Authors: Carl Zimmer
Berg and his colleagues used EcoR1 to cut open SV40’s chromosome. At one end of SV40’s DNA they added DNA from a virus of
E. coli
called lambda. In order to fuse the two pieces of DNA together, Berg and his colleagues added to their ends some extra bases that would form bonds. When they were done, they had created a viral hybrid.
Since the hybrid carried the lambda virus’s genes for invading
E. coli,
Berg wondered whether it could invade the microbe. He asked one of his graduate students, Janet Mertz, to design an experiment. For Berg and Mertz, the experiment started out as yet another interesting question. But some who learned about their plans were filled with dread.
One of the first people to confront Berg with these worries was a bioethicist named Leon Kass. Like Berg, Kass had worked on
E. coli,
but he had become disillusioned by how fast scientific discoveries were being made and the lack of thought being given to their ethics. Kass warned Berg that manipulating genes could lead to moral quandaries. If scientists could insert genes in embryos, parents might pick out the traits they wanted in their children. They wouldn’t just upgrade genes that would cause sickle-cell anemia or other genetic disorders. They would look for ways to enhance even perfectly healthy children.
“Are we wise enough to be tampering with the balance of the gene pool?” Kass asked Berg.
Berg brushed off Kass’s warning, but when other virus experts began to question his plans, he stopped short. Mertz described to another researcher how she and Berg were going to create a sort of Russian doll with SV40 in lambda and lambda in
E. coli.
The researcher replied, “Well, it’s
coli
in people.”
If an SV40-carrying
E. coli
escaped from Berg’s laboratory, some scientists feared it might make its way into a human host. Once inside a person, it might multiply, spreading its cancer-causing viruses. No one could say whether it would do no harm or trigger a cancer epidemic. In the face of these uncertainties, Berg and Mertz decided to abandon the experiment.
“I didn’t want to be the person who went ahead and created a monster that killed a million people,” Mertz said later.
At the time, Berg’s lab was the only one in the world actively trying to do genetic engineering. The researchers’ methods were elaborate, tedious, and time-consuming. When they scrapped their SV40 experiment, they could be confident that no one would be able to immediately take up where they left off. But it would not be long before genetic engineering would become far easier—and thus far more controversial.
Berg and Boyer continued to study how EcoR1 cuts DNA. They discovered that the enzyme does not make a clean slice. Instead, it leaves ragged fragments, with one strand of DNA extending farther than the other at each end. That dangling strand can spontaneously join another dangling strand also cut by EcoR1. The strands are, in essence, sticky. Berg and Boyer realized no tedious tacking on of extra DNA was necessary to join two pieces of DNA from different species. The molecules would do the hard work on their own.
Boyer soon took advantage of these sticky ends. Instead of viruses, he chose plasmids, those ringlets of DNA that bacteria trade. Working with the plasmid expert Stanley Cohen, Boyer cut apart two plasmids with EcoR1. Their sticky ends joined together, combining the plasmids into a single loop. Each plasmid carried genes that provided resistance to a different antibiotic, and when Boyer and Cohen inserted their new hybrid plasmid in
E. coli,
the bacteria could resist both drugs. And when one of these engineered microbes divided, the two new
E. coli
also carried the same engineered plasmids. For the first time a living microbe carried genes intentionally combined by humans.
Once Boyer and Cohen had combined two
E. coli
plasmids, they turned to another species. Working with John Morrow of Stanford University, they cut up fragments of DNA from an African clawed frog and inserted it in a plasmid, which they then inserted in
E. coli.
Now they had created a chimera that was part
E. coli,
part animal.
When Boyer described his chimeras at a conference in New Hampshire in 1973, the audience of scientists was shocked. None of them could say the experiments were safe. They sent a letter to the National Academy of Sciences to express their concern, and a conversation spread through scientific circles. What could scientists realistically hope to do with engineered
E. coli
? What were the plausible risks?
The possibilities sounded as outlandish as anything Haldane had dreamed of fifty years earlier.
E. coli
could make precious molecules, such as human insulin, which could treat diabetes.
E. coli
might acquire genes for breaking down cellulose, the tough fibers in plants. A person who swallowed cellulose-eating
E. coli
might be able to live on grass. Or maybe engineering
E. coli
would lead to disaster. A cellulose-digesting microbe might cause people to absorb too many calories and become hideously obese. Or perhaps it might rob people of the benefits of undigested roughage—including, perhaps, protection from cancer.
Paul Berg and thirteen other prominent scientists wrote a letter to the National Academy of Sciences in 1974 calling for a moratorium on transferred genes—also known as recombinant DNA—until scientists could agree on some guidelines. The first pass at those guidelines emerged from a meeting Berg organized in February 1975 at the Asilomar Conference Grounds on the California coast. Rather than calling for an outright ban on genetic engineering, the scientists advocated a ladder of increasingly strict controls. The greater the chance an experiment might cause harm, the more care scientists should take to prevent engineered organisms from escaping. Some particularly dangerous experiments, such as shuttling genes for powerful toxins into new hosts, ought not to be carried out at all. The National Institutes of Health followed up on the Asilomar meeting by forming a committee to set up official guidelines later that year.
To scientists such as Berg, these steps seemed reasonable. They had taken time to give genetic engineering some serious reflection, and they had decided that its risks could be managed. Genetic engineering was unlikely to trigger a new cancer epidemic, for example, because from childhood on people were already exposed to cancer-causing viruses. Many scientists concluded that
E. coli
K-12 had become so feeble after decades of laboratory luxury that it probably could not survive in the human gut. A biologist named H. William Smith announced at Asilomar that he had drunk a solution of
E. coli
K-12 and found no trace of it in his stool. But to be even more certain that no danger would come from genetic engineering, Roy Curtiss, a University of Alabama microbiologist, created a superfeeble strain that was a hundred million times weaker than K-12.
Other scientists did not feel as confident. Liebe Cavalieri, a biochemist at the Sloan-Kettering Institute in New York, published an essay in
The New York Times Magazine
called “New Strains of Life—or Death.” Below the headline was a giant portrait of
E. coli
embracing one another with their slender alien pili. Meet your new Frankenstein.
Soon the scientific critics were joined by politicians and activists. Congress opened hearings on genetic engineering, and representatives introduced a dozen bills calling for various levels of control. City politicians took action as well. The mayor of Cambridge, Massachusetts, Alfred Vellucci, held raucous hearings on Harvard’s entry into the genetic engineering game. The city banned genetic engineering altogether for months. Protesters waved signs at scientific conferences, and environmental groups filed lawsuits against the National Institutes of Health, accusing it of not looking into the environmental risks of genetic engineering.
Many critics were appalled that scientists would presume to judge how to handle the risks of genetic engineering on their own. “It was never the intention of those who might be called the Molecular Biology Establishment to take this issue to the general public to decide,” James Watson wrote frankly in 1981. The critics argued that the public had a right to decide how to manage the risk of genetic engineering because the public would have to cope with any harm that might come of it. Senator Edward Kennedy of Massachusetts complained that “scientists alone decided to impose a moratorium, and scientists alone decided to lift it.”
Some critics also questioned whether scientists could be objective about genetic engineering. It was in their interest to keep regulations as lax as possible because they would be able to get more research done in less time. “The lure of the Nobel Prize is a strong force motivating scientists in the field,” Cavalieri warned. Along with scientific glory came the prospect of riches. Corporations and investors were beginning to court molecular biologists, hoping to find commercial applications for genetic engineering. Financial interests might lead some to oversell the promise of genetic engineering and downplay its risks. Cetus Corporation, a company that recruited molecular biologists to serve on its board, made this astonishing prediction: “By the year 2000 virtually all the major human diseases will regularly succumb to treatment by disease-specific artificial proteins produced by specialized hybrid micro-organisms.”
Instead of a miracle, critics saw in genetic engineering the illusion of a quick fix. In 1977, the National Academy of Sciences held a public forum on the risks and benefits of the new technology. Picketers tried to shut down the meeting, calling genetic engineers Nazis. Amid the chaos, Irving Johnson, the vice president of research at Eli Lilly, talked about how genetic engineering could be used to treat diabetes. Eli Lilly, the country’s biggest provider of insulin, got the hormone from the pancreases of pigs. That supply was vulnerable, Johnson said, to a slump in the pork business or to an increase in the population of diabetics. Genetically engineering a microbe to make human insulin might provide a vast, cheap supply. “This is truly ‘science for the people,’” Johnson said.
Ruth Hubbard, a Harvard biologist and a leading critic of genetic engineering, testified against this sunny view. She pointed out that insulin does not prevent diabetes or even cure it. It merely counteracts some of the symptoms of the disease. “Before we jump at technological gimmicks to cure complicated diseases,” she warned, “we first have to know what causes the diseases, we have to know how the therapy that we are being told is needed works, we have to know what fraction of people really need it…. But what we don’t need right now is a new, potentially hazardous technology for producing insulin that will profit only the people who are producing it.”
While genetic engineering was distracting society from real solutions, critics warned, it could also put the world at risk. What made it particularly risky was its utter dependence on
E. coli.
“From the point of public health,” Cavalieri declared, “this bacterium is the worst of all possible choices. It is a normal inhabitant of the human digestive tract and can easily enter the body through the mouth or nose. Once there, it can multiply and remain permanently. Thus every laboratory working with
E. coli
recombinants is staffed by potential carriers who could spread a dangerous recombinant to the rest of the world.”
Even if scientists used a weakened strain of
E. coli
for genetic engineering, the microbes might survive long enough outside a lab to pass their engineered genes to more rugged strains. Critics warned of cancer epidemics caused by
E. coli
casually poured down a drain.
E. coli
might churn out insulin inside diabetics, sending them into comas. Genetically engineered organisms could cause bigger disasters than toxic chemicals because they had the reproductive power of life. Erwin Chargaff, an eminent Columbia University biologist, called genetic engineering “an irreversible attack on the biosphere.”
“The world is given to us on loan,” Chargaff warned. “We come and we go; and after a time we leave earth and air and water to others who come after us. My generation, or perhaps the one preceding mine, has been the first to engage, under the leadership of the exact sciences, in a destructive colonial warfare against nature. The future will curse us for it.”
These attacks left the champions of genetic engineering stunned. The debate had become “nightmarish and disastrous,” Paul Berg declared in 1979. Stanley Cohen called it a “breeding ground for a horde of publicists.”
James Watson, as usual, was bluntest of all. “We were jackasses,” he said, looking back at his support of the 1974 moratorium. “It was a decision I regret; one that I am intellectually ashamed of.” It had led the public to distract itself from real threats with illusions of apocalypse.
“I’m afraid that by crying wolf about dangers which we have no reason at all to worry about, we are becoming indistinguishable from my two small boys,” he wrote. “They love to talk about monsters because they know they will never meet one.”
E. COLI,
INC.
One figure noticeably absent from the debate was Herbert Boyer, the scientist who had triggered the genetic engineering controversy in the first place. He was busy hunting for companies and investors who could help him make money from his restriction enzymes. In 1976, he became a partner with a young entrepreneur named Robert Swanson. Each man ponied up $500 to launch a company they called Genentech (short for genetic engineering technology). Boyer had to borrow his share.
Boyer and Swanson set out to sell valuable molecules produced by engineered
E. coli.
They decided their first goal should be human insulin, for many of the reasons Irving Johnson had offered to the National Academy of Sciences. Boyer turned to Arthur Riggs and Keiichi Itakura at the City of Hope Hospital in Duarte, California, for help. Riggs and Itakura were among the first scientists learning how to build genes from scratch. When Boyer contacted them, they were in the midst of synthesizing their first human gene, which encoded the hormone somatostatin. Working with Genentech, Riggs and Itakura figured out how to add sticky ends to an artificial somatostatin gene and insert it into a plasmid. They put the plasmid in
E. coli,
which then began to produce somatostatin. It was yet another milestone in a very young science. In 1973, Boyer, Cohen, and Morrow had managed only to put a fragment of an animal gene in
E. coli.
Four years later, Genentech had
E. coli
that could make human proteins.