"Nothing new has to be invented. We just have to combine [genes] in a way that nature has not done before. We're speeding up evolution by billions of years," Venter told an energy conference on October 18 at the New America Foundation in Washington, D.C. "It's hard to imagine a part of humanity not substantially impacted." _SciAm
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| La Jolla Algal Growth Facility Synthetic Genomics |
Given algae's multibillion-year track record with photosynthesis and genetic experimentation Agradis's purpose is to turn that genetic cornucopia into improvements in agricultural crops, whether corn or canola—as well as use algae as a model for testing various new genetic combinations. A similar partnership between Monsanto and algae company Sapphire Energy will "use our algae platform that we developed to mine for genes that can transfer into their core agricultural products," explained Tim Zenk, Sapphire's vice president for corporate affairs in a prior interview with Scientific American. "When you do genetic screening in algae, you get hundreds of millions of traits in the screen and that accelerates the chances of finding something that can be transferred."
If that's not enough, Venter sees a role for synthetic biology in food beyond crops and livestock—specifically the growing hunger for meat around the world. "It takes 10 kilograms of grain to produce one kilogram of beef, 15 liters of water to get one kilogram of beef, and those cows produce a lot of methane," another potent greenhouse gas, Venter observed. "Why not get rid of the cows?" The replacement: meat grown in a test tube from microbes thanks to synthetic biology.
...look at the potential output from algae, and it's one to two orders of magnitude better than the best agricultural system. If we were trying to make liquid transportation fuels to replace all transportation fuels in the U.S. and you try and do that from corn it would take a facility three times the size of the continental U.S. If you try to do it from algae, it's a facility roughly the size of the state of Maryland. One is doable and the other's just absurd, but we don't have an algae lobby.
...We need three major ingredients: CO2, sunlight and seawater, aside from having the facility and refinery to convert all those things. We're looking at sites around the world that have the major ingredients. It helps if it's near a major refinery because that limits shipping distances. Moving billions of gallons of hydrocarbons around is expensive. But refineries are also a good source of concentrated CO2.
It's the integration of the entire process. [Synthetic Genomics] is not trying to become a fuel company. You won't see SGI gas stations out there, we're leaving that to ExxonMobil. We will help them shift the source of hydrocarbons to material recycled from CO2. _SciAm
Venter takes the "food vs. fuels" debate and turns it on its head: Why not make both, using the same type of platform?
Most journalists, energy analysts, policy makers, and academics have no concept of the biological potential of the planet Earth. Having fed their intuitions and imaginations on a steady diet of scarcity, they are at a loss in the larger world of actual possibilities.
But don't let the shortcomings of your overlords and masters in the media, government, and academia keep you from understanding the world as it is and as it could be. There is a whole new level of thought and existence coming. We simply need to survive until it gets here.
In the meantime: Hope for the best, prepare for the worst.
Craig Venter’s Bugs Might Save the World
In the menagerie of Craig Venter’s imagination, tiny bugs
will save the world. They will be custom bugs, designer bugs — bugs that only
Venter can create. He will mix them up in his private laboratory from bits and
pieces of DNA, and then he will release them into the air and the water, into
smokestacks and oil spills, hospitals and factories and your house.
Each of the bugs will have a
mission. Some will be designed to devour things, like pollution. Others will
generate food and fuel. There will be bugs to fight global warming, bugs to
clean up toxic waste, bugs to manufacture medicine and diagnose disease, and
they will all be driven to complete these tasks by the very fibers of their
synthetic DNA.
Right now,
Venter is thinking of a bug. He is thinking of a bug that could swim in a pond
and soak up sunlight and urinate automotive fuel. He is thinking of a bug that
could live in a factory and gobble exhaust and fart fresh air. He may not
appear to be thinking about these things. He may not appear to be thinking at
all. He may appear to be riding his German motorcycle through the California
mountains, cutting the inside corners so close that his kneepads skim the
pavement. This is how Venter thinks. He also enjoys thinking on the deck of his
95-foot sailboat, halfway across the Pacific Ocean in a gale, and while
snorkeling naked in the Sargasso Sea surrounded by Portuguese men-of-war. When
Venter was growing up in San Francisco, he would ride his bicycle to the
airport and race passenger jets down the runway. As a Navy corpsman in Vietnam,
he spent leisurely afternoons tootling up the coast in a dinghy, under a hail
of enemy fire.
What’s
strange about Venter is that this works — that the clarity he finds when he is
hurtling through the sea and the sky, the dreams he summons, the fantasies he
concocts in his most unhinged moments of excess actually have a way of coming
true. He dreamed of mapping the human genome, and he did it. He dreamed of
creating a synthetic organism, and he made it. In 2003, he scrawled a line
across a map of the world, hopped on his boat with a small team and sailed
around the planet in search of new forms of life. By the time they returned,
two years later, they had discovered more species than anyone in history.
And last
fall, Venter was back in motion at the end of another journey. He was crouched
atop his touring bike in the final stretch of a weeklong sprint through the
American Southwest, with a handful of friends trailing behind as he whipped
through the mountain foothills in a blur. In the days to come, he would return
to his office to piece together a design for the first of his custom bugs. But
as he streaked back toward the lab, he made a final detour, swerving into the
parking lot of a bakery to grab a slice of fresh pie. Venter hopped off his
motorcycle, lifted his helmet and grinned into the California sun. “We hit
110!” he said. “Now I feel like I can go back to work.”
A Sci-Fi Fantasy Made Possible?
The prospect
of artificial life is so outlandish that we rarely even mean the words. Most of
the time we mean clever androids or computers that talk. Even the pages of
science fiction typically stop short: in the popular dystopian narrative,
robots are always taking over, erecting armies, firing death rays and sometimes
even learning to love, but underneath their replicant skin, they tend to be
made of iron ore. From the Terminator to the Matrix to the awakening of HAL,
what preoccupies the modern imagination is the sentient evolution of machines,
not artificial life itself.
But inside
the laboratories of biotechnology, a more literal possibility is taking hold:
What if machines really were alive? To some extent, this is already happening.
Brewers and bakers have long relied on the diligence of yeast to make beer and
bread, and in medical manufacturing, it has become routine to harness organisms
like Penicillium to generate drugs. At DuPont, engineers are using modified E.
coli to produce polyester for carpet, and the pharmaceutical giant Sanofi is
using yeast injected with strips of synthetic DNA to manufacture medicine. But
the possibility of designing a new organism, entirely from synthetic DNA, to
produce whatever compounds we want, would mark a radical leap forward in
biotechnology and a paradigm shift in manufacturing.
The appeal
of biological machinery is manifold. For one thing, because organisms
reproduce, they can generate not only their target product but also more
factories to do the same. Then too, microbes use novel fuel. Chances are,
unless you’ve slipped off the grid, virtually every machine you own, from your
iPhone to your toaster oven, depends on burning fossil fuels to work. Even if
you have slipped off the grid, manufacturing those devices required massive
carbon emissions. This is not necessarily the case for biomachinery. A custom
organism could produce the same plastic or metal as an industrial plant while
feeding on the compounds in pollution or the energy of the sun.
Then there
is the matter of yield. Over the last 60 years, agricultural production has
boomed in large part through plant modification, chemical additives and
irrigation. But as the world population continues to soar, adding nearly a
billion people over the past decade, major aquifers are giving out, and
agriculture may not be able to keep pace with the world’s needs. If a strain of
algae could secrete high yields of protein, using less land and water than
traditional crops, it may represent the best hope to feed a booming planet.
Finally, the
rise of biomachinery could usher in an era of spot production. “Biology is the
ultimate distributed manufacturing platform,” Drew Endy, an assistant professor
at Stanford University, told me recently. Endy is trained as an engineer but
has become a leading proponent of synthetic biology. He sketched a picture of
what “distributed manufacturing” by microbes might look like: say a perfume
company could design a bacterium to produce an appealing aroma; “rather than
running this in a large-scale fermenter, they would upload the DNA sequences
onto the future equivalent of iTunes,” he said. “People all over the world
could then pay a fee to download the information.” Then, Endy explained,
customers could simply synthesize the bugs at home and grow them on their skin.
“They could transform epidermal ecosystems to have living production of scents
and fragrances,” he said. “Living perfume!”
Whether all
this could really happen — or should — depends on whom you ask. The challenge
of building a synthetic bacterium from raw DNA is as byzantine as it probably
sounds. It means taking four bottles of chemicals — the adenine, thymine,
cytosine and guanine that make up DNA — and linking them into a daisy chain at
least half a million units long, then inserting that molecule into a host cell
and hoping it will spring to life as an organism that not only grows and
reproduces but also manufactures exactly what its designer intended. (A line
about hubris, Icarus and Frankenstein typically follows here.) Since the late
1990s, laboratories around the world have been experimenting with synthetic
biology, but many scientists believe that it will take decades to see major
change. “We’re still really early,” Endy said. “Or to say it differently, we’re
still really bad.”
Venter
disagrees. The future, he says, may be sooner than we think. Much of the
groundwork is already done. In 2003, Venter’s lab used a new method to piece
together a strip of DNA that was identical to a natural virus, then watched it
spring to action and attack a cell. In 2008, they built a longer genome,
replicating the DNA of a whole bacterium, and in 2010 they announced that they
brought a bacterium with synthetic DNA to life. That organism was still mostly
a copy of one in nature, but as a flourish, Venter and his team wrote their
names into its DNA, along with quotes from James Joyce and J. Robert
Oppenheimer and even secret messages. As the bacteria reproduced, the quotes
and messages and names remained in the colony’s DNA.
In theory,
this leaves just one step between Venter and a custom species. If he can write
something more useful than his name into the synthetic DNA of an organism,
changing its genetic function in some deliberate way, he will have crossed the
threshold to designer life.
Unless he
already has.
To Seek Out
New Life
In person,
Venter is a sturdy 65-year-old with a ring of gray hair, a deep tan, perpetual
stubble and crow’s feet that dance around his eyes. When he caught the world’s
attention, in 1998, he was leading a private company, Celera Genomics, in a
race against the government’s Human Genome Project to complete the first map of
human DNA. That race ended in June 2000, when Venter and the director of the
government program, Francis S. Collins, shared a lectern at the White House to
declare a tie. Neither man particularly wanted to be there, and each believed
his own map was superior, but in the interest of science and at the urging of
President Bill Clinton, both grudgingly relented.
In the
decade since, Collins has gone on to lead the National Institutes of Health,
while Venter has mostly drifted away from the capital, where his challenge to
the N.I.H. did not particularly kindle friendships. Though his nonprofit
organization, the J. Craig Venter Institute, maintains a base in Rockville,
Md., Venter spends most of his time in California, where he grew up and is
currently building a $35 million laboratory on the campus of his alma mater,
the University of California, San Diego. The building is designed to be
carbon-neutral, with solar power and rainwater catchment, nestled on 1.75 acres
overlooking the Pacific Ocean; less than two miles away, Venter has renovated a
$6 million home with sweeping curvilinear architecture, which is perched on a
hilltop of breathtaking views.
In contrast
to his lavish home and office, Venter’s commercial enterprise makes a rather
humdrum sight. Tucked into a suburban office park, a few miles north of his
home, the headquarters of Synthetic Genomics Inc. is a leased two-story box
plopped beside a highway. Yet in some ways, the building is the more exciting
locus of Venter’s work. Though its grounds and mission are less expansive than
the institute, S.G.I. is where Venter’s breakthroughs will be refined and
marketed whenever they have real-world potential.
One day
recently, I visited the S.G.I. building to have a look around. I found Venter
in his office on the second floor, watching a video on his iPad of a race car
he nearly crashed last fall at 120 miles per hour. We watched that footage for
a while, then another video from a motorcycle trip, and Venter said he had
recently flown a helicopter for the first time.
For a
scientist, Venter spends little time in the lab, but it would be a mistake to
confuse this with a lack of focus. All critical decisions at his company and
his institute ultimately ascend to Venter, who monitors the work of about 500
scientists every day, imparting various kinds of guidance and direction, even
if he has to be patched in by satellite. After a few minutes in his office, we
were joined by Gerardo Toledo, the company’s senior director of microbial
discovery. Toledo is lean and angular with hazel skin and amused eyes. In his
spare time, he competes in Ironman triathlons and chases Venter on dirt bikes
through the California hills. He suggested we visit the labs on the first
floor, and as we descended a flight of stairs, he explained that part of the
company’s mission is to find, usually in nature, the genetic components that
might be useful in synthetic life. For Toledo, this meant scouring the planet
for intriguing microbes with uncommon genes. “The idea is to try to understand
the extent of microbe diversity,” he said.
Earth is a
microbial planet. Micro-organisms make up about half the planet’s biomass, and
without them, large animals could not survive. Because they are so small, so
abundant and so differentiated, they also contain most of the earth’s genetic
diversity. One of the most important discoveries to emerge from the
human-genome projects, both at the N.I.H. and at Celera, was the revelation
that humans have relatively few genes. Before the human-genome map, most
scientists assumed that there were about 100,000 genes in our DNA. In fact,
there are about 20,000, or fewer than those of a typical grape. That discovery
was one reason that Venter began trolling the oceans in search of new forms of
microbial life. Over the past nine years, he and his crew at the institute have
collected water samples from thousands of locations, sending them to his lab to
be screened and genetically mapped. In total, they have discovered hundreds of
thousands of new species (the number is imprecise because the term “species”
can be muddy) and about 60 million new genes. There were genes to help
organisms survive in chemically noxious water, genes that led to the production
of hydrogen and genes that trigger the manufacture of antibiotics, to name just
a few. How Venter might incorporate those genes into a designer species one day
remains to be seen. But as we walked down the hallways of S.G.I., Toledo
explained that the company’s quest to discover microbes is not limited to the
oceans.
He stopped
by a framed photograph of a hand filled with oily dirt. “That picture is in
Malaysia,” he said. “Oil palm is one of the highest oil-producing crops, but
we’re trying to see how that can be enhanced. First by understanding its genome
and how it can be better. And second to understand what is the ecosystem of all
the microbes that fit with it and help it, for example, to assimilate nutrients
and prevent diseases.”
We continued
past a series of glassed-in labs, where scientists hunched over flasks filled
with green fluid, and Toledo explained that some of the earliest organisms that
S.G.I. plans to modify will be strains of algae. That’s because algae, even in
a natural state, offer an enticing combination of features: they
photosynthesize, capturing energy from the sun; they can absorb carbon dioxide,
removing a greenhouse gas from the environment; and they produce oil to store
energy, which could be cultivated into food or fuel. For decades, scientists
have been tinkering with algae to make them more productive and efficient, but
success has been elusive. Venter is convinced that the problem will never be
solved by tinkering alone. “Algae didn’t evolve to produce tens of thousands of
gallons of oil per acre,” he said. “So we have to force the evolution.” For
now, S.G.I. is studying natural strains, but the goal is not to select any one
of them; it’s to combine the best qualities from each. “We’re collecting all
this knowledge,” Venter said, “and then we have to put it all together and
design something that hasn’t existed before.”
Yellow Algae
Is Just the Beginning
If the
promise of synthetic biology is expansive, the potential for catastrophe is
plain. The greater the reach of biomachinery, the more urgent the need to
understand its risks. As every hobby gardener knows, the introduction of an
outside species can quickly devastate an ecosystem. From the kudzu vine to the
gypsy moth to the Burmese python surge in the Everglades, we often discover the
impact of a species only when it’s too late. Looking to the dawn of a
biomachine age, many environmental groups worry that synthetic bugs could
become the ultimate invasive species. “It’s almost inevitable that there will
be some level of escape,” Helen Wallace, the executive director of the watchdog
group GeneWatch, told me. “The question is: Will those organisms survive and
reproduce? I don’t think anyone knows.”
The
reassurance offered by Venter and other proponents may not be convincing to
everyone. A synthetic bug, they say, has little chance of surviving in the
competitive natural ecosystem, and anyway, it could be designed to die without
chemical support. In 2010, President Obama ordered his bioethics commission to
examine the implications of Venter’s work, and the commission found “limited
risks.” Still, a person can be forgiven for recalling the moment in “Jurassic Park”
when Dr. Ian Malcolm smirks at a team of genetic engineers and warns them,
“Life finds a way.”
At the
S.G.I. office, Venter suggested we step outside to visit the greenhouse, where
the most promising strains of algae were already growing in open air. We met up
with Jim Flatt, the chief technology officer, and followed a narrow path
through woods until we emerged at a massive glass facility. We stepped into a
staging area filled with hoses and flasks, beside a laboratory stacked with
computers and machines. Through a wall of windows, we could see into the main
room, where algae was growing in vats under bright sunlight. Each was affixed
with a small plastic tube that piped in shots of carbon dioxide. “We use
bottled CO2,” Flatt said, “but in an industrial facility, we would use an
industrial source. That could be captured from a power plant. It could be
captured from a geothermal resource. It could be captured from a cement plant.
Or it could be captured from a refinery.”
As Flatt and
I poked around, Venter wandered over to chat with a scientist monitoring the
algae on a computer, then he stooped by a benchtop shaker with four conical
flasks of algae. Three of the samples were deep green; the fourth was brilliant
yellow. Venter explained that the yellow algae was the first strain engineered
by S.G.I. to include a portion of synthetic DNA. In fact, the color of the
algae was the
synthetic modification. Changing the pigment of algae may seem trivial, but it
represents a critical factor for commercial success. One challenge to growing
algae at scale is that a successful strain, by definition, tends to reproduce
quickly and turn dark green. This blocks sunlight to the algae below, and
requires more-frequent care and harvest. A strain engineered to a lighter color
could allow the organisms to grow more densely without obstructing essential
light. The yellow algae in Venter’s greenhouse was just the first to include a
synthetic adjustment, but it would be followed by a series of similar changes.
Even as the company modified pigment, it could also experiment with synthetic
alterations to boost the production of oil and even force the algae to secrete
that oil into surrounding water. “Their objective is to grow and survive,”
Flatt said, “not necessarily to produce things for us. So that’s where the
engineering comes into place. We say, ‘We’re going to force you to give it up.’
”
We stepped
into the main room of the greenhouse and walked between huge tubs filled with
algae. The next step, Venter said, was to move the algae outside into large
ponds. “None of this can be done at the lab scale and have any meaning,” he
said. “People take stuff in a little test tube and multiply it by several
million or something, and claim they have these yields. But nothing works the
same in a giant facility. Most things fail when you take them outside.” To that
end, S.G.I. had recently purchased an 81-acre parcel of land about 150 miles
away, right beside the Salton Sea, where it can begin to cultivate its most
successful strains. The site, he added, also sits near a geothermal power
plant, which doesn’t burn fossil fuels but does release carbon dioxide from
underground. Venter was already in discussion with the plant’s owner to divert
its carbon emissions into the algae. It was possible that, within months, his
algae would be turning pollution into food and oil.
We came to
the last tub in the room, filled with the telltale yellow: a culture of
synthetically modified organisms growing in the open air. They were the color
of lemon-lime sports drink and, in the bright sunlight, had a radiant glow. It
was like peering into a bathtub filled with the juice of 1,000 light sticks.
Venter gazed
happily at the algae. “The photosynthetic process has been working for about
three and a half billion years,” he said. “This is the first major change.”
The Art of
Creating Life
Venter’s
house above La Jolla is a swirl of clean, modern lines, with a sprawling
kitchen at one end and hideaway nooks all around. There is a wine room that
doubles as a walk-in humidor, an outdoor pool that seems to reach into the
ocean and, in the garage below, an electric Tesla Roadster that pops from 0-60
in less than four seconds.
Two weeks
ago, Venter met me at the door in jeans and a sweatshirt, and we sat down to
chat on a brown leather sofa overlooking the Pacific. Nearby, a six-foot
sculpture of a humpback whale leapt from a knotty burl of hardwood. Venter took
a sip of a drink and leaned back with a sigh. “It’s too bad we have to do an
interview,” he said.
Over the
last decade, I have followed Venter’s work closely, which often meant following
Venter himself on strange and harrowing journeys. Through the years, I’ve
sailed with him, flown with him, dived with him and raced across the desert on
motorcycles with him, often against my better judgment and at speeds I prefer
not to recall. Many of Venter’s peers in science find his reckless hobbies and
temperament obnoxious. No story about his work fails to mention the legion of
biologists who despise him or the legendary berth of his ego. This hostility
comes partly from his entrepreneurial approach to science. After he challenged
the Human Genome Project in the 1990s, he was accused by the eminent James D.
Watson, who was a co-discoverer of the structure of DNA in 1953, of trying to
“own the human genome the way Hitler wanted to own the world.” But to the
colleagues who have worked with Venter for decades, his reputation as an
egotist can be puzzling. At a dinner table or a cocktail party, Venter is far
more likely to brag about his skill at dominoes than any professional
accomplishment, and he quickly becomes awkward and irritable when a crowd of
admirers surrounds him at a reception.
This is not
to say that Venter is modest. He is not. But what defines him is less the show
of ego than its immovable mass. When Venter tackles a scientific problem, he
tends to ignore just about everyone else working on it and to dismiss whatever
approach they are taking — and shoot for the fastest way to beat them to the
finish line. Speed is Venter’s muse and siren. The same manic energy that
propels him into race cars and speedboats animates his professional life,
leaving behind as many enemies as breakthroughs.
When Venter
announced, in 2010, that he brought to life the first bacteria with entirely synthetic
DNA, he was met with equal parts ceremony and dismissal. Many scientists hailed
the achievement as a watershed moment in human history. “The ability to design
and create new forms of life,” the prominent physicist Freeman Dyson
proclaimed, “marks a turning point in the history of our species and our
planet.” Yet others insisted that, because the DNA was modeled on a natural
organism and was inserted into a natural cell, the claims of “synthetic life”
were overblown. “He has not created life, only mimicked it,” the Nobel laureate
David Baltimore insisted.
When I asked
the bioethicist Arthur Caplan about these extremes of adulation and
indifference, Caplan did not hesitate. Though he has criticized the Obama
ethics commission for underestimating the risk of synthetic biology, he praised
Venter himself as revolutionary. “He’s about three major innovations back from
the Nobel Prize he should have gotten already,” Caplan said. “When you have the
kinds of breakthroughs and insights that he’s had, it’s inexcusable that you
wouldn’t reward that kind of work with the Nobel — and it has to be battles
over personality and character, more about him than anything else.”
When I asked
Venter about his reception among scientists, he was uncharacteristically
nonchalant. “Some senior biologists, who in theory should know better than
anybody else, keep talking about the importance of the cell,” he shrugged.
“They argue: ‘Well, the cell contributed something. It can’t just be the DNA.’
That’s like saying God contributed something. The trouble for these people, it is just the DNA. You have to have the
cell there to read it, but we’re 100 percent DNA software systems.” He pointed
out that when his lab inserted the DNA of one organism into the cell body of
another, the cell became a different organism.
Venter was
quick to acknowledge that he still hadn’t created a microbe that serves an
innovative purpose. “Sorry we didn’t design some new creature that never
existed before as our opening gambit,” he said with a laugh. “What we published
was the proof of concept. It’s like: ‘Gee, it would be really nice if the
Wright brothers made a supersonic jet! Because that would have been much more
useful!’ ”
This seemed
like a good opportunity to ask Venter whether he had come any closer to that
goal — whether, in addition to the algae modification at S.G.I., his team at
the institute was working on another whole-genome assembly. Since the May 2010
announcement, Venter has been comparatively quiet, but it would be unlike him
not to silence his critics. I asked him how far he had come over the last two
years.
Venter was
quiet for a long time. He nodded his head, as if making some calculation, then
he said: “We’re doing a grand experiment. We’re trying to design the first cell
from scratch.” He suggested we head into town for dinner with his two closest
partners in synthetic biology, to discuss the leap they were about to take.
“It’s a
little bit of a black art,” he said.
Starting
From Scratch
Venter’s
closest collaborators in the lab are Hamilton O. Smith and Clyde A. Hutchison
III, each vaunted in his own right. Smith shared a Nobel Prize in 1978 for his
work on restriction enzymes, and Hutchison’s long pedigree in genetic mapping
began in 1975, when he helped the pioneer Frederick Sanger sequence the first
genome of a virus, for which Sanger shared his second Nobel in 1980. At 80,
Smith is tall and genial, with hearing aides and a slight stoop; Hutchison is
10 years younger, with a boyish flop of hair in his eyes and an air of
perpetual worry. Together they enjoy a crotchety rapport that delights Venter
endlessly. “They’re like the two old guys in the balcony on the Muppets,” he
said. “But they’ve both reached a point in their careers where they can afford
to take risks they never would’ve taken 20 years ago — it’s like having the
oldest, smartest postdocs in the world.”
As we
settled around a dinner table in downtown La Jolla, a waitress delivered foie
gras from the chef, setting a plate between Smith and Hutchison, who
immediately lurched forward to examine it.
“What’s
that?” Hutchison asked.
“Goose
liver,” Venter said.
“Oh,”
Hutchison said. “I like liver.”
Smith
frowned. “It’s glycogen,” he observed.
“Yeah,
glycogen,” Hutchison said. “Glycogen is almost like carbohydrate.”
“It is
carbohydrate,” Smith said.
Hutchison
nodded. “You shouldn’t eat a lot of liver if you’re on a low-carbohydrate
diet,” he said.
Then they
both attacked it with their forks.
Venter and
Smith first met at a conference in Spain in 1993, when Smith approached Venter
after a lecture. Venter was just 46, but he was already preceded by
controversy. He had recently left the N.I.H. to map gene fragments in his own
lab and was licensing the results to a private company, which raised alarms
about privatizing life. After his lecture, Venter recalled over dinner: “Ham
came up, and his first statement was, ‘Where are your horns?’ And I said,
‘What?’ He goes: ‘You’re supposed to be the devil. Where are your horns?”’
Smith let
out a guffaw. “Well,” he said, “he had inflamed a lot of the academics!”
Within
months, Smith had joined Venter’s nonprofit, and in 1995, they completed the
first genetic sequence of a bacterium, expanding on the work at Sanger’s lab
two decades earlier. As a follow-up, they reached out to Hutchison, who was
studying another bacterium at the University of North Carolina, and offered to
map its genome for him. Two days later, Hutchison mailed a vial of DNA to
Venter and Smith. “If that was to happen now,” Smith said, “it would have been
three months and a bunch of lawyers.” Hutchison shrugged. “They made me an
offer I couldn’t refuse,” he said.
Venter and
Smith worked quickly. Using the method they developed for the first bacterium,
they completed a genetic map for Hutchison in three months. But as all three
men studied the second genome, which was only a third the size of the first,
they began to wonder how much smaller a genome could get. What was the fewest
number of genes that could sustain a free-living organism?
“I think any
good inquisitive scientists in our position would have asked those same
questions,” Venter said. “But how do you get there? The limits of molecular
biology don’t give you enough tools.” Working together, they began to winnow
down the genome by inserting snippets of DNA that interrupt gene function, on
the theory that any gene that could be disrupted without killing the cell must
not be essential. In 1999, they published a
paper in the journal Science describing
“1,354 distinct sites of insertion that were not lethal,” and speculating that
more than a quarter of the bacterium’s DNA might be superfluous. But there was
still no way to be sure — no way to knock out all the nonessential genes at
once and see if the organism survived. In the final sentence of their 1999
paper, they proposed a novel solution: “One way to identify a minimal gene set
for self-replicating life would be to create and test a cassette-based
artificial chromosome.”
Create a
chromosome. This was still far beyond the reach of science, and in hindsight,
marks one of the earliest references to synthetic biology as we know it today.
But by the time the paper appeared, in December 1999, Venter and Smith had
turned their attention to the human genome project at Celera, which would
consume their attention for three years. Looking back, Venter says, “the human
genome was a detour.” As soon as the Celera map was complete, they returned to
the synthetic project. In 2003, they developed a new method to assemble fragments
of DNA and built their first virus; when that worked, they scaled up to
bacteria, ultimately writing their names and quotes in its code, but the real
prize was, and remains, to build the stripped-down organism they first proposed
in 1999 — a free-living bacterium with less DNA than any in nature. It would
not only test their theories about essential genes but would also provide an
ideal framework for future organisms. Once they had the minimal genome, they
could use it as a chassis to attach other genes: maybe a component to feed on
sulfur or a module to generate hydrogen or both.
“That’s why
it’s so valuable,” Venter said. “If we’re going to design really complex
biological machinery, it has to have these fundamentals.”
But the
minimal genome may raise an even more fundamental question, one that touches on
the nature of innovation itself. When we think about technological change, most
of us view progress through a narrow lens: we imagine new gadgets and devices
that will streamline our modern lives, bringing the most technically advanced
civilization in history to new heights of technical advancement. Yet the
innovations that really matter in the long term may not have much to do with
advancement at all. They may have less to do with improving our own standards
of living than with extending those standards around the world. As the global
population continues to rise, the greatest technological challenge we face may
be to avoid leaving large tracts of the earth behind. The synthetic biology
that Venter proposes, using a minimal genome as a platform to make advances in
food, fuel, medicine and environmental health, could backfire into a biological
calamity, but it could also offer the most transformative approach to a medley
of problems with no apparent solution.
“Agriculture
as we know it needs to disappear,” Venter said. “We can design better and
healthier proteins than we get from nature.” By this, he didn’t mean growing
apples in a Petri dish. He meant producing bulk commodities like corn, soy and
wheat, that we use in processed products like tofu and cereal. “If you can
produce the key ingredients with 10 or 100 times the efficiency,” he said,
“that’s a better use of land and resources.”
As we
enjoyed a decidedly real dinner of lobster and fresh vegetables, Venter
explained that he was just days away from trying the first synthesis of a
minimal genome. For two years, even as the team at S.G.I. has been working to
cultivate algae, the institute has been poring over research to design a new
genome. Eventually, the process grew tedious. “Up to three weeks ago,” Smith
said, “we were on a very gradual course, and we were looking at a long time to
get the thing completed. So Craig says, ‘Damn it, let’s make a guess, and
synthesize the darn thing based on what we know, and maybe it’ll work!’ ”
Venter
laughed. “I call it the Hail Mary Genome.”
Just days
earlier, he said, they completed two designs — one led by the office in
Maryland, the other by Hutchison’s team in California. In the days ahead, they
would begin assembling both. If either worked, it would represent the smallest
genetic code of any free-living creature on earth, one that would be impossible
to dismiss as a copy. Even as we sat at the dinner table, it was possible that
Venter, Smith and Hutchison already had it; that somewhere in their lab, they
held the design for the first custom organism made from synthetic DNA.
Hutchison
said he was encouraged that the two drafts overlapped. “There are about 30
genes different between the two,” he said.
Smith grinned.
“I’m gonna go with Clyde’s draft,” he said.
“Well, mine
is smaller,” Hutchison said. “I think maybe we’re going to pick some of the
pieces from one design and some from the other.”
“We’re also
trying to re-engineer the genome in a much more logical fashion,” Venter said.
“We’re doing it in the form that, if there was a God, this is how he would have
done it.”
“Evolution
is very messy,” Smith added.
“We’re
trying to clean it up,” Venter said.
“What’s the
time horizon?” I asked.
“I have some
ideas that, within the year — ” Hutchison began.
Venter shook
his head. “Before the end of summer,” he insisted.
Hutchison
chuckled.
“It might be
the end of summer,” Smith said.
“It’s going
to be the first rationally designed genome,” Venter said.
“Actually,
my preference would be not to do the fine needlework,” Smith said. “I would
just take the very largest 30 or 40 clusters and remove those.”
“We can do
that,” Hutchison said.
“Let’s do
it,” Smith said. “The hell with the rest of them.”
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