional structure of an enzyme, called HIV

protease, that is key to this deadly virus’ livelihood.

By using K. Barry Sharpless’ method to fix the

outcome of chemical reactions to produce singlehanded molecules, Ghosh painstakingly designed

sturdy compounds that attach themselves very

tightly to an important pocket of this critical viral

protein. In so doing, Ghosh landed a battery of

potential drugs that in some cases are 50 times

more potent than widely used protease inhibitor

drugs that are a standard component of AIDS

therapy in people. Ghosh has custom-designed new

compounds, which are currently undergoing testing

in animals, to overcome two soft spots inherent to

HIV protease inhibitors currently on the market.

Since the body’s digestive enzymes easily chew up

the chemical bonds that hold proteins together (socalled peptide bonds), Ghosh has focused on

molecules that look like mini-proteins but aren’t

recognized as such by enzymes that break down

proteins. Ghosh is attacking the resistance problem

by crafting compounds that grip the HIV virus’

protease enzyme in many different regions, since

scientists suspect that drug resistance is often triggered by a critical lack of chemical bonds

clamping the viral protease to a drug.

56 National Institute of General Medical Sciences
The Chemistry of Health I The Healing Power of Chemistry 57

Your diet, environment, and lifestyle can all

influence how you respond to medicines. But

another key factor is your genes. The study of

how people respond differently to medicines

due to their genetic inheritance is called pharmacogenetics. The term has been pieced

together from the words pharmacology (the

study of how drugs work in the body) and

genetics (the study of how traits are inherited).

An ultimate goal of this type of medical

research is to understand how a person’s

unique genetic make-up determines how well

a medicine works in his or her body, as well as

what side effects he or she might be prone to

developing. In the future, advances discovered

through such research will provide information

to guide doctors in getting the right

amount of the right medicine to a person—the

practice of “personalized medicine.”

swelling that are born of our own immune system’s

chemical weaponry—is caused by the drug working through that same biochemical pathway.

Serhan’s work sheds new light on the issue 

and may even lead the way to better antiinflammatory medicines. After he discovered

that aspirin treats inflammation by prompting the

body to manufacture its own anti-inflammatory

compound (a molecule called 15-epi-lipoxin A4),

Serhan set about to make synthetic look-alikes 

of this molecule. In recent animal studies, at least

one of the synthetic mimics worked 100 times 

better than aspirin and other stronger antiinflammatory medicines available by prescription

only. Serhan’s research paves the way toward finding more selective treatment strategies that bring

about less of the unwanted side effects produced

by aspirin and many other drugs currently used 

to treat inflammation.

Making Good Medicines Better

Acetylsalicylic acid—more commonly known as

aspirin—is a very old drug. It is also a very effective drug, available without a prescription for 

a wide variety of uses. Aspirin is an inexpensive

medicine used to treat pain and swelling caused 

by minor skin wounds or sunburns, and as 

a protectant against heart disease. Yet despite its

reputation as a wonder drug, scientists still don’t

know exactly how aspirin works so well in so

many ways. Charles Serhan of Brigham and

Women’s Hospital in Boston is one biological

chemist who is trying to figure aspirin out.

Aspirin isn’t a complete black box—scientists

already know that the drug works to alleviate pain

by blocking biochemical circuits that produce two

of the body’s natural compounds, called prostaglandins and thromboxanes. Based on this, many

researchers have assumed that aspirin’s knack for

halting inflammation—the painful irritation and

Medicines Just for You
obert Grubbs, a chemist at the California Institute of Technology in

Pasadena, is changing the way people make things. All kinds of things—

bike helmets, corrosion-resistant pipes...and medicines! Grubbs introduced a 

new twist to a brand of chemistry called “olefin metathesis” that underlies the

production of a wide variety of materials. Reactions that use this chemistry

hinge on one key element to pull off such a feat: an extremely versatile catalyst

that uses a metal called ruthenium. As molecules that make reactions happen,

catalysts are vital drivers of the chemical transformations that produce the

things we use and the drugs we take. Grubbs’ catalyst is currently being used to

manufacture a wide assortment of things biological, and has been a huge help

to pharmaceutical industry chemists, who are faced with the task of synthesizing complicated chemical structures day in and day out. The Chemistry of

Health asked Grubbs, who won the 2005 Nobel Prize in Chemistry for this

work, to fill in some of the details. CH: How can the same chemical process produce

bullet-proof vests, insect repellents, and medicines?

Grubbs: The ruthenium catalyst we developed

opens up carbon-carbon double bonds and then

attaches the pieces back together—in predictable,

or even novel, ways. Essentially, the catalyst zips

together chains of molecules into rings, which are a

common component of all kinds of materials. But

it also works to unzip the rings. It’s very useful

because there are double bonds everywhere.

CH: Why did the chemistry community need 

a new catalyst?

Grubbs: The old catalysts didn’t allow you to do

things very efficiently, and required chemists to use

protecting groups. Metals such as ruthenium give

chemists the flexibility to make things with a wide

variety of starting materials, and under many 

different conditions. It just makes everything easier.

R

QUESTION BOX

Tools for New Medicines
What is the function 

of a chiral catalyst?

How might synthetic

chemistry practices help

the environment?

Describe the difference

between peptides and 

peptidomimetics.

Name one reason 

why filter-feeding marine

organisms secrete chemicals into the water.

Discuss some of the 

possible advantages 

and disadvantages of 

personalized medicine.

Got It?

CH: Did you set about to find the catalyst?

Grubbs: No, although it was always a dream 

of mine. It’s funny—20 years ago, I was asked to

give a talk predicting the future in this area of

chemistry. I argued—strongly at the time—that

recommending support for such research shouldn’t

be in the report, since it would be so misleading

to the community. I’ve been surprised that it’s

worked out so well.

CH: What first got you interested in science?

Grubbs: I suppose a science teacher in junior

high. But things have changed somewhat.

Originally I wanted to be an agricultural chemist,

but dealing with all the animal matter wasn’t much

fun. Organic chemistry was something I discovered

I liked to do.

CH: What keeps you coming back to the lab 

every day?

Grubbs: I keep getting surprised all the time.

Originally I wanted to be an agricultural chemist,

but dealing with all the animal matter 

wasn’t much fun.

Organic chemistry 

was something I discovered I liked to do.
60 National Institute of General Medical Sciences

Among the questions still awaiting answers 

are these:

• How do the 6-foot long stretches of 

DNA in every cell in our bodies know 

how to keep our biochemical factories 

running smoothly?

• Who will find a way to outwit resistant 

bacteria?

• When will someone figure out how 

to fight disease by manipulating the 

intricate sugar coatings on our cells?

• Who will invent the tools that will 

revolutionize chemistry labs of the future?

• What unexpected places hold treasure 

troves for new medicines?

Curious minds of the future will sleuth these

and other problems and change the world. Will

one of those minds be yours?

s chemists, biologists, physicists, and other 

scientists continue to unveil nature’s

secrets, a flood of facts accumulates with stunning

momentum. Each answer is a new beginning—

material for new experiments. Many researchers

assert that there’s never been a more exciting time

to be a scientist. After much effort was spent in the

last century finding individual puzzle pieces, scientists can now revel in the process of fitting the

pieces together.

Not that everything’s been figured out—

not by a long shot. The science of today beckons

researchers to think big—to integrate singular

items, and even single pathways—into the grander

scheme of what it is that makes entire organisms

tick with such precision.

Perhaps ironically, as science grows larger in

scope and broader in focus, some of the most

promising tools to synthesize the hows, whats,

and wheres of human biology are exceedingly tiny.

Micromachines, tiny biosensors, and miniature

molecular reaction vessels will undoubtedly 

be standard items in a chemist’s toolbox in 10 

or 20 years.

Unraveling—and making sense of—the

genetic instructions that spell life for organisms 

as diverse as flies, plants, worms, and people has

sparked a most exciting revolution. Every minute

of every day, scientists all over the world work

feverishly, weaving a compelling tale of the 

chemistry that underlies our health.

It’s all very exciting, but the progress mandates

still more work. Much more work!

Chemistry for the Future

A
The Chemistry of Health I Glossary 61

Bi- | A prefix meaning two.

Biochemistry | The scientific study of the chemistry of living cells, tissues, organs, and organisms.

Biochip | An electronic device containing organic

materials.

Biopolymer | In a living organism, any large 

molecule (such as a protein, nucleic acid, lipid,

or polysaccharide) made from smaller parts.

Biosensor | A system or device that detects a 

chemical or chemicals in a biological material.

Biotechnology | The industrial use of living 

organisms or biological methods derived through

basic research; examples range from genetic 

engineering to making cheese or bread.

Bond | Physical forces holding together two

atoms in a molecule.

Carbohydrate | A chemical compound made 

up of a chain or ring of carbon atoms to which

hydrogen and oxygen atoms are attached in 

a defined ratio (2:1); includes simple sugars 

like glucose and complex sugars like chitin 

(the exoskeleton of crabs).

Carbohydrate biology | A branch of chemistry

dedicated to the study of the many types of carbohydrate molecules.

Catabolic | A type of reaction or series of reactions in which complex molecules are broken

down into simpler ones; the opposite of anabolic.

Alkaloids | A class of over 3,000 nitrogencontaining chemicals (such as caffeine and

cocaine) that are produced by plants but have

effects in humans and animals.

Amino acids | A class of 20 chemical units that 

are the building blocks of peptides and proteins.

Amylase | An enzyme found in saliva that breaks

down starch into simple sugars.

Anabolic | A type of reaction or series of reactions in which complex molecules are synthesized

from simpler ones; the opposite of catabolic.

Aquaculture | The underwater cultivation of

animals and plants for food or for other purposes.

-ase | A suffix common to many, but not all,

enzymes.

Atom | The smallest particle of matter that 

maintains the property of an element in the 

periodic table; atoms are composed of subatomic

particles called electrons, neutrons, and protons,

which themselves are composed of even tinier 

subatomic particles such as quarks.

ATP | Adenosine triphosphate; the energy 

currency of metabolism in all organisms.

ATP synthase | An enzyme in mitochondria 

that produces ATP by adding a phosphate group 

to the molecule ADP.

Base | A nitrogen-containing building block of

DNA; the two types are the purines adenine (A) 

and guanine (G), and the pyrimidines thymine (T) 

and cytosine (C).

Glossary
National Institute of General Medical Sciences

Catalyst | A substance that speeds up a chemical

or biochemical reaction that would have occurred

anyway (without help), but at a much slower rate;

enzymes are biological catalysts.

Catalytic antibody | An antibody that speeds

up a chemical reaction; also called “abzymes,” these

antibodies use a molecule called a hapten to mimic

the middle, “transition” state of a reaction.

Chaperone | Any of a class of proteins that helps 

proteins fold or escorts proteins or other molecules

throughout the cell.

Chirality | The ability of a chemical substance 

to exist in two mirror-image forms, each of which

rotates polarized light in opposite directions.

Cholesterol | A lipid unique to animal cells that

is used in the construction of cell membranes and

as a building block for some hormones.

Clinical trial | A scientific study in which 

physician-researchers study the effects of potential

medicines on people; usually conducted in three

phases (I, II, and III) that determine safety,

whether the treatment works, and if it’s better 

than current therapies, respectively.

Cofactor | A helper molecule (either inorganic,

such as a metal ion, or organic, such as a vitamin)

required by an enzyme.

Combinatorial chemistry | The random

assembly of various chemical units into large 

so-called “libraries” of new synthetic compounds.

Coprophile | A feces-loving organism.

Covalent bond | A force that holds together 

two or more atoms, formed when electrons travel

between the atoms’ nuclei (and are thus “shared”).

Cyanobacteria | A type of bacteria living in

damp soil or rocks, or fresh or salt water, that 

performs photosynthesis, a process in which light,

energy, water, and carbon dioxide are converted

into oxygen and carbohydrates (sugars).

Di- | A prefix meaning two.

DNA (deoxyribonucleic acid) | A doublestranded molecule that encodes genetic

information; composed of four nucleotides 

containing the bases adenine (A), cytosine (C),

guanine (G), and thymine (T).

DNA polymerase | An enzyme that copies,

and sometimes repairs, DNA.

Double bond | A type of covalent bond in which 

a pair of atoms shares two pairs of electrons.

Electrolyte | A charged molecule (such as a

sodium or potassium ion) that is present in 

body fluids.

Element | A component of the periodic table;

a pure substance that cannot be separated into

simpler substances by chemical means.

Enantiomer | One of two “mirror images” of

a chiral molecule.

62
The Chemistry of Health I Glossary 63

Host-guest chemistry |A branch of chemistry

in which researchers study the interactions

between two molecules (natural or synthetic) with

the goal of either mimicking or blocking a biological effect caused by the molecules’ interaction.

Inflammation | The body’s reaction to noxious

stimuli or foreign particles, resulting in swelling,

redness, and pain.

Hydrocarbon | An organic molecule consisting

of hydrogen and carbon atoms only.

-ine | A suffix common to many of the amino

acids.

Inorganic | Describing a substance not derived

from a living organism and/or not composed of

carbon and hydrogen (a hydrocarbon).

In silico | Literally “within silicon”; refers to

modeling research conducted with computers only.

Ion | An electrically charged atom.

Ionic bond |A force that holds together two 

electrically charged atoms (called ions).

Lipid | A fatty, waxy, or oily compound that will 

not dissolve in water; it contains hydrogen, carbon,

and oxygen, but proportionally far less oxygen 

than carbohydrates.

Lipid A | A key component of lipopolysaccharide.

Lipo- | A prefix meaning lipid, or fat.

Lipopolysaccharide | An integral part of the

outer cell membrane of certain types of bacteria

(so-called gram-negative strains).

Endotoxin | Any of a class of lipids found in 

the outer membranes of gram-negative bacteria;

in people, the toxins cause diarrhea and/or septic

shock.

Enterococci | Intestinal bacteria that are often

resistant to the antibiotic vancomycin.

Enzyme | A molecule that acts as a catalyst,

speeding up biochemical reactions.

Fluorescence | The property of giving off light 

at a particular wavelength (emission wavelength)

when illuminated by light of a different wavelength

(excitation wavelength).

Forensic science | The application of scientific

knowledge to questions of civil and criminal law.

Genetic engineering | The manipulation of

an organism’s genes—introducing, eliminating,

or changing them—using modern molecular 

biology techniques.

Glycolipid | A lipid covalently linked to a sugar.

Glycoprotein | A protein covalently linked to 

a sugar.

Glycosaminoglycan | A large molecule found

on the surface of membrane-encased cells that

consists of a network of long, branched chains of

sugars and smaller, nitrogen-containing molecules.

Hexa- | A prefix meaning six.
National Institute of General Medical Sciences

Mass spectrometry | A technique used to

determine the composition and abundance of

the atoms in a molecular substance, starting 

with a very small amount of sample.

Metabolic engineering | The targeted and 

purposeful alteration (using genetic engineering

techniques) of an organism’s metabolic pathways

in order to better understand how the pathways

work or to redesign them to produce a different 

set of products.

Metabolism | A set of enzyme-catalyzed reactions in a living organism that builds and breaks

down organic molecules, producing or consuming

energy in the process.

Metabolite | A chemical intermediate in metabolic reactions.

Model organism | A bacterium, animal, or 

plant used by scientists to study basic research

questions; common model organisms include

yeast, flies, worms, frogs, and fish.

Nano- |A prefix meaning one-billionth.

Nanotechnology |A branch of science and 

engineering devoted to the design and production

of extremely small electronic devices and circuits

built from individual atoms and molecules.

Neoglycopolymer |A glycoprotein mimic; a 

synthetic molecule consisting of polymers with 

carbohydrates attached.

Nuclear magnetic resonance

spectroscopy |A technique used to study the

physical, chemical, and biological properties of

matter; in this method, scientists subject a molecule to a strong magnet and watch what happens

to the atoms that make up the molecule, which

provides information about the molecule’s 

composition.

Nucleic acid |A large molecule composed of

units of nucleotides; includes both RNA and DNA.

Nucleotide |A subunit of RNA or DNA containing a base, a phosphate, and a sugar; thousands of

nucleotides link up to form a molecule of DNA 

or RNA.

Olefin metathesis |A chemical reaction in

which all of the double bonds in a hydrocarbon

molecule are broken and then rearranged.

Oligosaccharide |A molecule made up of

several simple sugars linked together.

Organic | Carbon-containing.

Organic chemistry |A branch of chemistry 

dedicated to the study of the structures, synthesis,

and reactions of carbon-containing compounds.

Organophosphate |A class of toxic organic

molecules containing phosphate, and often fluoride,

that are used as insecticides and nerve gases (such

as sarin); many of these molecules block the action

of an enzyme (acetylcholinesterase) that recycles

an important brain chemical called acetylcholine.

64
Plasma membrane |The membrane that 

separates the contents of a cell from its outside

environment; it consists of a double layer of

phospholipids with embedded proteins.

Polymer |A large molecule formed by combining

many similar, smaller molecules.

Polysaccharide |Any of a class of carbohydrates

consisting of chains of simple sugars.

Product |A substance formed as the result of a

chemical reaction.

Protecting group |A removable chemical unit

used by synthetic chemists to purposefully cover

up certain regions of a molecule so they do not

react with other compounds during a reaction.

Protein |A large molecule composed of one 

or more chains of amino acids in a specific order

and folded shape determined by the sequence 

of nucleotides in the gene encoding the protein.

Protein synthesis |The process in which the

genetic code carried by messenger RNA directs 

cellular organelles called ribosomes to produce

proteins from amino acids.

Reaction rate |A measure of how fast a 

chemical reaction occurs.

Ribonucleotide reductase |The enzyme in 

all organisms that catalyzes the conversion of

nucleosides to deoxynucleosides.

-ose |A suffix common to many carbohydrates.

Oxo- or oxy- |Prefixes meaning oxygencontaining.

Peptide |A molecule consisting of a chain of

amino acids; a small protein fragment.

Peptide bond |The chemical link joining amino

acids in peptides and proteins.

Peptidomimetic |A chemical compound that

mimics the ability of a peptide to recognize 

certain physiological molecules, such as proteins

and DNA.

Pharmacogenetics |The study of how people’s

genetic make-up affects their response to medicines.

Phenylketonuria |A genetic disorder in which

the body cannot break down the amino acid

phenylalanine; abbreviated PKU.

Phosphate group |A chemical unit consisting

of an atom of phosphate bound to four oxygen

atoms; often attached to other biological molecules, such as proteins, sugars, and lipids.

Phospho- |A prefix meaning phosphatecontaining.

Phospholipid |A lipid made up of glycerol and

fatty acids, with a phosphate group attached.

Phosphotriesterase |A bacterially produced

enzyme that breaks down organophosphates 

like sarin.

Physiology |The study of how living organisms

function.

The Chemistry of Health I Glossary 65
National Institute of General Medical Sciences

RNA |Ribonucleic acid; a chemical found in cells

that serves as an intermediate in the synthesis of

proteins.

Structural biology |A branch of biology 

dedicated to the study of the three-dimensional

structures of proteins and other molecules to 

help understand the function of these molecules 

in the cell.

Substrate |A molecule acted upon by an

enzyme.

Suicide substrate |An enzyme substrate 

that itself is not toxic but that produces a toxic

metabolic product.

Superoxide dismutase |A copper- and zinccontaining enzyme present in all oxygen-using 

organisms that scavenges free radicals and converts

them into hydrogen peroxide and oxygen.

Synthetic chemistry |A branch of chemistry 

in which chemists devise ways to make specific 

compounds of interest and/or develop new chemical reactions for this purpose.

Toxin |A poisonous substance.

Transition state |The activated form of a molecule that has partly undergone a chemical reaction.

Tri- |A prefix meaning three.

van der Waals force |A weak physical force

that holds together two molecules or two different

parts of the same molecule.

66
What Is NIGMS?

The National Institute of General Medical Sciences

(NIGMS) supports basic biomedical research on

genes, proteins, and cells. It also funds studies on

fundamental processes such as how cells communicate, how our bodies use energy, and how we

respond to medicines. The results of this research

increase our understanding of life and lay the

foundation for advances in the diagnosis, treatment,

and prevention of disease. The Institute’s research

training programs produce the next generation of

biomedical scientists, and NIGMS has programs to

encourage minorities underrepresented in biomedical

and behavioral science to pursue research careers.

NIGMS supported the research of most of the 

scientists mentioned in this booklet.
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