Newsgroup: it.scienza.biologia
Titolo: Science: una review sulla storia della biologia (lungo, ma molto bello)

Science Mar 10 2000: 1777-1782
GENOMICS: Journey to the Center of Biology
Eric S. Lander and Robert A. Weinberg*
Without doubt, the greatest achievement in biology over the past
millennium has been the elucidation of the mechanism of heredity.
Heredity is surely the strangest of physiological processes: Organisms
encapsulate instructions for creating a member of their species in their
gametes, these instructions are passed on to a fertilized egg, and then
they unfold spontaneously to give rise to offspring. The ancient Greeks
puzzled over these remarkable phenomena. Hippocrates imagined that
instructional particles were gathered together from throughout the adult
body, having been shaped by experience, while Aristotle believed that
the instructions were constant and inherent in the gametes. But
philosophers could do no more than speculate for the ensuing 2000 years,
because there was no way to probe the physical nature of these
instructions.
How the nature of heredity came to be understood over the past 200 years
is an extraordinary tale of scientific progress. In dizzying succession,
biologists found that the heredity instructions followed specific rules
of transmission, resided in the chromosomes contained in the nucleus,
were embodied in the molecule DNA, were written in a precise genetic
code, and could be read out in their entirety to specify organismic
shape and function.
The solution to the problem of heredity turned out to have breathtaking
elegance and generality. The instructions for assembling every organism
on the planet--slugs and sequoias, peacocks and parasites, whales and
wasps--are all specified in DNA sequences that can be translated into
digital information and stored in a computer for analysis. As a
consequence of this revolution, biology in the 21st century is rapidly
becoming an information science. Hypotheses will arise as often in
silico as in vitro. In this essay, we recount how this came to pass.
Mendel's Revolution: Transmitting the Instructions Heredity was the
province of philosophers until Anton van Leeuwenhoek's invention of the
simple microscope in the 17th century. Ironically, early microscopic
studies diverted the field; observers convinced themselves that they
could see tiny, preformed homunculi ensconced within individual
spermatozoa. Preformation obviated the need to store and transmit
instructions, but it raised perplexing philosophical questions, such as
whether the entire human lineage resided, like nested Russian dolls, in
Adam's sperm, and what role Eve played.
Scientific studies of heredity eventually emerged from a more practical
quarter--economic forces driving improvements in agriculture. The Age of
Discovery from the early 15th to the late 18th century brought thousands
of new plant species to Europe, many of which were propagated and
hybridized, improved cultivars being highly prized. The rapidly
expanding international trade held great promise for increased economic
returns on agricultural products.
One of the hotbeds of interest in agricultural improvement, including
animal husbandry, was the city of Brünn (now Brno) in Moravia, center of
the textile industry in the Austro-Hungarian Empire of the early 19th
century. The high price commanded by imported Spanish wool spurred great
interest in improving sheep breeds. Breeding programs, however, were
conducted largely by trial and error with no underlying rationale.
Possessed with remarkable foresight, Brünn's civic leaders organized
societies to promote scientific research, citing the importance of
discoveries such as those of Copernicus and Newton and expressing hope
that the world would someday be similarly indebted to a son of Brünn.
This extravagant hope was indeed to be fulfilled. C. F. Napp, head of
the Pomological and Oenological Society of Brünn and abbot of the
Augustinian monastery, kept his eye out for scientifically trained young
men to join his remarkable monastery. The best of these recruits was
Gregor Mendel, who had studied physics in Vienna before joining the
abbey. The revolution in the understanding of heredity that followed was
not triggered by a monk working in isolation who accidentally stumbled
upon the laws of genetics. Rather, Mendel worked in an incubator focused
on promoting scientific progress in what today would be called
agricultural biotechnology.
Mendel's pea breeding allowed him to observe genetic dominance and the
segregation of traits. In fact, these phenomena had been described
qualitatively decades earlier. But Mendel took a quantitative approach,
using his physics training and his breeding data to formulate a theory
providing, for the first time, a mechanistic description of the laws of
heredity.
Mendel proposed that heredity information was passed from parent to
offspring in discrete packets, which he called "factors." Different
factors were responsible for distinct aspects of a pea plant's
appearance, such as seed shape or flower color. His key insight was that
the factors occurred in pairs, with one member of the pair being passed
on from each parent. The two factors governing a trait might carry
conflicting instructions, in which case the voice of one might dominate
in determining the appearance of the individual. Nonetheless, the other
factor would persist in latent form, and its effects could reappear in
later generations in predictable ratios.
Mendel's 1865 report (1)in the Journal of the Brünn Society of Natural
Science fell on deaf ears. He worked at the periphery of the scientific
community, and he published in an obscure journal. But the real problem
was that Mendel's formalisms were mathematical and his factors were
abstractions. Mendel's laws would only gain a wide audience long after
his death, when they could be related to biological realities--visible
cellular structures.
Chromosomes: The Cellular Basis of the Instructions By the mid-1880s,
biologists began to recognize that the physical seat of heredity must
lie in the cell's nucleus. Microscopists found that recently fertilized
eggs carried two equally sized "pronuclei," which later fused. These
pronuclei derived from the sperm and the unfertilized egg, which seemed
to contribute equally to heredity. Moreover, close examination of a
spermatozoon indicated that this cell was little more than a nucleus
with a tail.
The most obvious components of the nucleus were its chromosomes, whose
behavior could now be studied with precision through greatly improved
staining and microscopy techniques. Like the entities that harbored
heredity instructions, chromosomes appeared to duplicate with each cycle
of cell growth and division. Still, researchers remained unsure about
the relation between chromosomes and heredity. Some theories, for
example, held that each chromosome carried a complete set of the
heredity instructions. The ensuing ferment revived interest in
understanding the laws of heredity via breeding experiments.
In the early months of 1900, three researchers--Hugo de Vries, Erich
Tschermak von Seysenegg, and Karl Correns-- independently reported
rediscovering Mendel's work and laws (2). Their work revealed little
more than what Mendel had found 35 years earlier, but the scientific
community was now primed to listen. The papers sparked the genetics
revolution that continued unabated throughout the 20th century.
An initial challenge was to prove the connection between genes and
chromosomes. The most important advances would come from the study of
the fruit fly Drosophila in the laboratory of Thomas Hunt Morgan at
Columbia University. Arguably, the greatest insights came from Alfred
Sturtevant, who was performing undergraduate research in Morgan's lab.
Sturtevant analyzed a large body of experimental results describing the
frequency with which pairs of genes were cotransmitted when passed from
parent to offspring. He realized that these data could be explained by a
simple model in which the genes were arrayed along a linear "linkage
map," with nearby genes being cotransmitted more often than gene pairs
located far from one another along his maps. Sturtevant realized that
these maps showing the positions of genes must correspond to the
threadlike chromosomes (3). Gene mapping rapidly became a powerful tool
of genetics, although the definitive proof of the connection between
linkage maps and chromosomes came later in the 1930s with studies by
Barbara McClintock on maize chromosomes (4).
DNA: The Biochemical Basis of the Instructions The early 20th century
witnessed the birth of another experimental science: biochemistry. This
marriage of biology and chemistry sought to understand life by isolating
molecules and reconstituting living processes in the nonliving extracts
prepared from cells. The biochemists had a clear agenda: to
systematically dismantle the notion of vitalism, which held that
ineffable "life forces" were responsible for the complex attributes of
living cells and tissues. By 1925, they had triumphantly shown that many
biochemical reactions could be reproduced in the test tube using the
organic catalysts called enzymes. The science of genetics, however, was
disconnected from this forward rush of biochemical progress. Genes
seemed hopelessly inaccessible: How could one possibly purify heredity
in a test tube? Indeed, could heredity ever be understood through
biochemistry and the increasing number of molecular species being
unearthed in living cells?
A first, tentative foray toward the molecular embodiment of genes came
from the 1927 work of Hermann Muller, then in Texas, who demonstrated
that x-rays could mutate the genes of Drosophila (5). This provided
geneticists with a powerful tool. They no longer needed to rely on the
spontaneous randomness of nature to generate variants of the "wild-type"
genes normally found in flies. Conceptually, Muller's discovery was even
more far-reaching, showing that genes were physical entities susceptible
to being damaged just like other molecules in the cell. But still, the
central question remained: What kind of molecules explained heredity?
A year later, some steps were taken toward an answer. Fred Griffith in
England made the serendipitous observation that an extract prepared from
virulent, disease-causing Pneumococcus bacteria could transmit the trait
of virulence to a benign strain. Once the benign bacteria had acquired
these instructions, they and their descendants in turn showed all the
traits of virulence. The instructions for inducing disease, whatever
their nature, persisted in the virulent bacteria long after their death
by heat treatment (6).
By the mid-1930s, Oswald Avery, Colin McLeod, and Maclyn McCarty,
working at the Rockefeller Institute in New York, took on the daunting
task of purifying the elusive substance that conferred virulence. By
1944 they had the answer. Deoxyribonucleic acid (DNA) molecules
extracted from virulent bacteria sufficed to transfer the genetic
instructions for virulence. Destruction of the DNA resulted in loss of
these instructions, while destruction of bacterial proteins seemed to
have no effect on the information transfer (7).
Their conclusion was controversial. DNA molecules were widely regarded
as boring, monotonous chains composed of four nucleotides--ostensibly
structural scaffolds of the chromosomes. Protein molecules were far more
interesting. They were biochemically and structurally more complex, and
for this reason seemed to offer far more possibilities for harboring
genetic information. But DNA survived the skeptics. When purified of all
but 0.02% of contaminating protein, DNA continued to be potent in
transmitting genetic information. Most compelling were the 1952
experiments of Alfred Hershey and Martha Chase, who showed that when
bacterial viruses inject their genetic information into host cells, DNA
enters the cell, while the protein coat remains on the outside (8).
Still missing was an understanding of how DNA--or any molecule--could
store and encode heredity instructions. This intellectual puzzle had
attracted the interest of some eclectic physicists, including Niels Bohr
and his student Max Delbrück. They struggled to explain the long-term
stability of genes in terms of molecules residing in deep potential
wells and even suggested that new laws of physics might be needed to
explain life. These issues were distilled by Erwin Schrödinger in a
brilliant and popular 1945 book, What is Life? (9).
Schrödinger proposed that genes must be "aperiodic crystals" consisting
of a succession of a small number of isomeric elements whose precise
sequence constitutes the heredity code in the manner of the Morse code.
Although these ideas did nothing to identify the responsible molecular
structures, they did attract many newcomers to the field--including a
youthful James Watson, who set off to Cambridge, England, determined to
work on the nature of the gene. There, he teamed up with former
physicist Francis Crick.
Watson and Crick's revelation of the double-helical structure of DNA
struck like a thunderbolt in April 1953 (10). Just as Schrödinger had
predicted, DNA was an aperiodic crystal, being composed of four
nucleotide bases along its strands. The double helix, by pairing A with
T and G with C on opposite strands, explained how genetic information
could be copied (the complementarity of nucleotides meant that each
strand could serve as a template for the assembly of a complete double
helix) and how mutations could arise (occasionally the copying process
might go awry). In one stroke, Watson and Crick had explained the key
problems of genetics.
The Genetic Code Through the Recombinant DNA Revolution: Deciphering the
Instructions The Watson-Crick model made clear that the instructions
must be encoded by the sequence of the bases in the strands of the DNA
double helix. But how, specifically, were these instructions read out to
build the components of a living organism? By 1964, the outlines of the
solution had been worked out. The DNA segment corresponding to each gene
is copied into a messenger RNA molecule, whose base sequence is then
used to direct the synthesis of a specific protein from amino acid
building blocks. Marshall Nirenberg used synthetic RNAs to crack the
genetic code by which triplets of bases (nucleotides) constitute genetic
"words" specifying particular amino acids (11). In principle, the secret
of life had been laid bare.
In practice, there was a catch. Although biologists had deciphered the
code for translating DNA information into proteins, they could not yet
read any natural DNA sequences--not even the sequence of a single gene
out of the thousands present within a cell. They lacked the text on
which to practice their newfound deciphering skills. It took another 15
years for this problem to be fully solved by the two recombinant DNA
technologies of cloning and sequencing.
Cloning circumvented the limitations of traditional biochemistry, which
relies on isolating molecules from a complex mixture based on their
chemical idiosyncrasies. The biochemical approach is useless for
purifying individual genes because chemically, they are virtually
identical--each is simply a stretch of DNA bases. Cloning introduced a
new twist on purification: Large genomes were cut into small segments;
each was attached to a special "vector" molecule and then introduced
into bacterial cells, which faithfully reproduced the foreign DNA as the
cells grew. Each bacterium received a single DNA molecule, ensuring that
descendant cells would together constitute a "clone," all harboring
exact replicas of this specific DNA segment. Scientists thus purified
individual DNA segments by propagating them in distinct clones, a
collection of which came to be called a "gene library." Experimenters
then devised clever steps to enable them to screen the millions of
separate clones in a complete gene library and pick out the rare clones
carrying the DNA segment and thus gene of interest.
The development of the vectors capable of directing the bacterial cell
to reproduce the individual DNA segments was a key technical step in the
creation of these libraries. Here, biologists exploited highly
successful experiments of nature such as viruses and plasmids, which are
cellular parasites known to co-opt cells into making hundreds or
thousands of copies of viral and plasmid DNA molecules (12).
DNA sequencing technology formed the other half of the recombinant DNA
revolution of the 1970s. Two strategies--one pioneered by Fred Sanger,
the other by Walter Gilbert--made it possible to determine with
relatively high accuracy the sequences of DNA fragments a few hundred
bases long (13). Soon, individual genes cloned from large cellular
genomes became objects of study.
Sequencing technology advanced rapidly, driven by an unquenchable thirst
for sequence information. In the late 1970s, an entire doctoral thesis
might be devoted to reporting the sequence of a gene of several thousand
DNA bases. By century's end, technologists had developed automated
sequencing machines capable of cranking out up to a half-million bases
per day.
The Genomics Revolution DNA sequencing soon produced surprises by
revealing connections between genes that previously had seemed
unrelated. Two early examples involved cancer-causing genes: the
oncogenes sis and erbB. One research team cloned these genes and
determined their DNA sequences. Meanwhile, unrelated groups of
researchers who were more biochemically inclined isolated two
proteins--platelet-derived growth factor (PDGF) and the receptor for
epidermal growth factor (EGF)--and determined the amino acid sequences
of both. To everyone's surprise, the DNA sequences of the oncogenes
corresponded nearly perfectly to the amino acid sequences of the
well-studied growth-controlling proteins (14). These identifications
revealed instantaneously how the sis and erbB oncogenes transform normal
cells into cancer cells.
Such connections were only the beginning. Comparisons of gene sequences
revealed that strikingly similar proteins were encoded in the genomes of
organisms as distantly related as yeast and mammals. For example, the
proteins governing the progression of a yeast cell through its cycle of
growth and division were found in very similar form in the cells of
humans. These cross connections soon numbered in the thousands, then
tens of thousands. It became clear that the evolution of life on this
planet was stunningly conservative. Once nucleated cells evolved more
than 1.5 billion years ago, the great majority of the proteins invented
at the time were perpetuated in myriad descendant cells--sometimes with
only minor changes. Often the genes encoding these early proteins
multiplied and diversified a billion years later, spawning large
families of related genes and proteins having diverse, sometimes totally
novel functions.
Recognition of gene families produced enormous synergy in research, as
the function of one member could often be deduced from that of its known
relatives. When the gene responsible for cystic fibrosis was cloned,
sequence analysis immediately suggested that it belonged to a family of
proteins that transport ions through membranes--a fact that was then
readily tested and confirmed in the laboratory (15).
The connections across vast phylogenetic distances also drove biologists
to reconceptualize their research. Those researching organisms such as
worms, flies, and yeast began portraying their work as opening windows
on the universal rules of life on this planet, not just on the
idiosyncrasies of the arcane organisms they studied. Researchers working
on sea urchin and frog development found themselves catapulted into
cancer research meetings, using a common vocabulary with cancer
researchers to describe proteins that play equally important roles in
early embryogenesis and in the development of human malignancies.
Sequence analysis also revolutionized the study of evolution, by making
it possible to draw phylogenetic trees relating organisms on the basis
of similarities in their genes rather than shared physical
characteristics. By the 1980s, the availability of vast quantities of
sequence data and sophisticated computer-based analytic tools led to a
wholesale redrawing of the branches and twigs of the tree of life.
The studies of individual genes represented stunning achievements, but
these successes soon promoted an even grander vision: the systematic
study of complete genomes, soon referred to as genomics. The first foray
into genomics was a proposal to use DNA technology to extend
Sturtevant's original concept of genetic mapping to the human being.
Instead of tracing the inheritance of visible mutations as had been done
in fruit flies, David Botstein and colleagues proposed in 1980 that one
could construct a complete genetic map of the human chromosomes by
following the inheritance of common DNA sequence variations, termed DNA
polymorphisms (16). Each polymorphism could be used to plant a sequence
marker at a specific site on a genetic map of a chromosome. One could
then localize genes causing specific human diseases by matching their
inheritance patterns with those of the signposts on these genetic maps.
The first success using this strategy came in 1983, when the gene
causing Huntington's disease was shown to map to the tip of the short
arm of human chromosome 4 (17). The first comprehensive human genetic
map with 400 signposts was constructed by 1987, and much denser maps
with more than 10,000 such markers were available a decade later.
Medical genetics was revolutionized as the genes causing more than 1000
human diseases were soon mapped to specific chromosomal sites.
An even more expansive vision was expounded in 1985: The entire human
genome would be sequenced, providing a complete catalog of every human
gene. On its face, the proposal seemed quixotic, a logistic
impossibility. The human genome encompasses 3 billion bases of DNA;
then-current sequencing technology could only read out lengths of about
300 bases in each analysis. Decades of work by vast hordes of
technicians would surely be required to complete the task.
Moreover, some argued that sequencing the human genome was a fool's
errand because the vast majority of it--perhaps 95%--does not encode
proteins or regulatory information. These sequences were derogatorily
labeled "junk DNA." Why, some asked, expend enormous effort to acquire
detailed sequence information about DNA that had slim prospect of ever
yielding insight into biological function?
But the proposal prevailed. Several years of debate restructured the
initial plan into a series of staged subprojects. The relatively small
genomes of important experimental organisms--bacteria, yeast, flies, and
worms--would be attacked first, before turning to that of the human.
Biologically interesting in their own right, these genomes would serve
as pilot projects designed to refine the tools for automated sequencing
and computational analysis of genomic information. These efforts were
organized in 1990 as the international Human Genome Project, biology's
first attempt to create a large-scale infrastructure for studying life.
The first project to get under way was the sequencing of the
12-million-base (Mb) genome of the yeast Saccharomyces cerevisiae, with
sequences of individual chromosomes pouring out between 1992 and 1996 in
an international collaboration involving dozens of labs (18). In 1995,
the first complete bacterial genome was produced--the 1.8-Mb Haemophilus
influenzae. It was all generated in a single laboratory using a
"shotgun" technique in which the whole genome is randomly fragmented,
the fragments are sequenced, and the results are merged and reassembled
into one coherent genome-length sequence (19).
The results transformed cell biology. For the first time, biologists
could enumerate the full complement of genes and proteins required to
run a living cell. Included here were the essential hardware components
of nucleated (eukaryotic) cells and those of the simpler nonnucleated
(prokaryotic) cells.
By 1998, the genome of the first multicellular organism--the 97-Mb DNA
sequence of the roundworm Caenorhabditis elegans--was published (20).
And sequencing of the genomes of the mustard weed Arabidopsis thaliana
and the fruit fly Drosophila melanogaster was already nearing completion
as this past century drew to a close. One truly astounding result, long
suspected, was definitively confirmed by these sequencing efforts: The
number of distinct genes required to template a complex organism such as
the fruit fly (which has some 13,000 genes) was found to be not much
greater than the ~6000 carried in the genome of the single-celled
baker's yeast.
The pace of sequencing has only quickened. The sequence of the human
genome is expected to be completed in rough form this year and in
finished form not long thereafter. Biologists have begun to think of the
complete sequence of an organism's genome as a necessary starting point
for serious research.
The Future: Global Views of Biology The availability of the complete
parts lists of organisms, that is, catalogs of all their genes and thus
all their proteins, has been redirecting biologists toward a global
perspective on life processes--to study the role of all genes or all
proteins at once. Twentieth century biology triumphed because of its
focus on intensive analysis of the individual components of complex
biological systems. The 21st century discipline will focus increasingly
on the study of entire biological systems, by attempting to understand
how component parts collaborate to create a whole. For the first time in
a century, reductionists have yielded ground to those trying to gain a
holistic view of cells and tissues.
This new approach promises stunning breadth of perspective. At the same
time, it threatens to inundate scientists in a flood of data that will
overwhelm their ability to interpret it. Powerful new types of
bioinformatics will clearly be required to assimilate and interpret the
data that will issue from various types of genomics research. We focus
here on a few of these new global perspectives whose outlines are
already clear.
Human genetics will be affected in profound ways. Once the human genome
is sequenced, a follow-on task will be to understand the spectrum of
genetic variation in the human gene pool and its relation to disease.
This turns out, surprisingly, to be a tractable problem because of the
relatively recent vintage of our species. The current world population
of 6 billion people descends from a few tens of thousands of progenitors
who inhabited Africa some 150,000 to 200,000 years ago. Such small
populations can maintain only a limited degree of genetic
diversity--typically, only a few common variants in the coding sequences
of each gene in their genome. Moreover, the few thousand generations of
subsequent exponential population expansion have been too few on an
evolutionary time scale to alter the spectrum of common variation
substantially. As a result, the modern human population has much less
intraspecies genetic variation than, for example, chimpanzees. Recent
experimental studies have confirmed the limited number of common
variants in typical genes, raising the prospect that it will be possible
to catalog all of the common variants (alleles) of all human genes.
Such common variants attract enormous interest, because it is suspected
that they may hold the key to inborn susceptibility to common diseases.
A few cases in point are already known, such as common variants in the
apolipoprotein E gene that predispose carriers to Alzheimer's disease or
in the clotting factor V gene that predispose carriers to deep venous
thrombosis (21). Some human geneticists believe that such examples
represent only the tip of an enormous iceberg. The challenge here will
be to identify the full collection of variants and then test their
correlation with diseases.
Just as comparison within the human species will be revealing, so too
will comparisons between species. Evolution is a grand experiment in
which myriad sequence changes within a gene are tried and tested in the
crucible of selection. Evolutionary comparison among organisms
illuminates those sequences that play important functional roles in
protein structure or gene regulation, and thus have been retained
unaltered over extended periods of evolutionary time. Identifying
evolution's successful experiments will reveal key functional features
of important genes and proteins, obviating years of painstaking
laboratory experimentation.
Evolutionary sequence comparison should allow us to identify genes that
were crucial to the creation of new species; such genes are likely to
have undergone strong selection and more rapid sequence evolution. One
putative example of such a gene has been proposed in the fruit fly (22).
It would be fascinating to find candidates for the genes and genetic
changes that triggered the speciation between our progenitors and those
of chimpanzees.
Global approaches are also proving central to efforts to understand the
physiology of cells and organisms. Key here will be our ability to
survey which genes within a given cell are being read out (expressed)
and which ones are silent. A starting point will come from successful
monitoring of how the level of each expressed RNA and protein differs
among the cells of different tissues in response to different
physiologic signals, or in various disease states. Already, microarray
detectors exist that allow researchers to measure the RNA levels
corresponding to each of the 10,000 or so known genes (still only 10% of
the total), and various approaches are being developed for studying
complex mixtures of expressed proteins--the new science of proteomics.
Because the spectrum of expressed proteins within a cell determines its
biology, such comprehensive descriptions will provide the basis for
understanding precisely why, for example, brain cells differ from kidney
cells. They will identify biological markers characteristic of disease
states, leading to techniques for early identification. They will help
classify cancers into distinct subtypes, making it possible to know a
tumor's lineage, the nature of the genetic mutations that led to its
appearance, and, in the long run, whether it will respond to a
particular therapy. And they will reveal the strategies of attack that a
pathogen launches against its host and the defenses mounted by the host
to defeat the invading pathogen.
Proteins that interact physically invariably communicate with one
another. So other techniques, such as the "two-hybrid screen" and its
relatives, are being developed to identify these interactions. Maps of
these associations will, in turn, shed much light on the design of the
channels that send and process signals within living cells.
The long-term goal is to use this information to reconstruct the complex
molecular circuitry that operates within the cell--to map out the
network of interacting proteins that determines the underlying logic of
various cellular biological functions including cell proliferation,
responses to physiologic stresses, and acquisition and maintenance of
tissue-specific differentiation functions. A longer term goal, whose
feasibility remains unclear, is to create mathematical models of these
biological circuits and thereby predict these various types of cell
biological behavior.
More powerful tools will be needed to realize these goals, at the level
of both instrumentation and the computerized processing of biological
information, which has now become the cottage industry of
bioinformatics. Biologists will require gene-specific reagents to
disrupt the function of each component in the cell and study the
rippling effects of each such disruption on other genes and proteins
within the cell. Various techniques, such as antisense reagents
complementary to individual genes and small-molecule screening, are
currently being explored with the aim of finding a general technique for
disrupting intracellular circuits in a specific, highly targeted
fashion. The challenge of disrupting every gene in a human cell is
daunting but perhaps not insurmountable--after all, human genes number a
mere 100,000 or so, a figure that seems less formidable with the passage
of time.
Biology enters this century in possession, for the first time, of the
mysterious instruction book first postulated by Hippocrates and
Aristotle. How far will this take us in explaining the vast complexity
of the biological world? Will we ever be able to draw a protozoan or a
peacock, knowing only its DNA sequence? We are hard pressed to provide
an answer at the beginning of the century. Still, we proceed with great
optimism: The solutions to many problems long resistant to attack are
now within reach. The prospects of 21st century biology are surely
breathtaking.
At the same time, we must confront this new world soberly and with some
trepidation. The genetic diagnostics that can empower patients to seek
personalized medical attention may also fuel genetic discrimination. The
understanding of the human genetic circuitry that will provide cures for
countless diseases may also lead some to conclude that humans are but
machines designed to play out DNA cassettes supplied at birth--that the
human spirit and human potential are shackled by double-helical chains.
So the most serious impact of genomics may well be on how we choose to
view ourselves and each another. Meeting these challenges, some quite
insidious, will require our constant vigilance, lest we lose sight of
why we are here, who we are, and what we wish to become.
References and Notes
1.  G. Mendel, Verh. Naturforsch. Ver. Brünn 4, 3 (1866). (The original
    paper was published in Verh. Naturforsch. Ver. Brünn 1865, which
    appeared in 1866.) 
2.  K. G. Correns, Ber. dtsch. bot. Ges. 18, 158
    (1900); E. Tschermak von Seysenegg, Ber. dtsch. bot. Ges. 18, 232
    (1900); H. de Vries, Ber. dtsch. bot. Ges. 18, 83 (1900).
3.  A. H.  Sturtevant, A History of Genetics (Harper & Rowe, New York,
    1965); A. H. Sturtevant, J. Exp. Zool. 14, 43 (1913). 
4.  H. B. Creighton and B. McClintock, Science 17, 492 (1931). 
5.  H. J. Muller, Science 46, 84 (1927). 
6.  F. Griffith, J. Hyg. 27, 113 (1928). 
7.  O. T. Avery, C. M. MacLeod, M. McCarty, J. Exp. Med. 79, 137 (1944).
8.  A. D. Hershey and M. Chase, J. Gen. Physiol. 36, 39 (1952). 
9.  E. Schrödinger, What is Life? (Cambridge University Press, New York,
    1945). 
10. J. D. Watson and F. H.C. Crick, Nature 171, 737 (1953). 
11. M. W. Nirenberg and J. H. Matthaei,Proc. Natl. Acad. Sci. U.S.A. 47,
    1588 (1961); M. Nirenberg and P.Leder, Science 145, 1399 (1964). 
12. J. D. Watson, M. Gilman, J. Witkowski, M. Zoller, Recombinant DNA 
    (Freeman, 2nd ed., New York,1992). 
13. A. M. Maxam and W. Gilbert, Proc. Natl. Acad. Sci. U.S.A. 74,
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14. J. Downward et al., Nature 307, 521 (1984); R. F. Doolittle et al.,
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23. Related work of E.S.L. is supported by a grant from the National
    Institutes of Health/National Human Genome Research Institute. The
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    the text.


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-- 
Ciao, Carlo Fusco
* Quegli strani simboli che vedi qui sopra costituiscono una firma *
* digitale. Impara anche tu a farne uso insieme alla crittografia  *
* nelle tue mail private, e` molto importante: 
http://www.pgpi.com
 *

 Without doubt, the greatest achievement in biology over the past
[snip]
Ciao Carlo,
volevo vivamente ringraziarti per i contributi, le indicazioni,
i riferimenti, in una sola parola: gli INPUT, d'altronde "freschissimi",
o, in alternativa, "caldissimi", che, di tanto in tanto, gentilmente,
fornisci a tutti noi. Voglio dire, sono davvero felice che tu ci sia,
nell'NG. Davvero. E non e' per "sviolinare". Sai, mai quanto oggi
possiamo dire che nella biologia (ma forse in tutte le scienze) restare
aggiornati e' divenuto ormai un "imperativo". Pena: trattare di
minestrine riscaldate; magari gia' ammuffite; comunque passate ...
Ebbene, fa piacere sapere che l'NG possa fungere (anche) da "bacheca"
per questa o quella nuova informazione. Certamente l'adagio e' quello
solito de "l'unione fa la forza". E tutti noi, in qualche misura,
direttamente o indirettamente, contribuiamo ad aggiornare questa
"bacheca". Ma il tuo ruolo, credo, e' senza dubbio fondamentale.
(Non so se il mio encomio ti imbarazza. Se cosi' e', ti chiedo scusa.
Mi andava di farlo e l'ho fatto.)  Non ti stancare mai. Grazie ancora.
Un abbraccio,
Alessandro.

Mi andava di farlo e l'ho fatto.)  Non ti stancare mai. Grazie ancora.
Mi associo nel ringraziare.
Alex (5630)

 scrivermi tranquillamente.
Miiiii.... all'arrembaggio.... ;-)))

> Science Mar 10 2000: 1777-1782
Mi e' piaciuto molto: conto di usarlo per il mio (oscuro )lavoro di
insegnante di scienze.
Sapete che dico ai miei ragazzi all'inizio di ogni anno? "Che cos'e' la
biologia? Informazione".