For more than a decade, synthetic biologists have promised to
revolutionize the way we produce fuels, chemicals, and pharmaceuticals.
It turns out, however, that programming new life forms is not so easy.
Now some of these same scientists are turning back to nature for
inspiration.
George Church is an imposing figure—over six feet tall, with a large,
rectangular face bordered by a brown and silver nest of beard and
topped by a thick mop of hair. Since the mid-1980s Church has played a
pioneering role in the development of DNA sequencing, helping—among his
other achievements—to organize the Human Genome Project. To reach his
office at Harvard Medical School, one enters a laboratory humming with
many of the more than 50 graduate students and postdoctoral fellows over
whom Church rules as director of the school's Center for Computational
Genetics. Passing through an anteroom of assistants, I find Church at
his desk, his back to me, hunched over a notebook computer that makes
him look even larger than he is.
Church looms especially large these days because of his role as
one of the most influential figures in synthetic biology, an ambitious
and radical approach to genetic engineering that attempts to create
novel biological entities—everything from enzymes to cells and
microbes—by combining the expertise of biology and engineering. He and
his lab are credited with many of the advances in harnessing and
synthesizing DNA that now help other researchers modify microörganisms
to create new fuels and medical treatments. When I ask Church to
describe what tangible impact synthetic biology will have on everyday
life, he leans back in his chair, clasps his hands behind his head, and
says, "It will change everything. People are going to live healthier a
lot longer because of synthetic biology. You can count on it."
Such grandiosity is not uncommon among the practitioners of
synthetic biology. Ever since Church and a few other researchers began
to combine biology and engineering a dozen years ago, they have promised
it would "change everything." And no wonder. The very idea of synthetic
biology is to purposefully engineer the DNA of living things so that
they can accomplish tasks they don't carry out in nature. Although
genetic engineering has been going on since the 1970s, a rapid drop in
the cost of decoding and synthesizing DNA, combined with a vast increase
in computer power and an influx into biology labs of engineers and
computer scientists, has led to a fundamental change in how thoroughly
and swiftly an organism's genetics can be modified. Church says the
technology will eventually lead to all manner of breakthroughs: we will
be able to replace diseased tissues and organs by reprogramming cells to
make new ones, create novel microbes that efficiently secrete fuels and
other chemicals, and fashion DNA switches that turn on the right genes
inside a patient's cells to prevent arteries from getting clogged.
Even though some of these applications are years from reality,
Church has a way of tossing off such predictions matter-of-factly. And
it's easy to see why he's optimistic. The cost of both decoding DNA and
synthesizing new DNA strands, he has calculated, is falling about five
times as fast as computing power is increasing under Moore's Law, which
has accurately predicted that chip performance will double roughly every
two years. Those involved in synthetic biology, who often favor
computer analogies, might say it's becoming exponentially easier to read
from, and write into, the source code of life. These underlying
technology trends, says Church, are leading to an explosion in
experimentation of a sort that would have been inconceivable only a few
years ago.
Up to now, it's proved stubbornly difficult to turn synthetic
biology into a practical technology that can create products like cheap
biofuels. Scientists have found that the "code of life" is far more
complex and difficult to crack than anyone might have imagined a decade
ago. What's more, while rewriting the code is easier than ever, getting
it right isn't. Researchers and entrepreneurs have found ways to coax
bacteria or yeast to make many useful compounds, but it has been
difficult to optimize such processes so that the microbes produce
significant quantities efficiently enough to compete with existing
commercial products.
Church is characteristically undeterred. At 57, he has survived
cancer and a heart attack, and he suffers from both dyslexia and
narcolepsy; before I visited him, one of his colleagues warned that I
shouldn't be surprised if he fell asleep on me. But he has founded or
taken an advisory role in more than 50 startup companies—and he stayed
awake throughout our time together, apparently excited to describe how
his lab has found ways to take advantage of ultrafast sequencing and
other tools to greatly speed up synthetic biology. Among its many
projects, Church's lab has invented a technique for rapidly synthesizing
multiple novel strings of DNA and introducing them simultaneously into a
bacterial genome. In one experiment, researchers created four billion
variants of E. coli in a single day. After three days, they
found variants of the bacteria in which production of a desired chemical
was increased fivefold.
The idea, Church explains, is to sort through the variations to
find "an occasional hopeful monster, just as evolution has done for
millions of years." By mimicking in lab experiments what takes eons in
nature, he says, he is radically improving the odds of finding ways to
make microbes not just do new things but do them efficiently.
A DNA Turn-On
In some ways, the difficulties researchers have faced making new,
more useful life forms shouldn't come as a surprise. Indeed, a lesson of
genome research over the last few decades is that no matter how
elegantly compact the DNA code is, the biology it gives rise to is
consistently more complex than anyone anticipated. When I began
reporting the early days of gene discovery 30 years ago, biologists, as
they often do, thought reductively. When they found a gene involved in
disease, the discovery made headlines. Scientists said they believed
that potent new medicines could soon deactivate malfunctioning versions
of genes, or that gene therapy could be used to replace them with
healthy versions in the body.
The early biotech companies also employed a one-gene-at-a-time
approach. Companies would locate the gene that made a particular
protein, such as insulin; then, using gene-splicing technology first
developed in the 1970s, they would snip open the DNA of a bacterium and
slide in the insulin-making gene. It's a technology that has led to
today's biotech industry.
Yet some scoffed at the idea that such techniques involved any
real engineering. "To us, it was no more engineering than changing a red
light bulb with a green light bulb," says James Collins, a Boston
University bioengineer who is credited with helping create the field of
synthetic biology in 2000. "Many of us thought that working at the
single-gene level was just a starting point, that we really needed to
figure out how all these newly identified genes arising from the Human
Genome Project fit into networks, pathways, and circuits inside the
cell." By comparison, says Collins, "synthetic biology is genetic
engineering on steroids."
I met Collins on a rainy winter day in his office on the BU campus.
He's an enthusiastic storyteller, full of details, digressions, and
gossip. And at 46, he has lived through the conception and birth of
synthetic biology. Collins told me how he and other engineers in the
late 1990s felt left out of what appeared to be the most important
science of the time, the sequencing of the human genome. It seemed that
every other cover of the journal Science was hailing some new
gene breakthrough. But with a slew of unanalyzed DNA data piling up in
computer databases, it was becoming clear that biologists didn't know
how genetic parts worked together. Collins says, "We had felt like we
were kids outside a candy store. So we figured, 'How can we get in?'"
Collins wanted to study cellular processes by constructing gene
networks rather than taking them apart. As a first step, he built a
biological toggle circuit. A toggle is a mechanism with two possible
states—in the case of a light switch, on or off. In the switch he and
his colleagues built from DNA, two genes next to each other in a
bacterial genome both produced proteins when they were "on." But Collins
set things up so that each protein would block production of the
other—if gene 1 was on, it would keep gene 2 off, and vice versa. With
the aid of chemicals or a thermal pulse, Collins could flip between the
two states.
The DNA toggle switch was analogous to an electronic transistor,
able to store a single bit of information. It was also an engineered
example of the kind of feedback loop that often determines whether cells
grow, divide, or die. "The idea that you could build a circuit out of
biological parts helped launch the field of synthetic biology," says
Collins. The results were published in January 2000.
Soon Collins's toggle was joined by an expanding list of DNA
circuits, including biosensors, oscillators, bacterial calculators, and
similar molecular gadgetry. Researchers even established a Registry of
Standard Biological Parts: 7,100 different DNA structures are available
to order. Scientists were excited by the idea that biology might be
modular and predictable, like something made with Lego blocks or
computer code. Many scrambled to found companies that they hoped would
commercialize the technology to produce fuels, drugs, or other products.
While comparisons to computer programming inspired many
researchers, however, these tended to oversimplify biology, which has
not proved entirely predictable. Furthermore, the claims that some
synthetic-biology companies made now appear to have been overly
optimistic, Collins says.
Indeed, Collins believes the rush to commercialize has been a
mistake. "The companies are sucking the oxygen out of the field," he
says, noting that they have hired scores of geneticists from university
labs. They're "scooping up our seed corn, the young researchers who
should be staying in academic labs working through new ways to engineer
biology." He worries that the race to apply the new technology means
"there's going to be a number of biotech carcasses on the side of the
road in the near future."
Not even George Church has been immune: Codon Devices, a company he
cofounded in 2004, was forced to shut down. Codon, in Church's words,
was established to be the Intel of the bioengineering industry, building
ready-made synthetic-biological modules that researchers could use to
redesign, say, a yeast. The company "burned through its cash," he
laments.
Nature's Code
Church hopes his latest enterprise avoids a similar fate. Called
Warp Drive Bio, the company combines computer science, chemistry, and
genetic engineering in ways that would not have been possible until
recently. It aims to use ultrafast DNA sequencing and synthetic-biology
techniques, some of which Church pioneered, to hunt for potential
medicines by scouring the DNA of millions of environmental samples that
drug companies have collected and stored over several decades. Warp
Drive is, in effect, searching for genetic parts that nature has already
programmed to make particularly potent, useful chemicals. Church's
technology will be used to generate copies of those parts, incorporate
them into bacteria, and optimize their performance. Then the bacteria
can be used to produce chemicals that, if all goes according to plan,
have new and interesting therapeutic properties.
Warp Drive, which was launched in January, employs fewer than a
dozen full-time staffers and occupies only about 1,000 square feet of
office and lab space in Cambridge, Massachusetts. But the startup, which
has raised $125 million in investments, has already formed a strategic
partnership with the French pharmaceutical company Sanofi. If Warp Drive
Bio meets certain milestones, it has the option to demand that Sanofi
purchase the company for $1 billion or more. The deal was struck after
Warp Drive's principal founder, Harvard biochemist Gregory Verdine, was
invited to Paris last May and gave a two-hour presentation that had
Sanofi's head of research, Elias Zerhouni, and several other staffers
crowding around his laptop.
Zerhouni, a former head of the U.S. National Institutes of Health,
immediately grasped the novelty and potential of Warp Drive's idea for
sifting through nature's existing stockpile of DNA parts. "We've been
plagued by a lack of creativity," he says. "It made sense to give them
the resources they need."
Verdine's insight is that nature is particularly adept at creating
chemicals that act safely and precisely on a desired biological target.
He says that half the small-molecule drugs developed over the last 30
to 35 years have been natural products or derivatives of such products.
"It struck me that probably something useful in evolution helped tailor
properties in these compounds that made them better suited to work in
complex cell systems like the human body," he says. "Nature seemed to
have already engineered in complexities that drug chemists don't
understand."
I interviewed Verdine in a spare room, no bigger than a walk-in
closet, just outside Warp Drive's lab in a converted book factory in
Cambridge. If Church and Collins are intent on creating new synthetic
parts and bioengineering techniques, Verdine is hoping to use many of
the same techniques to unwrap the mysteries of how nature does it. Over
the decades, he explained to me, pharmaceutical researchers have
collected and stored tens of thousands, and more likely millions, of
environmental samples, including dirt and pond scum. The idea was to
discover some potent chemical in these mixtures by dripping extracts
onto cancer cells or into petri dishes of bacteria. But that process is
laborious and subject to chance. Most drug companies have scaled back
such research.
The answer, Verdine decided, was to search for DNA instead. Given
the plummeting cost of DNA sequencing, it's now feasible to simply
decode all the genetic material present in, say, a drop of pond water
teeming with microörganisms. Verdine says many of the natural drugs that
have already been identified have similar DNA signatures—clusters of
genes that often occur together in a microbe's genome. The trick, he
adds, is to scan the samples' DNA to locate familiar-looking clusters
that might be recipes for synthesizing a natural product—ideally, an
important one that hasn't been found before.
Once identified, the DNA sequences will need to be engineered into
a bacterium so that the company can produce the chemical and study the
potential drugs. This is where the synthetic-biology techniques
developed by Church will be crucial: in transforming the code into
actual compounds. "We use genomics and informatics to find a gene
cluster. But that's an information unit," Verdine says. "We have to get
the molecule. Synthetic biology involves coaxing the cluster into
biosynthetic factories, which then produce the molecules. If we don't
have the molecule, the cluster is useless."
The idea of resorting to nature's stockpile for parts, Church
says, is "ironic and interesting" given synthetic biology's interest in
producing entirely new DNA circuits and, ultimately, generating entire
organisms from scratch. Researchers today may alter, copy, and paste DNA
with increasing ease, but they still struggle when it comes to actually
composing DNA that does anything useful. They are still editing
nature's code and learning from it. It turns out that for now, nature is
still the best programmer.
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