Thursday,
Jan. 24, 2008
Scientist
Creates Life — Almost
By
Alice Park
Not only has Venter
constructed the first man-made genome, he has also sequenced his own dna, which
is now part of a public genetic database
If you were setting out to design a human being
from scratch, odds are you wouldn't take J. Craig Venter as your template. You
wouldn't choose to put him at risk for Alzheimer's disease, for example, but
Venter has a predisposition that places him in danger of it. You might choose
his startling blue eyes, both for their color and the hard clarity of their
gaze. You'd surely go for his first-rate brain, though you might pass on what
his detractors consider the vainglorious temperament that comes bundled with
it.
It's something of an irony then that such an
imperfect organism as Venter has devoted much of his career to understanding
the engineering of other organisms. He was the leader of one of two teams that
in 2000 sequenced the human genome—the entire 25,000-gene cookbook that
makes us people in the first place and not chimps or birds or banana trees
— and he has conducted the same work with many other organisms. But
Venter, 61, may have just done something that is at once more thrilling and
promising and unsettling than all that. According to a just-released paper in
the journal Science, he has gone beyond merely
sequencing a genome and has designed and built one. In other words, he may have
created life.
Certainly, defining what we mean when we say life has become a moving target over
the years. Are we alive? Yes. Is a virus alive? Maybe. Still, a half-century
after the discovery of the double helix, nobody doubts that it is our DNA that
determines what we are — in the same way that lines of code determine
software or the digital etchings on a CD determine the music you hear. Etch new
signals, and you write a new song. That, in genetic terms, is what Venter has
done. Working with only the four basic nucleotides that make up all DNA —
adenine, cytosine, guanine and thymine — he has assembled an entirely new
chromosome for an entirely new one-celled creature. Insert that genome into a
cell — like inserting a disc into a computer — and a new species of
living thing will be booted up. Venter hasn't done that yet, which is why even
he won't say that he has technically invented life. He has, however, already
shown that a genome transplanted from an existing cell to another will shut
down the host's genetic programming and bring its own online. If that cellular
body-snatching works with an ordinary chromosome, there's little reason to
think it won't with a manufactured one. "The fact that this is even
possible is mind-boggling to most people," Venter says.
That's not an overstatement. The genome in Venter's
lab in Rockville, Md., could revolutionize genetics, introducing a new world
order in which the alchemy of life is broken down into the ultimate engineering
project. Man-made genomes could lead to new species that churn out drugs to
treat disease, finely tuned vaccines that target just the right lethal bug,
even cells that convert sunlight into a biofuel.
Creating such small, single-purpose organisms is
nowhere near as complex as creating larger, multicelled creatures —
things with mobility, behavior, a purpose, a face. Those fanciful and frightful
things are surely many years away and may prove too challenging and disturbing
for society to allow. What Venter appears to have done, however, is crack the
manufacturing code. Once you've done that, there may be little limit on what
you can eventually build.
It was not always evident that Venter would become
such a transformative figure — particularly when he was a boy. He was
never a terribly engaged student (his 2007 autobiography, A Life Decoded, includes his eighth-grade report
card, filled with Cs and Ds). He fondly recalls testing the patience of both
his parents and the pilots at San Francisco International Airport when he and
his friends, pedaling furiously on their bicycles, would race planes taxiing
for takeoff on a remote runway. (Airport officials eventually fenced it off.)
In 1967 he went to Vietnam, where he had been drafted to serve as a hospital
corpsman in the Navy. As a relief from what he describes as "M*A*S*H without the jokes and pretty
women," Venter, with the help of some Marines on China Beach, taught
himself to sail 19-ft. (5.8 m) sailboats known as Lightnings. "When you're
in the middle of a war, freedom is something you think a lot about," he
says. "I always had a dream of sailing around the world."
Like many who live through a war, Venter returned a
different man. He wanted to attend medical school and enrolled in community
college and then at the University of California at San Diego. By graduation in
1972, he had become enamored of biochemistry and decided to pursue a graduate
degree instead. He ended up taking a job with the National Institutes of Health
(NIH) in Washington, walking the mazelike halls of the government building as a
civil servant.
As energized as he was by the work, the ambitious
and freethinking Venter chafed at what he calls the "bureaucratic
hell" there and longed for the opportunity to test the innovative ideas he
had for transforming the emerging field of genetics. In 1992 he secured private
funding and created his own company, the Institute for Genomic Research in
Rockville. Within three years he completed the first-ever genome sequencing of
an entire organism—Haemophilus
influenzae, the
bacterium that causes meningitis. The firm soon became a go-to place for
sequencing projects, and it wasn't long before Venter hungered for the biggest
prize in biology: the map of the human genome. In the 1990s such a project was
almost unthinkable, a feat of mind-numbing complexity that involved determining
the placement and makeup of every one of the human genome's genes, some of
which can contain thousands of nucleotides.
By now, however, Venter had brainstormed a way to
automate the process, pulling in supercomputers to do the work of recording
each letter in all the necessary snippets of DNA and then knitting the
fragments together in a simple and predictable way. If a page of text from a
book were torn into pieces, it could be easily reconstructed as long as the
tears were made at predetermined places — always before the word only, for example, whenever it
appeared on the same page as the word and. Venter's system worked in a similar way, and in 1998 he
brashly predicted that using his method, which he called shotgun sequencing, he
could finish the map faster and less expensively than the government's $3
billion sequencing effort led by Dr. Francis Collins.
To ensure he'd have the resources to make good on
that boast, Venter joined hands with global technology giant Perkin-Elmer,
forming a new company called Celera, which took its name from the middle of the
word accelerate. The Celera-backed Venter and the
NIH-backed Collins briefly explored collaborating, but those efforts fell
through, and over the next two years the two camps worked feverishly,
occasionally volleying in the press over whose method was better or whose
intentions were purer. Collins sniffed at Venter's plans to create a genome
database whose basic map he would make available for free — as the NIH
planned — but to charge anyone who wanted the data processed or analyzed.
In 2000, Venter delivered on his promise, finishing
just ahead of Collins, but a government official who knew both men, hoping to
quiet the feuding, brokered a truce between the groups, which included the
sweetener of a joint announcement at the White House in 2000. President Bill
Clinton lauded the completed genome as "the most important, most wondrous
map ever produced."
The high times did not last long. Back at Celera,
the competing interests of a free public database and a corporation's
stockholders proved hard to reconcile, and just two years after the White House
ceremony, Venter was fired by the board. For solace, he decided to get away.
Still a sailing enthusiast, he hit on a grand plan to mimic the journey of the
H.M.S. Challenger, the vessel that in the 1870s
conducted the first global mission to sample life from the oceans of the world.
Venter would circumnavigate the globe with a crew of scientists and sailors and
every 200 miles (320 km) would dip canisters into the ocean at various depths,
filter whatever life-forms floated in — mostly microscopic — and
send them back to his newly created lab, the J. Craig Venter Institute in
Rockville. Over 2½ years, the journey yielded 6 million new genes and
400 new microbial species. "Most people thought the ocean was a homogenous
soup," Venter says. "But 85% of the species we found were
unique."
As he shuttled between his ship and his lab, Venter
was overseeing another, equally grand and potentially revolutionary science
project: creating life in the lab. Among the organisms he and his team
sequenced in the years leading up to the human-genome work was Mycoplasma genitalium, an unlovely bacterium whose
preferred target on the animals it infects is evident by its name. That
organism, which the team sequenced in 1995, has one of the smallest known
chromosomes of any self-replicating life-form — just 485 genes. What,
Venter wondered back then, was the minimum genome an organism needed to survive
and reproduce? If you could figure that out, you could determine the basic DNA
chassis of all living things and then use it to design your own souped-up or
dressed-down versions of life.
A decade ago, the only way to establish whether the
microbe needed a gene was to knock each of the 485 out, one by one and then in
combinations, and see if the bug survived. By 2002, however, advances in both
genetic understanding and gene-handling technology had leaped forward. Instead
of having to deconstruct Mycoplasma
genitalium,
Venter's team could build it from scratch. This meant that whereas once they
had to reverse-engineer the organism and see when it quit working, they could
take the more elegant approach of assembling it from off-the-shelf nucleotides
and seeing when it switched on — essentially building life.
But elegant does not mean easy. DNA's nucleotides
are strung together like beads on a string, but because it adopts a crystalline
structure, that string behaves more like glass. "Even doing normal things
like pipetting the pieces would shatter it," says Venter. And although
tiny in the microbe world, the mycoplasma's genome still required more than
580,000 nucleotides to assemble.
So Venter decided to start small, with one or two
genes, and work his way up by splicing together longer and longer pieces of
DNA. That very act of sticking them together proved to be a challenge, since
the strands often fall apart. The answer was to design a section of Velcro-like
DNA at the ends of each fragment. Since adenine sticks only to thymine and
cytosine only to guanine, all the team had to do was end each strand with a
nucleotide that would adhere to the one that began the next.
Such painstaking cut, study and paste eventually
did the job. Not only did Venter's team members succeed in building their own
mycoplasma at their own lab benches, they also took the opportunity to rewrite
its genetic score. First, they introduced a mutation that would prevent it from
causing disease. Then they branded it with a series of watermarks that would
distinguish it as a product of their lab. Using a code built around selected
genes, they spelled out five words that Venter coyly refuses to reveal, saying
only that any molecular-biology study can suss them out and promising that
there are no obscenities. The next step, which could happen in a matter of
months, will be to insert the gene into a cell and see if it indeed stirs to
life. "This team is betting its reputation that that will happen in
2008," Venter says.
Not everyone believes he will succeed — or if
he does, that it will matter much. Corporate giants like DuPont already put
synthetic biology to industrial use. In the company's Loudon, Tenn., plant, for
example, billions of E.
coli bacteria
stew inside massive tanks. The bacteria's genomes contain 23 alterations that
instruct it to digest sugar from corn and produce propane diol, a polyester
used in carpets, clothing and plastics. The hard-working bugs churn out 100
million lbs. (45 million kg) of the stuff each day, and all it took was a
little tinkering with their genomes, not the construction of a new one.
"In terms of whether I can think of anything I can only do with a whole
synthetic chromosome that I can't do now, the short answer is no," says
John Pierce, vice president of technology at DuPont Applied BioSciences.
Collins, Venter's once and perhaps future rival,
whose group at the NIH is also working on creating synthetic genes, echoes that
doubt. "Suppose I have a pile of dirt in my backyard and I want to move
it," he says. "I could spend months building the components, but I
already have a lawn tractor, so what I need to do is add a front loader. Why
not take the shortest path?"
Venter agrees that this all makes sense — but
only if you accept a limited view of the science. He is not alone. "We are
starting to turn the corner," says Jay Keasling, a bioengineer at the
University of California, Berkeley. "The technologies are starting to be
put in place, and it's crazy to keep doing biology the way we are doing
it."
Still,
after spending his career trying to digitize, quantify and standardize biology,
even Venter recognizes that there may be some aspects of life that simply can't
be understood without a nod to what he calls the "mystery and
majesty" of the cell. Well before he became involved constructing
artificial life, he christened his sailboat with a name that may reveal as much
about that awareness as about what he is trying to accomplish: he called it Sorcerer.