Return Of Frankensteins 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.

Drugs made through genetic engineering have also turned out to be just as vulnerable to market forces as conventional ones. Drug companies have been trying to increase their sales by expanding our definition of what it means to be sick. Genetically engineered drugs have been promoted this way as well. Genentech originally got approval from the Food and Drug Administration to sell its E. coli-produced growth hormone to treat children whose bodies couldn't make it themselves. But in 1999 the company had to pay $50 million to settle charges that its drug was being marketed to children who were merely shorter than average.

E. coli's thirty-year history of genetic engineering is worth considering when we judge the new biotechnology that has come in its wake. We must resist empty fear and empty hype. We must instead be realistic, always remembering how both nature and society actually work.

One of the great dreams of biotechnology has been to end famine, for example. Julian Huxley speculated as far back as 1923 that scientists would create a limitless supply of food (along with purple oceans). The dream lived on in the 1960s with promises of oil-fed yeast. When scientists successfully inserted foreign genes in E. coli, advocates for genetic engineering promised more food for a starving world. In the 1970s, the Green Revolution—the result of breeding new varieties of crops and using plenty of fertilizer—had dramatically increased farm productivity. But the world's population, and thus its hunger, were still growing. Scientists began trying to engineer bacteria to make fertilizer by capturing nitrogen from the air. Most recently, scientists have turned their attention to engineering plants themselves. Transgenic crops are being promoted not as a way to make bigger profits but as a way to fight hunger and malnutrition. Crops that can resist viruses and insects will increase harvests. Crops that can resist herbicides will allow farmers to fight weeds more effectively, increasing the yield even more. Norman Borlaug, who won a Nobel Peace Prize for his work on the Green Revolution, claimed that genetically modified crops would pick up where his own work had left off, feeding the world for another century.

Anyone who questioned this prediction, Borlaug suggested, was dooming the world's poor to famine. "The affluent nations can afford to adopt elitist positions and pay more for food produced by the so-called natural methods; the 1 billion chronically poor and hungry people of this world cannot," he wrote in 2000. "New technology will be their salvation, freeing them from obsolete, low-yielding, and more costly production technology."

One of the promising crops Borlaug—as well as many other advocates—pointed to was Golden Rice, a strain of rice engineered to make vitamin A. Vitamin A deficiency affects roughly 200 million people worldwide. Up to half a million children become blind each year, half of whom will die within a year of losing their sight. In the late 1990s, Swiss scientists began inserting genes from daffodils and bacteria into the rice genome to produce vitamin A. They formed a partnership with the corporation Syngenta to develop the rice and distribute it free to farmers who make less than $10,000 a year. Ingo Potrykus, one of the inventors, appeared on the cover of Time in 2000, alongside the headline "THIS RICE COULD SAVE A MILLION KIDS A YEAR," which was followed in small print by ".. .but protesters believe such genetically modified foods are bad for us and our planet. Here's why."

Potrykus had little patience for those protesters. "In fighting against 'Golden Rice' reaching the poor in developing countries," he declared in 2001, "GMO opposition has to be held responsible for the foreseeable unnecessary death and blindness of millions of poor every year."

Strong words, particularly given how embryonic the research on Golden Rice was when Potrykus uttered them. He and his colleagues had published their first results only the previous year. They had managed to produce only small amounts of vitamin A in the rice's tissues, far too little to wipe out vitamin A deficiency. In 2005, four years after Potrykus accused his critics of mass murder, Syngenta scientists discovered that adding an extra gene from corn helped boost the level of the vitamin A precursor more than twentyfold. It was a huge increase, but there's no solid evidence yet of how much benefit it brings to people who eat it. Some nutritionists have warned that it may not bring much benefit at all, because vitamin A has to be consumed along with dietary fat in order to be properly absorbed by the body. It's possible to suffer vitamin A deficiency—even to go blind—on a diet that contains vitamin A. Foods such as milk, eggs, and many vegetables offer the right combination of vitamin A and fat, but rice does not. Just because Golden Rice is at the cutting edge of genetic engineering doesn't mean that it will cut down vitamin A deficiency any more than conventional methods have.

Using words like salvation to describe transgenic crops makes as little sense as calling them Frankenfoods. We are thrown back and forth between the extremes of abject terror and hope for miracles of loaves and transgenic fish. Genetically modified crops are hardly miraculous. They are living things, as much subject to the rules of life as E. coli or humans. And just as E. coli has evolved defenses against some of our best antibiotics, natural selection is undermining the worth of the most popular transgenic crops.

About 80 percent of all the transgenic crops planted in 2006 were engineered for the same purpose: to be resistant to a herbicide known as glyphosate. Glyphosate kills plants by blocking the construction of amino acids that are essential to their survival. It attacks enzymes that only plants use, with the result that it's harmless to people, insects, and other animals. And unlike other herbicides that wind up in groundwater, glyphosate stays where it's sprayed, degrading within weeks. A scientist at the Monsanto Company discovered glyphosate in

1970, and the company began selling it as Roundup in 1974. In 1986, scientists engineered glyphosate-resistant plants by inserting genes from bacteria that could produce amino acids even after a plant was sprayed with herbicides. In the 1990s, Monsanto and other companies began to sell glyphosate-resistant corn, cotton, sugar beets, and many other crops. Instead of applying a lot of different herbicides, farmers found they could hit their fields with a modest dose of glyphosate alone, which wiped out weeds without harming their crops. Studies indicated that farmers who grew the transgenic crops used fewer herbicides than those who grew nontransgenic plants—77 percent fewer in Mexico, for example—while getting a significantly higher yield.

For a while it seemed as if glyphosate would avoid the fate of many other herbicides before it: the evolution of weeds resistant to herbicides. Glyphosate seemed to strike at such an essential part of their biology that no defense could possibly evolve. Of course, it also seemed for a while as if E. coli couldn't evolve resistance to Michael Zasloffs antimicrobial peptides. And after glyphosate-resistant crops had a few years to grow, farmers began to notice horseweed and morning glory and other weeds encroaching once more on their fields. Farmers in Georgia have had to destroy fields of cotton because of infestations of resistant Palmer amaranth. When scientists have studied these resurgent weeds, they've discovered genes that now make the plants resistant to glyphosate.

There's no evidence that these weeds acquired their resistance from the transgenic crops. They most likely got it the old-fashioned way: they evolved it. Using glyphosate on transgenic crops proved to be so cheap and effective that farmers flooded huge swaths of land with a single herbicide. They created an enormous opportunity for weeds that could resist glyphosate and drove the quick evolution of stronger and stronger resistance. And once the weeds evolved their resistance, they appear to have passed on the resistance genes to other weedy species.

When antibiotics fail against E. coli and other bacteria, it may take years for a new kind of antibiotic to emerge. The pipeline of transgenic crops is equally sludgy. It wasn't until 2007, more than twenty years after the invention of glyphosate-resistant crops, that scientists announced they had engineered plants with genes that make them resistant to another herbicide, known as dicamba. Monsanto licensed the technology but said it wouldn't have dicamba-resistant crops ready for sale for another three to seven years. In the meantime, farmers can resort to old-fashioned methods to slow the evolution of resistance, rotating crops and using a combination of herbicides.

Although there's a lot of déjà vu in biotechnology today, some scientists have been carefully studying the fate of E. coli in the 1970s in order to avoid some of the mistakes their predecessors made. Synthetic biologists have become particularly keen historians, learning how the pioneers in their field grappled with risks, regulations, and the public perception of their work. Rather than make synthetic biology the privileged domain of an elite, Drew Endy and his colleagues are inviting the public to join in the experience. Anyone can download the codes for BioBricks. The E. coli camera is now appearing in science museums, and high school students are entering synthetic biology competitions. And rather than put all their efforts into creating a big moneymaker like insulin, synthetic biologists are trying to make cheap drugs for malaria, to demonstrate the good that can come of their work.

Synthetic biologists want to preserve this open-source spirit despite the fact that their tools may someday be used for evil ends. It's conceivable, for example, that a government might design an organism for biological warfare. Synthetic biologists fear that if the government takes over their research, innovations will dry up. They argue that the best way to defeat an engineered pathogen is to harness the collective creativity of an open community. By keeping synthetic biology free of excessive regulations and patents, its founders hope they can foster an artificial version of the open-source evolution that has served E. coli so well for millions of years.

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