Microcosm (26 page)

The hard part of the work came when it was time to join the two sets of genes. The students engineered the light receptors so that they could pass a signal to molecules normally made by
E. coli.
Those molecules were then able to grab on to the microbe’s DNA and shut down the production of
Synechocystis’
s pigment enzymes. It takes
E. coli
ten to fifteen hours of exposure to develop an image, which has a rather ghostly appearance. But because each microbe can adjust its own color, the photograph has a very high resolution, about ten times that of a high-resolution printer.

These sorts of experiments give synthetic biologists great hope. Soon it will be possible for them to synthesize entirely new genes from scratch at very little cost. No one can actually invent a completely new gene for a particular function, but it is possible to tinker with existing genes and simulate how their proteins would change as a result. Already researchers have fashioned new genes that allow
E. coli
to detect nerve gas and TNT. One of the most ambitious projects in all of synthetic biology is taking place at the University of California, Berkeley, where scientists have been developing new genetic circuits that may allow
E. coli
or yeast to produce a drug for malaria. The drug, known as artemisinin, is normally produced only by the sweet wormwood plant. If a microbe could make artemisinin, the price might drop by 90 percent.

Meanwhile, Christopher Voigt and his colleagues have created strains of
E. coli
that might someday fight cancer. The microbes seek out tumors by sensing their low levels of oxygen; having found a tumor, they deploy needles to inject toxins into the cancer cells. Voigt hopes someday to turn
E. coli
or some other microbe into a smart drug, able to make its own decisions about when to produce molecules to treat a disorder. Other researchers are trying to turn
E. coli
into a solar battery, able to trap sunlight and turn it into fuel. Synthetic biologists plan to move beyond
E. coli,
just as genetic engineers did. Someday they may be able to hack the programming of human cells, causing them to build new organs.

These are the things synthetic biologists think about when they’re in a good mood. When they’re in a bad mood, they think about all the challenges they still face.

Engineers, for example, need standardized parts. When engineers design a lathe or a lawn mower, they don’t have to design the nuts and bolts that hold the parts together. They just specify which size the nuts and bolts should be. Yet this shortcut is a relatively recent luxury. Before the mid-1800s, the threads on a nut made in one shop might not fit the threads on a bolt made in another. The standardization of those threads sped up the pace of invention and may even have played a major role in driving the Industrial Revolution.

For now, synthetic biology is a craft practiced by artisans. It took Elowitz and his colleagues—some of the world’s top experts on
E. coli
and its genes—more than a year to produce blinking bacteria. And once they had their successes, it was very difficult for other scientists to improve their circuits or incorporate them into more elaborate ones. For one thing, a scientist would have to reconstruct the circuit. And the circuit might work only in a particular strain of
E. coli.
Scientists can keep track of
E. coli
strains only with elaborate pedigree charts, tracing the bacteria like royalty. Such are the challenges that make engineers despair.

Since 2001, Drew Endy and Thomas Knight of MIT have been building a catalog of standardized parts for synthetic biology. If you want to add a toggle switch to your particular circuit, you can search for it on the BioBricks Web site, download the DNA sequence, order the corresponding fragments of DNA from a biotech firm, and insert them in
E. coli.
With more than 160 parts in its inventory, BioBricks has not only made synthetic biology easier but has also begun to foster a community. Endy and Knight made BioBricks the basis of the annual synthetic biology competition for students. The students themselves add more parts to the registry, opening the way for future inventions.

But as synthetic biologists try to build more ambitious circuits, they may find a new obstacle in their path:
E. coli
itself. For all of the attention scientists have lavished on it, there is still much about the microbe they do not understand. Six hundred genes remain absolute mysteries. The microbe’s genetic network is particularly murky. Scientists can identify most of
E. coli’
s transcription factors, the proteins that grab DNA to switch genes on and off, but they know only about half their targets. And what synthetic biologists do understand about
E. coli
sometimes makes their hearts sink. Its circuits overlap with one another, forming tangles that no self-respecting engineer would ever design. It is very hard to predict how extra circuits will change the behavior of such a messy network.

Some synthetic biologists are trying to overcome
E. coli’
s mystery by taking it apart and rebuilding it from scratch. At Harvard University, for example, George Church and his colleagues have drawn up a list of 151 genes, which they think would be enough to keep an organism alive. Scientists understand these genes—which are drawn mostly from
E. coli
and its viruses—quite well. There should be relatively little mystery when they come together. Church hopes to create a genome with these essential genes. By combining it with a membrane and protein-building ribosomes, he hopes to create a living thing. Call it
E. coli
2.0.

Meanwhile, at Rockefeller University, Albert Libchaber took an even simpler approach. He and his colleagues cooked up a solution of ribosomes and other molecules found in
E. coli.
Instead of a full genome, they engineered a small plasmid. They then added oily molecules from egg yolks, which form bubbles that scoop up the genes and molecules. These bubbles, Libchaber’s team found, could live—at least for a few hours. One of the genes Libchaber added to the plasmids encoded a pore protein. The protocells read the gene, built the proteins, and inserted them in the membrane. There they could allow amino acids and other small molecules to move into the protocell without letting the plasmid and other big molecules out. To track the production of new proteins, the scientists also added a gene from a firefly. The protocells gave off a cool green glow. Libchaber doesn’t call his creation a living thing. He prefers the term
bioreactor.
To go from bioreactor to life will take much more work. For one thing, Libchaber and his colleagues will need to add genes to allow the bioreactors to divide into new bioreactors.

Church and Libchaber are only just starting to figure out how to use parts of
E. coli
to create new life-forms. They cannot just throw together DNA and some other molecules and let them come to life on their own. Life is not like a computer, which simply boots up at the press of a button. Every
E. coli
alive today emerged from an ancestor, which emerged from ancestors of its own. Together they form an unbroken river of biology that has flowed continuously for billions of years. Life as we know it has always been part of that river. Perhaps now we will make a canal of our own.

RETURN OF FRANKENSTEIN’S MICROBE

In May 2006, synthetic biologists met in Berkeley, California, for their second international meeting. Along with the standard research talks, they set aside time to draft a code of conduct. The day before, thirty-five organizations—representing, among others, environmentalists, social activists, and biological warfare experts—released an open letter urging that the biologists withdraw the code. They should join a public debate about synthetic biology instead and be ready to submit to government regulations. “Biotech has already ignited worldwide protests, but synthetic biology is like genetic engineering on steroids,” said Doreen Stabinsky of Greenpeace International.

These days, biotechnology is experiencing an intense case of déjà vu. The questions people are debating about synthetic biology are strikingly similar to the ones that came up when genetically engineered
E. coli
made news in the 1970s. Do the benefits justify the risks? Is there any intrinsic wrong in tinkering with life? The new debate is far more complex than the old one, in part because
E. coli
is not the only thing scientists are manipulating. Now we must consider transgenic crops, engineered stem cells, human-animal chimeras. The new debate often turns on subtle points of medicine, conservation biology, patent law, and international trade. But for all the differences, the parallels are still powerful and instructive. To understand the potential risks and benefits of the new biotechnology, it helps to look back at the fate of genetically engineered
E. coli
over the past three decades.

The dire warnings that
E. coli
would create tumor plagues and insulin shock epidemics seem quaint today. In thirty years no documented harm from genetically engineered
E. coli
has emerged, despite the fact that many factories breed the bacteria in 40,000-liter fermenters in which every milliliter contains a billion
E. coli.
No one has a God’s-eye view of the fate of every engineered
E. coli
in the past thirty years, so it’s impossible to know for sure why the predicted plagues never came. Some clues have come from experiments. Scientists put
E. coli
K-12 carrying human genes in tubs of sludge and tanks of water and animal guts. They found that the bacteria rapidly disappeared. Genetically engineered
E. coli
channel a lot of energy and raw materials into making the proteins from inserted genes. But those proteins, such as insulin and blood thinners, probably don’t boost
E. coli’
s growth or odds of surviving in the wild. In the carefully controlled conditions scientists create in laboratories, they can thrive. But pitted against other bacteria, they fail.

Genetic engineers did not introduce genes to
E. coli
from other species for the first time. In a sense,
E. coli
and its ancestors have been genetically engineered for billions of years. But most of the transfers have been complete failures. Bacteria cannot make proteins from many horizontally transferred genes, and natural selection favors mutations that strip most alien genes from their genomes.

Unfortunately, the absence of evidence is not a slam-dunk case for the evidence of absence. If an engineered strain of
E. coli
escapes from a factory and manages to survive in the outside world for a few days, it may be able to pass its genes to other bacteria. If a soil microbe picks up a gene for human insulin or some other alien protein, it probably would not benefit from it. But the possibility can’t be ruled out. Studies suggest that even if an alien gene gave bacteria a competitive advantage, it would remain too rare for scientists to detect for decades, perhaps even centuries.

While we’ve been waiting for a genetically engineered monster to emerge,
E. coli
O157:H7 has emerged as a serious threat to public health. It was in 1975—the same year in which scientists gathered at Asilomar to ponder the potential dangers of genetically engineered
E. coli—
that a woman suffered the earliest known attack of
E. coli
O157:H7. But that pathogen was not the work of a human genetic engineer with an intelligent design. Over the course of centuries,
E. coli
O157:H7 acquired many genes from viruses carrying deadly instructions. They acquired these genes from other strains of
E. coli
or other species of bacteria. They acquired syringes and toxins and molecules that alter the behavior of host cells. This genetic engineering is still taking place as one new strain after another evolves. But the insertion of a bundle of genes in a single microbe was only the first step in this transformation. Natural selection then had to favor those genes in their new host; it had to fine-tune them.

The transformation required an entire ecosystem that could produce the conditions that would drive natural selection. We provided it.
E. coli
O157:H7 had been pumped from humans to livestock through farm fields and slaughterhouses, through rivers and sewers rife with toxin-bearing viruses. There’s little evidence for a similar evolutionary pump for genetically engineered
E. coli.
Our unplanned engineering of
E. coli
may give us more to worry about than anything brewed up in a lab.

Thirty years have passed since the backers of genetic engineering predicted recombinant DNA would bring great rewards. They were right, up to a point.
E. coli
and other engineered cells not only produce a vast number of valuable molecules; they have also sped up the pace of science enormously.
E. coli
was a crucial partner in the sequencing of the human genome, for example. In order to read the genome, scientists inserted chunks of it into
E. coli,
which then produced many copies that scientists could analyze. Other scientists have used
E. coli
to churn out millions of proteins so that they can discover what the proteins do. By inserting human genes into
E. coli,
scientists discovered that they are made up of two kinds of DNA. Some segments of the genes, known as exons, encode parts of proteins. But they alternate with other segments, called introns, that encode nothing. Our cells edit out the introns from RNA in order to make proteins. They can even use different combinations of exons to produce a number of proteins from a single gene.

As important as these accomplishments have been, however, genetic engineering has fallen far short of the more extravagant promises offered thirty years ago. Cetus predicted that all major diseases would surrender to genetically engineered proteins by 2000. I’m writing in 2007, and cancer, heart disease, malaria, and other diseases continue to kill by the millions. Maybe the people at Cetus were just wrong about the date. Perhaps another thirty years will bring some major breakthrough in genetic engineering that will wipe out all major diseases. I wouldn’t bet on it, though. Most major diseases are fiendishly complex, and a single engineered protein is not going to make them go away. Diabetes, the poster child for the promise of genetic engineering, has not disappeared over the past thirty years. In fact, it has exploded. The incidence of type 2 diabetes has doubled in the United States, and cases of diabetes worldwide have increased tenfold.
E. coli
has provided insulin for millions of people with diabetes, but, as Ruth Hubbard warned, it did nothing to prevent the disease. Genetic engineering could not block the sources of the diabetes epidemic, which may include the availability of cheap sugar. That sugar comes increasingly from high-fructose corn syrup, whose low price we owe to breakthroughs in genetic engineering.