Genomics: Journey to the Center of Biology

Eric S. Lander; Robert A. Weinberg

Science, New Series, Vol. 287, No. 5459. (Mar. 10, 2000), pp. 1777-1782.

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 P A T H W A Y S OF D I S C O V E R Y

Genomics: Journeyto
the Center of Biology
Eric S. Lander and RobertA Weinberg

Without &ub& the gratest achievtment inbiology over thc pas millennium has been the dueidation
of the mechanism of k d t y . H d t y is m l y the srrangest of physiological processes: C h p h n s
encapdate lnstnmctionsforcreatinga~ofthcir@esintheir~thescMonsan APRIL
passed on to a fmilizad egg, and then hey unfold spatanmusly to give rise to offspring The ancient Infectious
Grecks puzzled ova these rendable phenomena. Hippocratcs imagined that itlstructid &clcs DiSe&scs
gathad together tiom h u & l r t the adult body, having baa shaped by experience, while
M e beii& that the imwkia~sw ue consfant and inhemt in the gamas. But philosophers
~&nomthanspeculatefortheeasuing2000years,~rhere~no~topbttht
physical nature of t k itwtrudm MAY
H w ~ n a ~ o f ~ t y c a n e t o b c ~ o v e r t h a p a s t 2 0 0 y e a r s i s a n c x t r a a r d i n a r y ~ e Materials
of scidfm pmgns. In dizzying d m , that the M i t y khwtions f o U d
specific d e s of W o n , resided in the
in the molecule DNA, mwritten in a p m k genetic code,and could bc read W in thcir entirety to
specify oqgmhic shapeand hctioa. JUNIE
Ttse solutjm to the problemof M t y nuncdora to have b m t b h g e i w and gmcdity, The Cloning and
inshuctions far assembling every organism on the plan&- Stem &Us
slugs and sequoias, pacocks ad parasites, whales and
umps+m dl specified in DNA sapen- that can be
tmn&ted into digital information and stoped in a computer
fm aoalysis. As a ansapme of this nvolution, biology in JULY
the 2lst cenh~yis rapidly becoming an infixmation sci- Communlcattonr
ence* Hypo& will arise as o h in dlloo a invim. In and W,ence
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Hmdilywes thepmvincc ofphilosophem until Anton van Quantum
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Scientific studies of herd-
dorntnant trait; recessive traits ity eventually emtrgod h m a
mom practical quarter--0-
pendent assorhrwnt of tnrits (in nomic forces &king impwe-
t h i s ~ d ~ a n d ~ ) . ments in agriculture, The Age
of Discovery from the early
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5 were propagata~and bbridiaxi, impowxi cu~tivarsbeing highly prized. ~ h rapidlyc aprndinp in-

I tennational arads held great promise fix incrrasedeconomic returns on agricrultrtral products.
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o f M h n ( m ~ B m oi)n M a a a v i a , c c n t c l . o f t A e m t i l e i m i ~ i n b A u s t ~ ~ H ~ ~ o f r h e
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~~~Brebd-Engpsograms,~,~conrhrctcd~yby~ddmwidrrao

m r w s d c w m SCIENCE VOL 287 70 MARCH 2000

 P A T H W A Y S 0F D I S C O V E R Y
underlying rationale. Possessed with remarkable foresight,
Briinn's civic leadersorganized societiesto promote scientific
mearch, citingthe importanceof discoveriessuch as thoseof
Copernicus and Newton and expressing hope that the world
would somedaybe similarly indebted to a sonof Briinn.
This extravagant hope was indeed to be Mfilled. C. E
Napp, head of the Pomological and Oenological Society of
Briinn and abbot of the Augustinian monastery, kept his eye
out for scientifically trained young men to join his remark-
able monastery. The best of these recruits was Gregor
Mendel, who had studied physics in Vienna before joining
the abbey. The revoIution in the understanding of heredity
that followed was not triggered by a monk working in isola-
tion who accidentally stumbled upon the laws of genetics.
Rather, Mendel worked in an incubator focused on promot-
ing scientificprogress in what today would be called agricul-
tural biotechnology.
Mendel's pea breeding allowed him to observe genetic
dominance and the segregationof traits. In fact, these phenom-
ena had been described qualitatively decades earlier. But
Mendel took a quantitative approach, using his physics train-
ing and his breeding data to formulate a theory providing, for
the fm time, a mechanisticdescriptionof the laws of heredity.
Mendel proposed that heredity information was passed
from pamt to offspring in discrete packets, which he called
"fact~rs.~'Different factors were responsible for distinct as-
pects 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 par-
ent. The two Wrs governing a trait might carry conflicting
instructions, in which case the voice of one might dominatein
determining the appearance of the individual. Nonetheless,
the other factor would m i s t in latent form. and its effects
couldreappear in later &eratiom in predictablemtios.
Mendel's 1865report (I) in theJournal of the Briinn Soci-
ety of Natuml Science fell on deaf ears. He worked at the pe-
riphery of the scientific community, and he published in an
obscurejournal. But the real problem was that Mendel's for-
malisms were mathematicaland his Wrs were abstractions.
Mendel's laws would only gain a wide audience long after his
death, when they could be related to biological realities--
visible cellularstructures.
Chmmosomes:The Cellular Baslsof the Instructions
By the mid-1880s, biologists began to recognize that the
physical seat of heredity must lie in the cell's nucleus. Mi-
croscopists 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
examhation of a spermatozoon indicated that this cell was
littlemore than a nucleuswith 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 har-
bored heredity instructions, chromo-
somes 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 chro-
mosome carried a complete set of the heredity instructions.
The ensuing f m e n t revived interest in understanding the
laws of heredity via breeding experiments.
10 MARCH 2000 VOL 287 SCIENCE www.sciencemag.org
In the early months of 1900,three researchewHugo de
Vries, ErichTschermakvon Seysenegg, and Karl Comns-
independently reported rediscovering Mendel's work and
laws (2). Theu work revealed little more than what Mendel
had found 35 years earlier,but the scientificcommunity was
now primed to listen. The papers sparked the genetics revo-
lution that continuedunabatedthroughoutthe 20th century.
An initial challenge was to prove the comection between
genes and chromosomes.The most importantadvanceswould
come from the study of the h i t fly Dmophifa in the labora-
tory of Thomas Hunt Morgan at Columbia University. Ar-
guably, the greatest insights came fromAlfied 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
be explained by a
simple model in
which the genes WE
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 d-
ized that these maps
showingthe positiok
of genes must c o r n
spond to the thread-
Father of gene mapping. Alfred Sturte like
"ant realized early last century that (3)- Gene
geneswere Linkedinlinear anays. rapidly became a
powerful tool of ge-
netics, although the defmitivep m f of the connectionbetween
linkage maps and chromosomes came later in the 1930swith
studiesby Eiarbam McCliick on maize chromosomes (4).
DNkThe BiochemicalBasisof the Instructions
The early 20th century witnessed the birth of another experi-
mental science: biochemistry. This maniage of biology and
chemistry sought to understand life by isolating molecules 3
and reconstituting living processes in the nonliving extracts
prepared from cells. The biochemists had a clear agenda: to 2
systematically dismantle the notion of vitalism, which held 5
that ineffable "life forces" were responsible for the complex g
attributes of living cells and tissues. By 1925, they had tri- 8
umphantly shown that many biochemical reactions could be g
reproduced in the test tube using the organic catalysts called 8
emjmes. The scienceof genetics, however, was disconnected 5
from this forward rush of biochemical progress. Genes
seemedhopelessly inaccessible: How could one possibly puri-
fL heredity in a test tube? Indeed, could hedity ever be un-
derstood through biochemistry and the increasing number of z i
molecuIar speciesbeing unearthed in living cells?
A first, tentative foray toward the molecular embodiment F
8
of genes came from the 1927work of Hermann Muller, then
in Texas, who demonstrated that x-rays could mutate the e I
genes of Dmsophila (5). This provided geneticists with a
powerful tool. They no longer needed to rely on the sponta- %
neous randomness of nature to generate variants of the "wild- 8
 P A T H W A Y S OF D I S C O V E R Y
type" genes normally found in flies. Conceptually, Muller's helix, by pairing A with T and G with C on opposite strands,
discovery was even more far-reaching, showing that genes explained how genetic information could be copied (the
were physical entities susceptible to being damaged just like complementarity of nucleotides meant that each strand could
other molecules in the cell. But still, the central question re- serve as a template for the assembly of a complete double he-
mained: What kind of molecules explained heredity? lix) and how mutations could arise (occasionally the copying
A year later, some steps were taken toward an answer. process might go awry). In one stroke, Watson and Crick had
Fred Griffith in England made the serendipitousobservation explained the key problems of genetics.
that an extractprepared from virulent, disease-causing Pneu-
mococcus bacteria could transmit the trait of virulence to a The GeneticCodeThroughthe Recombinant DNA Revolution:
benign strain. Once the benign bacteria had acquired these DeciphedngtheInstructions
instructions, they and their descendants in turn showed all the The Watson-Crick model made clear that the instructionsmust
haits of virulence. The instructions for inducing disease, be encoded by the sequence of the bases in the strands of the
whatever their nature, persisted in the virulent bacteria long DNA double helix. But how, specifically, were these instruc-
after their death by heat treatment (6). tions read out to build the cdmponents of a living organism?
By the mid- 1930%Oswald Avery, Colin McLeod, and By 1964,the outlinesof the solutionhad been worked out.The
Maclyn McCarty, working at the Rockefeller Institutein New DNA segment corresponding to each gene is copied into a
York, took on the daunting task of purifying the elusive sub- messenger RNA molecule, whose base sequence is then used
stancethat conferred virulence. By 1944they had the answer. to direct the synthesis of a specific protein from amino acid
Deoxyribonucleic acid (DNA) molecules extracted from vir- building blocks. Marshall Nirenberg used synthetic RNAs to
ulent bacteria sufficed to transfer the genetic instructionsfor crack the genetic code by which triplets of bases (nucleotides)
virulence. Destruction of the DNA resulted in loss of these constitute genetic "words" specifying particular amino acids
instiuctions,while destructionof bacterial proteins seemed to (11). In principle,the secret of life had been laid bare.
have no effect on the information transfer (7). In practice, there was a catch. Although biologists had
Their conclusion was controversial. DNA molecules were deciphered the code 'for translating DNA information into
widely regarded as boring, monotonous chains composed of proteins, they could not yet read any natural DNA se-
four nucleotide~stensiblystructural scaffolds of the quences-not even the sequence of a single gene out of the
chromosomes. Protein molecules were far more interesting. thousands present within a cell.They lacked the text on
They were biochemicallyand smcturally more complex,and which to practice their .newfounddeciphering skills. It
for this reason seemed to offer far more possibilities for took another 15 years for this problem to be fully
harboring genetic information. But DNA survived the solved by the two recombinant DNA technologies of
skeptics.When purified of all but 0.02% of contarninat- cloning and sequencing.
ing protein, DNA continuedto be potent in transmitting Cloning circumvented the limitations of traditional
genetic information. Most compelling were the 1952 biochemistry, which relies on isolating molecules from a
experimentsof Alfred Hershey and Martha Chase, who complex mixture based on their chemical idiosyncrasies.
showed that when bacterial vimw inject their genetic The biochemical approach is useless for purifLing indi-
information into host cells, DNA enters the cell, while vidual genesbecause chemically,they are virtually identi-
the protein coat remainson the outside (8). cal--each is simply a stretch of DNA bases.
Still missing was an understanding of how Cloning introduced a new twist on
DNA-or any molecule--could store and encode rification: Large genomes were cut
heredity instructions.This intellectual puzzle had at- into small segments; each was at-
tracted the interest of some eclectic physicists, in- tached to a special "vector"
cluding Niels Bohr and his student Max Delbriick. molecule and then introduced into
They struggled to explain the long-term stability of bacterial cells, which faitfilly repro-
genes in terms of molecules residing in deep poten- duced the foreign DNA a
tial wells and even suggested that new laws of grew. Each bacterium rec
physics might be needed to explain life. These issues DNA molecule, ensuring that descendantcells
were distilled by Erwin SchrGdingerin a brilliant and gether constitute a "clone," all h
popular 1945book, What is Lif? (9). this specificDNA segment
Schriidinger proposed that genes must be "aperi- vidual DNA segments by propagati
odic crystals" consisting of a succession of a small clones, a collectionof which came to
number of isomeric elementswhose precise sequence brary." Experimentersthen devised clever steps to enable
constitutes the heredity code in the manner of the them to screen the millions of separate clones in a com-
p Morse code. Although these ideas did nothing to plete gene library and pick out the rare clones carrying
$ identify the responsible molecular structures, they did the DNA segment and thus gene of interest.
attract many newcomers to the field-including a The development of the vectors capable of directing
youthful James Watson, who set off to Cambridge, the bacterial cell to reproduce theindividual DNA seg-
$ England, determined to work on the nature of the ments was a key technical step in the creation of these
3 gene.There, he teamedup with former physicist libraries. Here, biologists exploited highly successful
4" FrancisCrick. experiments of nature such as viruses and plasmids,
Watson and Crick's revelation of the dou- which are cellular parasites known to co-
ble-helical structure of DNA shuck like a opt cells into making hundreds or thou-
[ thunderbolt in April 1953 (10). Just as sands of copies of viral and plasmid DNA
3 Schriidinger had predicted, DNA was an ape- molecules (12).
$ riodic crystal, being composed of four nu- Miracle helices. In 1953, DNA's now iconic DNA sequencing
z cleotide bases along its strands. The double molecular structurewas first revealed. technology'formed

www.sciencemag.org SCIENCE VOL 287 10 MARCH 2000

 P A T H W A Y S 0I F D I S C O V E R Y
the other half of the recombinant DNA revolution of the drove biologists to reconceptualize their research. Those re-
1970s. Two s t r a t e g i e ~ n peioneered by Fred Sanger, the searchingorganisms such as worms, flies, and yeast began
other by Walter Gilbert-de it possible to determinewith portraying their work as opening windows on the universal
relatively high accuracy the sequences of DNA fragments a rules of life on this planet, not just on the idiosyncrasies of
few hundred bases long (13). Soon, individual genes cloned the arcane organisms they studied. Researchers working on
from large cellulargenomesbecame objectsof study. sea urchin and frog development found themselves cata-
Sequencing technology advanced rapidly, driven by an pulted into cancer research meetings, using a common vo-
unquenchable thirst for sequence information. In the late cabulary with cancer researchers to describe proteins that
1970s, an entire doctoral thesis might be devoted to report- pIay equally important roles in early embryogenesis and in
ing the sequence of a gene of several thousand DNA bases. the developmentof human malignancies.
By century's end, technologistshad developed automated se- Sequence analysis also revolutionized the study of evolu-
quencing machines capable of cranking out up to a half- tion, by making it possible to draw phylogenetic trees relating
million bases per day. organismson the basis of similarities in their genesrather than
shared physical characteristics. By the 1980s, the availability
The GenomicsRevolution of vast quantities of sequence data and sophisticated comput-
DNA sequencing soon produced er-based analytic tools led to a whole-
surprises by revealing connec- sale redrawing of the branches and
tions between genes that previ- twigs of the tree of life.
ously had seemed unrelated. Two The studies of individual genes
early examples involved cancer- represented stunning achievements,
causing genes: the oncogenessis but these successes soon promoted an
and erbB. One research team even grander vision: the systematic
cloned these genes and deter- study of complete genomes, soon re-
mined their DNA sequences. ferred to as genomics. The first foray
Meanwhile, unrelated groups of into genomics was a proposal to use
researchers who were more bio- DNA technology to extend Sturte-
chemically inclined isolated two vant's original concept of genetic rnap-
proteins-platelet-derived Life's bar code. Raw genetic sequence data, like this ping to the human being. Instead of
growth factor (PDGF)and the autoradiograph, began chan,ging biological research tracing the inheritance of visible muta-
receptor for epidermal growth in the 1970s. tions as had been done in fruit flies,
factor (EGF)-and determined David Botstein and colleagues pro-
the amino acid sequences of both. To everyone's surprise, posed in 1980 that one could construct a complete genetic
the DNA sequences of the oncogenes corresponded nearly map of the human chromosomes by following the inheri-
perfectly to the amino acid sequences of the well-studied tance of common DNA sequence variations, termed DNA
growth-controlling proteins (14). These identifications re- polymorphisms (Id). Each polymorphism could be used to
vealed instantaneously how the sis and erbB oncogenes plant a sequence marker at a specific site on a genetic map
transform normal cells into cancer cells. of a chromosome. One could then localize genes causing
Such connections were only the beginning. Comparisons specific human diseases by matching their inheritance pat-
of gene sequences revealed that strikingly similar proteins terns with those of the signpostson these genetic maps.
were encoded in the genomes of organisms as distantly relat- The first success using this strategy came in 1983, when
ed as yeast and mammals. For example, the proteins govern- the gene causing Huntington'sdisease was shown to map to
ing the progression of a yeast cell through its cycle of growth the tip of the short arm of human chromosome 4 (1 7). The
and division were found in very similar f m in the cells of first comprehensive human genetic map with 400 signposts
humans. These cross connections soon numbered in the thou- was constructed by 1987, and much denser maps with more

3
sands, then tens of thousands. It be- than 10,000 such markers were available a decade later.
. came clear that the evolution of life Medical genetics was revolutionized as the genes causing
; - - 7 on this planet was stunningly con- more than 1000 human diseases were soon mapped to spe-
servative. Once nucleated cells cificchromosomal sites.
evolved more than 1.5 billion years An even more expansive vision was expounded in 1985:
ago, the great majority of the pro- The entire human genome would be sequenced, providing a
teins invented at the time were per- complete catalog of every human gene. On its face, the pro-
petuated in myriad descendant posal seemed quixotic, a logistic impossibility. The human
cells-sometimes with only minor genome encompasses 3 billion bases of DNA;then-current $
changes. Often the genes encoding sequencing technology could only read out lengths of about 8
these early proteins multiplied and diversifieda billion years 300 bases in each analysis. Decades of work by vast hordes of g
later, spawning large b i l i e s of related genes and proteins technicianswould surelybe required to completethe task. c
having diverse, sometimestotally navel functions. Moreover, some argued that sequencing the human 3
Recognition of gene familiesproduced enormous synergy genome was a fool's errand because the vast majority of it- $
in research, as the function of one member could often be de- perhaps 9 5 Y 1 o e snot encode proteins or regulatory infor- 4 -
duced from that of its known relatives. When the gene respon- mation. These sequences were derogatorily labeled "junk
sible h r cystic fibrosis cloned, sequence analysis h e - DNA." Why, some asked, expend enormouseflort to acquire
diately suggested that it belonged to a family of proteins that detailed sequence information about DNA that had slim P
transport ions through membranem fact that was then read- prospect of ever yielding insight into biological function?
ily tested and codirmed in the labomtory(15). But the proposal prevailed. Several years of debaterestruc-
The connections across vast phylogenetic distances also tured the initial plan into a series of staged subprojects. The

10 MARCH 2000 VOL 287 SCIENCE www.sciencemag.org

 PATHWAYS OF DISCOVERY
relatively small genomes of important experimental organ-
isms-bacteria, yeast, flies, and worms-would be attacked
first, before turning to that of the human. Biologically interest-
ing in their own right, these genomes would serve as pilot pro-
jects designed to refine the tools for automated sequencingand
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 infras-
tructure for studying life.
The first project to get under way was the sequencing of
the 12-million-base (Mb) genome of the yeast Saccha-
romyces cerevisiae, with sequences of individual chromo-
somes pouring out between 1992 and 1996in an internation-
a1 collaboration involving dozens of labs (18). In 1995, the
first complete bacterial genome was produceddhe 1.8-Mb
Haemophilusinjuenzae. It was all generated in a single labo-
ratory using a "shotgun" technique in which the whole
genome is randomly fragmented, the fragments are se-
quenced, and the results are merged and reassembled into
one coherent genome-length sequence (19).
The results transformed cell biology. For the first time, bi-
ologists 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 organ-
ism--the 97-Mb DNA sequence of the roundworm Caenor-
habditis elegans-was published (20).
And sequencing of the genomes
of the mustard weed Ambidop-
sis thaliana and the h i t fly
Drosophila rnelanogaster
was already nearing
completion as this past
century drew to a close.
One truly astounding ,.a.m,
result, long suspected,
was definitively con-
firmed by these se- "t,
quencing efforts: The
number of distinct genes
required to template a
complex organism such a
the fruit fly (which has some
13,000 genes) was found to be not ',"" sm.m
much greater than the -6000
of Genome
camied in the genome of the sin-
map of firstwg.n;sm
gle-celled baker's yeast. (Haemophilus influenzae)
The Pace of sequencing has to be fully sequenced.
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 asa necessary startingpoint for seriousresearch.
2s The Future: GlobalViewsof Biology
p The availabilityof the complete parts lists of organisms, that
is, catalogs of all their genes and thus all their proteins, has
g been redirecting biologists toward a global perspective on
g life processes-to study the role of all genes or all proteins
$ at once. Twentieth century biology triumphed because of its
5 focus on intensive analysis of the individual components of
2 complex biological systems. The 21st century discipline will
e0 focus increasingly on the study of entire biological systems,
a by attempting to understand how component parts collabo-
www.sciencemag.org SCIENCE VOL 287
rate to create a whole. For the first time in a century, reduc-
tionists have yielded ground to those trying to gain a holistic
view of cells and tissues.
This new approach promises stunning breadth of perspec-
tive. 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 outlinesare 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, surprising-
ly, to be a tractable problem because of the relatively recent
vintage of our species. The current world population of 6 bil-
lion people descends from a few tens of thousands of progeni-
tors who inhabitedAfrica 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 popu-
lation expansion have been too few on an evolutionary time
scale to alter the spectrum of common variation substantially.
As a result, the modem human population has much less in-
traspecies genetic variation than, for example, chimpanzees.
Recent experimental studies have confirmed the limited nurn-
ber of common variants in typical genes, raising the prospect
that it will be possible to catalog all of the common vari-
ants (alleles) of all human genes.
Such common variants attract enormous inter-
est, because it is suspected that they may hold
'
the key to inborn susceptibility to common dis-
eases. A few cases in point are already known,
,,, such as common variants in the apolipopro-
tein E gene that predispose carriers to
Alzheimer's disease or in the clotting factor
-.m V gene that predispose carriers to deep ve-
nous thrombosis (21). Some human geneti-
" cists believe that such examples represent only
the tip of an enormous iceberg. The challenge
here will be to identifythe fbll collection of vari-
ants 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 se-
quence changes within a gene are tried and tested in the cru-
cible 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 successfbl experimentswill reveal
key functional features of important genes and proteins, obvi-
ating years of painslaking laboratoryexperimentation.
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 fas-
cinating 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
10 MARCH 2000
 PATHWAYS OF DISCOVERY

w . .
are being read out (exuressed) and which Each month, Britannica.com enhances t h e man genes number a mere 100.000 or so.
ones are silent. A startinipoint will Pathways Discovery essay with links
w
to a figure that seems less formidSLble wi&
relevant items within and without Encylope-
come from successful monitoring of how ddi Britannica~s vast stores of info,,ation.k the passage of time.
the level of each expressed RNA and access this month's Pathways essay and-all Biology enters this century in posses-
protein differs among the cells of differ- Previous Ones. g o t o ~ w w ~ b r ~ t a n n i c a . c o msion, for the first time, of the mysterious
ent tissues in response to different physi- and click o n the "Science" channel. instruction book first postulated by Hip-
ologic signals, or in various disease pocrates and Aristotle. How far will this
states. Already, microarray detectors exist that allow re- take us in explaining the vast complexity of the biological
searchers to measure the RNA levels corresponding to each world? Will we ever be able to draw a protozoan or a peacock,
of the' 10,000 or so known genes (still only 10% of the total), knowing only its DNA sequence? We are hard pressed to pro-
and various approaches are being developed for studying vide an answer at the beginning of the century. Still, we pro-
complex mixtures of ceed with great optimism: The solutions to many
expressed proteins-the problems long resistant to attack are now within
new science of proteomics. reach. The prospects of 2lst century biology are
Because the spectrum surely breathtaking.
of ex~resseduroteins with- At the same time. we must confront this new
in a ckll deteknes its biol- I world soberly and wik some trepidation. The ge-
ogy, such comprehensive netic diagnostics that can empower patients-to
descriptions will provide seek personalized medical attention may also he1
the basis for understanding genetic discrimination. The understanding of the
precisely why, for example, human genetic circuitry that will provide cures for
brain cells differ from kid- countless diseases mav also lead some to con-
ney cells. They will identifL I clude that humans are but machines designed to
biological markers charac-
teristic of disease states,
leading to techniques for
I play out DNA cassettes supplied at birth-&at the
human spirit and human potential are shackled by
double-helical chains. sithe most serious impah
early identification. They of genomics may well be on how we choose to
will help classify cancers view ourselves and each another. Meeting these
into distinct subtypes, mak- , ,,lg wlLn gene chips one, re- challenges, some quite insidious, will require our
ing it possible to know a tu- searchers can study thousands of genes a t once. constant vigilance, lest we lose sight of why we are
mor's lineage, the nature of here, who we are, and what we wish to become.
the genetic mutations that led to its appearance, an4 in the
long run,whether it will respond to a particular therapy. And References and Notes
they will reveal the strategies of attack that a pathogen launch- 1. C. Mendel Verh. Naturforsch. Ver. B ~ n 4.3 n (1866). (The original paper was
publishedin Verh. Naturfo~ch.Ver. Briinn 1865, which appeared in 1866.)
es against its host and the defenses mounted by the host to de- 2. K. C. Correns, Ber. dtsch. b o t Ges. 18,158 (1900); E. Tschermak von Sey-
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A. H. Sturtevant,j. Exp. Zoo1 14,43 (1913).
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The long-term goal is to use this information to recon- 9. E. Schrodinger, What is Life? (Cambridge University Press, New York, 1945).
struct the complex molecular circuitry that operates within the 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
cell-to map out the network of interacting proteins that de- (1961); M. Nirenberg and P. Leder, Science 145.1399 (1964).
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functions including cell proliferation, responses to physiologic man, 2nd ed., New York. 1992).
13. A. M. Maxam and W. Gilbert, Proc. N a t l Acad. Sci. U.S.A. 74,560 (1977); F.
stresses, and acquisition and maintenance of tissue-specific Sanger, Science 214,1205 (1981).
differentiation functions. A longer term goal, whose feasibility 14. J. Downward et dl., Nature 307, 521 (1984); R. F. Doolittle et a/., Science $
remains unclear, is to create mathematical models of these bi- 221,275 (1983); M. D.Waterfield et al, Nature 304,35 (1983). ?!
ological circuits and thereby predict these various types of cell 15. J. R. Riordan et al, Science 245.1066 (1989).
16. D. Botstein, R. L White, M. Skolnick, R. W. Davis, Am. j. Hum. Genet. 32, 2
6
biological behavior. 314 (1980). E2
More powerhl tools will be needed to realize these goals, 17. J. F. Cusella et dl.. Nature 306,234 (1983).
at the level of both instrumentation and the computerized pro- 18. R.A. Clayton, O.White, K.A. Ketchum, J. C.Venter, Nature 387,459 (1997). $
cessing of biological information, which has now become the
19. R. D. Fleischmann et a/., Science 269,496 (1995).
20. The C. elegans SequencingConsortium, Science 282,2012 (1998).
gZ
cottage industry of bioinformatics. Biologists will require 21. W. J. Strittmatter et a/., Proc. Natl. Acad. Sci. U.S.A. 90,1977 (1993); R. M. 3
Bertina et a/., Nature 369,64 (1994). 3
gene-specific reagents to disrupt the function of each compo- B
22. C.-T.Ting, 5.-C.Tsaur, M.-LWU, C.-I.Wu, Science 282, 1501 (1998). z
nent in the cell and study the rippling effects of each such dis- 23. Related work of E.S.L is supported by a grant from the National Institutesof 2
ruption on other genes and proteins within'the cell. Various HealthlNational Human Genome Research Institute.The authors would like E
z
techniques, such as antisense-reagentscomplementary to indi- to thank Maureen T. Murray for her comments on the text a

vidual genes and small-molecule screening, are currently be- g

-
with the aim of finding a technique for Eric 5. Lander and Robert A. Weinberg are members o f the White-
ing head Institute for Biomedical Research and professors i n the Depart-
disrupting intracellular circuits in a specific, highly targeted ment o f Biology a t the Massachusetts Institute o f Technology, Cam- 5
fashion. The of disrupting every gene in a hlUmtI bridge, M A 02142. R;A.W. is a Daniel K. Ludwig Professor and an
cell is daunting but perhaps not insurmountable-after all, hu- American Cancer Society Research Professor. 5
t

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Genomics: Journey to the Center of Biology
Eric S. Lander; Robert A. Weinberg
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References and Notes

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