CRA and Genomics-BusinessWeek Cover Article:
The Genome Gold Rush
Who will be the first to hit pay dirt?
In humanity's ongoing quest for knowledge, explorers are about to reach one of
history's great milestones: sequencing the human genome--the entire set of human
genes and everything in between. They have traveled the entire length of our
twisting ladder-like strands of DNA, reading the code of each of the three billion
individual ''rungs'' along the way. That will throw the door open to a vast
continent containing the answers to many of the riddles of how we grow, how
we get sick, and how we die.
In June, J. Craig Venter, the controversial president and chief scientific officer of
Celera Genomics in Rockville, Md., will announce that he has virtually finished
the task. Indeed, he has already turned to the next prize, disclosing on June 1
that Celera has decoded one-third of the 3 billion ''rungs'' in the mouse genome.
That will give Celera a crucial leg up on rivals in trying to find and understand
human genes.
Venter has plenty of competition, though. The federal government's genome
project will soon announce that it, too, has completed a draft of the human
genome. A goal that seemed impossible to some when it was first discussed in
the mid-1980s will have been reached years sooner than expected. For the
winners, ''Nobel prizes and huge potential profits are out there,'' says geneticist
Frederick R. Blattner of the University of Wisconsin.
The ultimate impact will be almost unfathomable. Trying to understand biology
from the few thousand genes now known has been like exploring the U.S. with
only the dim light of a few street-lamps scattered here and there across the
nation. Now, suddenly, the entire country will be illuminated--every mountain
peak, every cul-de-sac, every blade of grass.
Yet for today's genetic Lewises and Clarks, the journey of exploration has only
just begun. Researchers can now see the genetic code, but that doesn't mean
they understand it. Indeed, they know so little that they can't even say how many
genes are there to be discovered. In late May, a team of scientists at the
University of Washington estimated that the 3 billion bits of human DNA harbor
34,000 genes. Yet in the same scientific journal, a group at The Institute for
Genomic Research (TIGR) used similar methods to put the estimate at 120,000
genes.
With the genome sequence in hand, scientists will be able to determine exactly
how many genes there are and discover what they do. That will pave the way for
a revolution in medicine, making today's treatments seem like ''medieval
anachronisms,'' as Venter puts it. But that will take years--perhaps even
decades. And the crucial question is: Who will be the quickest and the best at
turning the treasures of the genome into medical advances and commercial
profits? ''Once the sequence is there, the game begins,'' says Stanford biochemist
and Nobel laureate Paul Berg.
Already, companies like Rockville's Human Genome Sciences and Incyte
Genomics in Palo Alto, Calif., have staked out claims for thousands of genes
they have fished out of cells. Others are using a variety of ''DNA chips'' and
innovative laboratory techniques to speed the race to understand biology and
develop new treatments. And still others are experimenting with fruit flies, zebra
fish, and mice, because these simpler organisms share much of their fundamental
biology with humans.
''BABBLING PHASE.'' Meanwhile, big pharmaceutical companies are
seeking the best targets for drugs amid the flood of new gene discoveries (page
160). Even IBM is getting into the act. Big Blue has focused its most advanced
computing resources on the problem of analyzing genomic data. The whole field
of genome-based medicine is like a rapidly growing child, says analyst Viren
Mehta, director of Mehta Partners. ''Right now, we're in the babbling phase and
are on the verge of writing paragraphs,'' he says. ''The companies that can turn
those paragraphs into masterpieces are the companies of the future.''
If Venter has his way, one of those companies will be his upstart, Celera. Can he
pull it off? Few are counting him out. After all, Venter is someone who has
always taken his own path--and accomplished what many believed was not
possible.
His career had an unlikely beginning. After high school, ''I worked as a night
clerk at Sears to support my surfing habit,'' Venter recalls. Then, faced with the
Vietnam era draft, he signed up with the Navy--on the promise that he, a
champion backstroker, would be on the swim team. The team was disbanded,
but Venter, who had aced the Navy's intelligence tests, had his pick of
assignments. He chose the duty that ''gave me the least chance of being killed''--
hospital corpsman in Da Nang. ''I learned that by taking active control to
whatever extent I can, I can have a dramatic effect on the outcome,'' he says.
His time in Vietnam ''was a lifetime of education packed into one year,'' he
recalls.
He came back with driving ambition. He zipped through college and earned a
biochemistry PhD in a mere six years, while supporting himself as a respiratory
therapist, and immediately landed a faculty post. ''I basically caught up with my
peers, only with a hell of a lot more experience of life than they had,'' he says.
Winning the respect of his fellow scientists took a lot longer. He burst into the
limelight in the early 1990s, at a time when it took years to find a single gene.
Then at the National Institutes of Health, Venter developed an automated
method for discovering hundreds in a few weeks.
BOLD PLANS. It was a direct challenge to the plans of the Human Genome
Project, a 15-year effort to sequence the entire genome that began in 1990. And
some of the project's leaders, who had dismissed Venter as a second- or
third-tier scientist, saw him as ''an intruder, a faker, and a blabbermouth,'' recalls
one top scientist. Says Venter: ''I had one of the most impressive enemy lists
anyone had accumulated.''
After being turned down for funding for his bold plans to discover thousands of
genes, Venter jumped from NIH to his own gene-hunting institute, TIGR. By
1998, he felt he could beat the genome project at its own game--and he said so.
With backing from equipment maker PE Corp. and its aggressive CEO Tony L.
White, the one-time surfer set up a PE unit, Celera Genomics, to use a risky,
unproven approach that would ultimately beat the public effort to the prize. ''The
remarkable thing is that we set out to do this without actually knowing how we
would do it,'' says Venter.
The method worked better than anyone--Venter included--had expected. In the
traditional approach to sequencing, scientists divide human DNA into large
pieces. They first painstakingly figure out where each piece belongs, then they
begin decoding each piece. Celera, in contrast, shortened the process with a
whole genome ''shotgun'' approach: Venter devised a way to blow the genome
into many bits and sequence them without regard to their position. The challenge
was whether, like all the king's horses and all the king's men, he could put the
parts together again. For that, he relied on a supercomputer and clever computer
algorithms.
To test the method, Venter picked a difficult genome to sequence--that of the
fruit fly. ''It was a gutsy move,'' he says. ''We knew it would either work
spectacularly or be the biggest flameout in history.''
It worked. One early indicator came when Venter sold his 82-foot sailboat,
Sorcerer. ''I said I would sell Sorcerer and get a bigger boat if Celera was
successful,'' he says. ''So when I sold it, everyone was nervous.'' On March 24,
just over a year after he started, Venter and his team published the entire
sequence of the fruit fly, along with dazzling new information about the numbers
and functions of its genes. Now he's building a replica of the legendary 144-foot
New England schooner Bluenose.
By 1999, the Human Genome Project had responded by dramatically stepping
up its own pace. And Venter and Dr. Francis S. Collins, the head of the
government project, began a war of words that put Wall Street on a
roller-coaster. In April, for instance, Celera announced that it had finished
sequencing--but not yet assembling--one person's entire genome. The
company's stock jumped 24%. A few days later, Collins fired back, saying
Venter's data was incomplete and possibly flawed. Celera stock plunged 18%.
Collins, derisively dubbed St. Francis by his critics for his unique blend of
do-gooding and ruthlessness, also has accused Venter of trying to lock up the
secrets of the genome for commercial gain. And he and his team say Venter
hasn't played fair because Celera has used data from the public project. Venter
retorts that Collins doesn't understand what Celera is doing, and besides, why
shouldn't he make use of taxpayer-funded research that's available to everyone
else? Collins' behavior, Venter says, has been ''despicable.''
''WASTE OF TIME?'' But for all the drama behind the unveiling of humanity's
genetic code, the race marks a beginning, not an end. In fact, the pharmaceutical
and biotech industries are already drowning in a flood of genetic information,
says Mihael Polymeropolous, vice-president for pharmacogenetics at Novartis.
''That's why this race for me is a little silly,'' he says. ''The real race is who will
develop the tools to analyze the genome first.''
There, Venter has another set of rivals. Celera may have won the headlines, ''but
they are too late,'' scoffs Incyte CEO Roy A. Whitfield. ''From a commercial
point of view, sequencing the genome is just a complete waste of time.''
That's too skeptical for most experts. But all agree that making sense of the
genome will not be easy. The first problem is that only about 3% of the three
billion rungs on the DNA ladder make up genes. The rest of the DNA,
commonly called junk, fills up not only the gaps between genes but also holes
within the genes themselves. No one really knows why most of the ''junk'' exists.
Because the genes, and the proteins they make, are the key to devising new
treatments ''there's gold in that 3% if you can find it,'' says Elliott Sigal, senior
vice-president of early discovery and applied technology at Bristol-Myers
Squibb Co.
That's a big ''if.'' The difficulty, says Gerald M. Rubin, the University of California
at Berkeley geneticist who collaborated with Celera to sequence the fruit fly
genome, is that the genome ''is written in a language no one knows how to read.''
Scientists know that there are certain patterns that are telltale signs of genes, and
they have developed sophisticated computer programs for spotting those
patterns. On May 8, for instance, DoubleTwist Inc., an Internet startup in
Oakland, Calif., grabbed headlines when it announced that it had pinpointed the
probable locations of 105,000 genes by analyzing the genome sequence
information already available in public data bases.
JAMBOREE. Unfortunately, such computer predictions are merely good
guesses. After Celera finished sequencing the fruit fly DNA, for example, it used
two computer programs to identify fruit fly genes and came up with significantly
different results. ''No algorithm can say, 'that's a gene,''' explains Venter. ''You
have to have good people sitting in front of the computer screen to make sense
of what's really a gene and what isn't.''
That's why Celera plans to host an unusual meeting in late June of top geneticists
and biologists from around the world. They will gather for what's playfully called
an ''annotation jamboree'' as they attempt to use their lifetimes of knowledge and
intuition--along with the latest computer programs--to decide where genes
actually lie on the human genome and what they might do.
Other outfits have taken a rival tack. In a method pioneered, ironically, by
Venter, Incyte and Human Genome Sciences are identifying genes by searching
for the instructions they send to protein factories elsewhere in the cell. Both
Incyte and HGS say they've already found pieces of almost every human gene,
though critics say the data is incomplete and often wrong. ''When we publish the
genome, the Incyte and HGS databases will be worthless,'' Venter claims.
What's more, the genes aren't actually the only interesting parts of the genome.
Why does Julia Roberts look different from a chimp? It can't be just the genes,
since those of humans and our simian cousins are virtually identical. The real
difference lies in how those genes are turned on and off. It turns out that some
bits of DNA act as master switches--and they can be located far from the genes
they turn on and off, hidden in the junk DNA.
How can scientists find these regulatory regions? Celera has an ace up its
sleeve--the mouse genome. The mouse has just about all the same genes and
genetic switches as humans, yet its junk is quite different. So as Venter's army of
robots reads the code of the billions of rungs on the mouse DNA ladder, his
scientists are laying the sequence alongside the human genome. The comparison
immediately reveals not only the genes but also the shared genetic switches. And
Celera's scientists are discovering that the approach is also bringing key insights
about the structures of individual genes, revealing which parts contain instructions
for proteins and which parts are the so-called noncoding regions, or introns.
Venter believes that the mouse will give him a crucial leg up on competitors like
Incyte and HGS. ''The mouse genome does for us what no one else can do,'' he
explains. ''It tells us the exact structure of the unknown gene. That gives Celera
and its subscribers a tremendous edge.''
Celera plans to publish the human genome and basic information about it by the
end of the year. But it is also making money by selling access to its much larger
database of information about DNA sequences and their functions. Venter
figures he needs about 10 major pharmaceutical companies to sign up at a rate
of some $10 million a year to pay for much of the company's operations. So far,
he has deals with Pharmacia, Novartis, Amgen, Pfizer, and Takeda. And on
May 7, he signed up his first academic paying customer, Vanderbilt University.
Because Venter's human genome database will be more complete than its rivals',
''all the companies that develop drugs may have to pass largely through Celera,''
says Dr. Faraz Naqvi, co-manager of Dresdner RCM Biotechnology fund. ''It's
like controlling the gate to the Internet.''
To turn that information into drugs and treatments, researchers must determine
what individual genes do. A whole biotech sector, called functional genomics,
has sprung up to unlock these mysteries. Dr. Robert Tepper, chief scientific
officer at Millennium Pharmaceuticals Inc. in Cambridge, Mass., wryly dubs the
field ''dysfunctional'' genomics because it poses such difficult challenges. One
major strategy relies on comparing human genes with those of other organisms,
such as the mouse, the fruit fly, and a worm called C. elegans. Exelixis Inc. in
South San Francisco, for example, has used this approach to try to understand
the biological pathways underlying diseases like Alzheimer's.
In another example, researchers at Immunex Corp. discovered an
interesting-looking molecule sticking out of the surface of the cell--a so-called
receptor. They knew that the receptor was part of a large family of similar
molecules that play key roles in inflammation, the activation of cells, or the ability
of cells to survive. But they didn't know what this particular receptor did. So
they created mice that lacked a functioning gene for the receptor--and thus
lacked the receptor itself. The resulting mice had a distinctive feature. Their cells
that are normally responsible for breaking down unwanted bone didn't develop
or work properly, causing the animals to have extra-thick bones. The discovery
suggests that the receptor might be a good target for drugs to prevent
osteoporosis.
WRONG TARGET. Leading this new field of functional genomics are
Millennium, Incyte, and Human Genome Sciences, with many others following
behind. But that understanding of basic biology will still take medicine only
partway toward its real goal: creating revolutionary new drugs and treatments.
Through most of the 1990s, drugmakers had hoped that when they discovered a
gene that causes a disease, they could use knowledge of that gene to devise a
new drug. ''It was the wrong promise. It oversold and stifled the development of
the whole industry,'' says Novartis' Polymeropolous, who discovered the gene
that causes Parkinson's disease. ''Now we know that the gene that causes a
disease is actually irrelevant as a drug target.''
Instead, the key is understanding the whole biological chain of events that occurs
when disease strikes--and then picking the best place in that chain to intervene.
Genentech researchers, for instance, realized that some breast cancer cells turn
on a gene that makes a unique molecule appear on the cancer cell surface. So
they devised a drug, Herceptin, that binds to the molecule and helps rein in the
cancer. Herceptin's sales for the first quarter of 2000 were $68.7 million.
Similarly, scientists at startup Hyseq are collaborating with Chiron to analyze 6
million samples from cancer patients, trying to find genetic clues that explain why
some cancers spread and others don't. Their search has turned up 31 genes, 25
of them previously unknown, that may play crucial roles in metastasis.
Fueling these discoveries are advances in scientific tools. To study the changes in
activity of many genes at once, companies like Affymetrix and Agilent
Technologies Inc. have created ''chips'' that contain probes that recognize tens of
thousands of genes. The chips--typically pieces of glass on which the probes are
attached--enable researchers to almost instantly see which genes are active in a
particular cell. In another strategy, Aurora Biosciences Corp. in San Diego has
developed collections of thousand of cells, each designed to study the effects of
one drug on one gene. If the drug turns the gene on, the cell turns blue; if not, it
stays green. Using the technology, researchers can evaluate as many as 100,000
drug compounds in a single day. ''It's this kind of killer application that's going to
rule,'' proclaims John D. Mendlein, chief knowledge officer at Aurora. On May
31, the Cystic Fibrosis Foundation announced that it would invest up to $47
million in Aurora to screen for potential new cystic fibrosis drugs. Such
innovative approaches, analysts say, have turned Aurora, Affymetrix, Agilent (a
spin-off from Hewlett-Packard Co.), and others into promising opportunities for
investors.
CRAP SHOOT. The tools promise to slash the time--and thus the cost--of
drug development. How? The old-fashioned approach is a bit of a crap shoot. A
company always hopes that the drug candidates it has created hit only the
intended target. But until the compound is tested or used widely in people,
there's no way of knowing if it causes damaging side effects. The diabetes drug
Rezulin, for instance, had to be pulled from the market because it caused severe
liver damage in a few patients. With a full collection of genes and rapid screening
tests, ''it will be possible to try a drug against all possible targets,'' explains the
University of Wisconsin's Blattner. That will enable companies to weed out
problematic drugs long before lengthy and expensive clinical trials begin.
In a glimpse of the future, Vertex Pharmaceuticals Inc. signed a groundbreaking
deal on May 9 with Novartis to develop drugs aimed not at one or even several
targets but rather at every member of an entire family of proteins--about 1,000 in
total. ''This is the natural follow-on to having the human genome,'' explains
Vertex CEO Joshua S. Boger.
What's more, the ability to study many genes at once also means that researchers
are able to piece together complete biological pathways. Until now, ''biologists
have mostly studied individual genes, not the larger system,'' says gene pioneer
Dr. Leroy Hood, now director of the Institute for Systems Biology in Seattle,
Wash. That, he says, is like trying to figure out a car's function by having one
mechanic study the ignition, another the brakes, another the suspension. You can
discover the functions of the parts, says Hood, ''but what does the hunk of metal
actually do?''
At Millennium, for example, researchers are figuring out the biology underlying
one of America's great obsessions--fat. Working with colleagues at
Hoffmann-LaRoche, they have uncovered a whole network of genes that help
control body weight. Some govern the production and metabolism of fat inside
cells. Others operate in the gut, controlling the absorption of fat. Still others exert
their influence in the brain to control appetite. The discoveries have pinpointed a
wealth of new targets for drugs--and Millennium now has 10 candidates ready
for clinical trials in obesity. ''This disease is just being broken wide open,'' says
CEO Mark J. Levin. ''That could never have happened without these
technologies.''
Some companies, working on the proteins rather than the genes, have created an
entire new field, called proteomics. Their aim is to find and understand the
estimated 1 million human proteins. Leading this booming new field are
companies like Myriad Genetics, Cytogen, and CuraGen. Myriad's scientists
have devised a method for rapidly discovering which proteins interact with which
others. As a result, they are now constructing networks of proteins--and using
them to find new proteins that may be promising drug targets in diseases like
breast cancer.
Many other biotech companies are jumping in as well. Incyte, for instance, has
ambitious plans to chart proteins in every part of the body. ''We want to create a
profile of human anatomy at the molecular level,'' explains President and Chief
Scientific Officer Randal W. Scott. Working with AstraZeneca, Incyte has
already begun testing drug candidates in the lab to see how they affect the levels
of thousands of proteins.
PROTEIN PAYOFF. Celera, meanwhile, is building a facility that will be able
to sequence a million proteins a day. And it plans to develop protein
''chips''--protein counterparts of the DNA chips already in use--and other
technologies that can be used to chart protein activity in every type of cell in the
body. Venter figures the effort will have a tremendous payoff. He expects to
uncover new hormones and other proteins that could be used as drugs.
Moreover, he expects that combining the genomic and protein data will offer far
more value than either alone. While other companies, such as Incyte, are
following the same strategy, Venter believes that his data are far more complete
and will be indispensable. ''We can give the genome sequence away for free
because we know that no other institution can process it or build the kind of data
sets we are building,'' Venter says. Indeed, he predicts that, eventually, the
information in his databases will be so valuable--and accessible--that ordinary
people will use it to learn about their own genes (page 155). ''Celera's ultimate
customers are the 6 billion people on the planet,'' Venter argues.
Another consequence of this flood of information is that the computer has
become one of the most important tools in biology. Consider these experiments.
You want to measure how each of tens of thousands of drugs affects every one
of humanity's 34,000 to 120,000 genes and its 1 million proteins. Or you want to
compare the sequences of thousands of unknown proteins with the 3 billion bits
of DNA in the human genome. In each case, the amount of data to analyze is
mind-boggling. ''We have reached a point where processing information is one of
the major bottlenecks,'' says Sharon L. Nunes, senior researcher at the
computational biology center at IBM's T.J. Watson Research Center.
Once the information problem has been solved, scientists will be left with a
wealth of possibilities. Having the full human genome sequence and all these new
tools ''will keep researchers busy for a long time,'' says Vincent Dauciunas, head
of strategic planning in the chemical analysis group at toolmaker Agilent. ''I call it
the Full-Employment Act for the millennium.''
It won't happen overnight. The lesson of the gene sleuthing of the past is that
wonderful new science takes longer to pay off than first hoped, and finding the
treasure in the human genome is no exception. ''Most of the miracles are going to
involve unknown genes and unknown functions that we are going to take
decades to solve,'' says Venter.
Undoubtedly, Venter will be in the thick of that gene-sleuthing. Leading a recent
tour of Celera, he proudly shows off black banks of supercomputers and a vast
room filled with silent sequencing robots. But as he passes down the hallway
papered with press clippings on the way to his office, he points out that one
article is conspicuously missing--a 1995 Business Week cover story labeling
Venter and then-partner William A. Haseltine, CEO of Human Genome
Sciences, as biotech's two ''Gene Kings.'' Forget Haseltine, he says. ''I think I
should be on the cover of Business Week as the single gene king,'' he says. Well,
Craig, you've earned it.
By JOHN CAREY
With Ellen Licking in New York and Amy Barrett in Philadelphia |
