Say an immunologist was trying to solve a fundamental riddle in immunology: the mechanism by which T cells recognize and kill foreign cells in the body. For decades, it had been known that T cells sense the presence of invading cells and virus-infected cells by virtue of a sensor found on the surface of the T cell. The sensor, called the T cell receptor, is a protein made uniquely by T cells. The receptor recognizes proteins on the surface of foreign cells and binds to them. The binding, in turn, triggers a signal to kill the invading cell, and thereby acts as a defense mechanism for an organism.
But what was the nature of the T cell receptor? Biochemists had approached the problem with their typical penchant for reduction: they had obtained vats upon vats of T cells, used soaps and detergents to dissolve the cell’s components into a gray, cellular froth, then distilled the membranes and lipids away, and purified and repurified the material into smaller and smaller parts to hunt down the culprit protein. Yet the receptor protein, dissolved somewhere in that infernal soup, had remained elusive.
A gene cloner might take an alternative approach. Assume, for a moment, that the distinctive feature of the T cell receptor protein is that it is synthesized only in T cells, not in neurons, or ovaries, or liver cells. The gene for the receptor must exist in every human cell—human neurons, liver cells, and T cells have identical genomes, after all—but the RNA is made only in T cells. Could one compare the “RNA catalog” of two different cells, and thereby clone a functionally relevant gene from that catalog? The biochemist’s approach pivots on concentration: find the protein by looking where it’s most likely to be concentrated, and distill it out of the mix. The geneticist’s approach, in contrast, pivots on information: find the gene by searching for differences in “databases” created by two closely related cells and multiply the gene in bacteria via cloning. The biochemist distills forms; the gene cloner amplifies information.
In 1970, David Baltimore and Howard Temin, two virologists, made a pivotal discovery that made such comparisons possible. Working independently, Baltimore and Temin discovered an enzyme found in retroviruses that could build DNA from an RNA template. They called the enzyme reverse transcriptase—“reverse” because it inverted the normal direction of information flow: from RNA back to DNA, or from a gene’s message backward to a gene, thereby violating Crick’s “central dogma” (that genetic information only moved from genes to messages, but never backward).
Using reverse transcriptase, every RNA in a cell could be used as a template to build its corresponding gene. A biologist could thus generate a catalog, or “library” of all “active” genes in a cell—akin to a library of books grouped by subject.III There would be a library of genes for T cells and another for red blood cells, a library for neurons in the retina, for insulin-secreting cells of the pancreas, and so forth. By comparing libraries derived from two cells—a T cell and a pancreas cell, say—an immunologist could fish out genes that were active in one cell and not the other (e.g., insulin or the T cell receptor). Once identified, that gene could be amplified a millionfold in bacteria. The gene could be isolated and sequenced, its RNA and protein sequence determined, its regulatory regions identified; it could be mutated and inserted into a different cell to decipher the gene’s structure and function. In 1984, this technique was deployed to clone the T cell receptor—a landmark achievement in immunology.
Biology, as one geneticist later recalled, was “liberated by cloning . . . and the field began to erupt with surprises.” Mysterious, important, elusive genes sought for decades—genes for blood-clotting proteins, for regulators of growth, for antibodies and hormones, for transmitters between nerves, genes to control the replication of other genes, genes implicated in cancer, diabetes, depression, and heart disease—would soon be purified and cloned using gene “libraries” derived from cells as their source.
Every field of biology was transformed by gene-cloning and gene-sequencing technology. If experimental biology was the “new music,” then the gene was its conductor, its orchestra, its assonant refrain, its principal instrument, its score.
* * *
I. Notably, Darwin and Mendel had both bridged the gap between the old and the new biology. Darwin had started out as a natural historian—a fossil collector—but had then radically altered that discipline by seeking the mechanism behind natural history. Mendel, too, had started out as a botanist and a naturalist and radically swerved that discipline by seeking the mechanism that drove heredity and variation. Both Darwin and Mendel observed the natural world to seek deeper causes behind its organization.
II. Watson borrowed this memorable phrase from Ernest Rutherford, who, in one of his characteristically brusque moments, had declared, “All science is either physics or stamp collecting.”
III. These libraries were conceived and created by Tom Maniatis in collaboration with Argiris Efstratiadis and Fotis Kafatos. Maniatis had been unable to work on gene cloning at Harvard because of concerns about the safety of recombinant DNA. He had moved to Cold Spring Harbor on Watson’s invitation so that he could work on gene cloning in peace.
Einsteins on the Beach
There is a tide in the affairs of men,
Which, taken at the flood, leads on to fortune;
Omitted, all the voyage of their life
Is bound in shallows and in miseries.
On such a full sea are we now afloat.
—William Shakespeare, Julius Caesar, act 4, scene 3
I believe in the inalienable right of all adult scientists to make absolute fools of themselves in private.
—Sydney Brenner
In Erice, near the western coast of Sicily, a twelfth-century Norman fortress rises two thousand feet above the ground on a furl of rock. Viewed from afar, the fortress seems to have been created by some natural heave of the landscape, its stone flanks emerging from the rock face of the cliff as if through metamorphosis. The Erice Castle, or Venus Castle, as some call it, was built on the site of an ancient Roman temple. The older building was dismantled, stone by stone, and reassembled to form the walls, turrets, and towers of the castle. The shrine of the original temple has long vanished, but it was rumored to be dedicated to Venus. The Roman goddess of fertility, sex, and desire, Venus was conceived unnaturally from the spume spilled from Caelus’s genitals into the sea.
In the summer of 1972, a few months after Paul Berg had created the first DNA chimeras at Stanford, he traveled to Erice to give a scientific seminar at a meeting. He arrived in Palermo late in the evening and took a two-hour taxi ride toward the coast. Night fell quickly. When he asked a stranger to give him directions to the town, the man gestured vaguely into the darkness where a flickering decimal point of light seemed suspended two thousand feet in the air.
The meeting began the next morning. The audience comprised about eighty young men and women from Europe, mostly graduate students in biology and a few professors. Berg gave an informal lecture—“a rap session,” he called it—presenting his data on gene chimeras, recombinant DNA, and the production of the virus-bacteria hybrids.
The students were electrified. Berg was inundated with questions, as he had expected—but the direction of the conversation surprised him. At Janet Mertz’s presentation at Cold Spring Harbor in 1971, the biggest concern had been safety: How could Berg or Mertz guarantee that their genetic chimeras would not unleash biological chaos on humans? In Sicily, in contrast, the conversation turned quickly to politics, culture, and ethics. What about the “spectre of genetic engineering in humans, behavior control?” Berg recalled. “What if we could cure genetic diseases?” the students asked. “[Or] program people’s eye color? Intelligence? Height? . . . What would the implications be for humans and human societies?”
Who would ensure that genetic technologies would not be seized and perverted by powerful forces—as once before on that continent? Berg had obviously stoked an old fire. In America, the prospect of gene manipulation had principally raised the specter of future biological dangers. In Italy—not more tha
n a few hundred miles from the sites of the former Nazi extermination camps—it was the moral hazards of genetics, more than the biohazards of genes, that haunted the conversation.
That evening, a German student gathered an impromptu group of his peers to continue the debate. They climbed the ramparts of the Venus Castle and looked out toward the darkening coast, with the lights of the city blinking below. Berg and the students stayed up late into the night for a second session, drinking beers and talking about natural and unnatural conceptions—“the beginning of a new era . . . [its] possible hazards, and the prospects of genetic engineering.”
In January 1973, a few months after the Erice trip, Berg decided to organize a small conference in California to address the growing concerns about gene-manipulation technologies. The meeting was held at the Pacific Groves Conference Center at Asilomar, a sprawling, wind-buffeted complex of buildings on the edge of the ocean near Monterey Bay, about eighty miles from Stanford. Scientists from all disciplines—virologists, geneticists, biochemists, microbiologists—attended. “Asilomar I,” as Berg would later call the meeting, generated enormous interest, but few recommendations. Much of the meeting focused on biosafety issues. The use of SV40 and other human viruses was hotly discussed. “Back then, we were still using our mouths to pipette viruses and chemicals,” Berg told me. Berg’s assistant Marianne Dieckmann once recalled a student who had accidentally flecked some liquid onto the tip of a cigarette (it was not unusual, for that matter, to have half-lit cigarettes, smoldering in ashtrays, strewn across the lab). The student had just shrugged and continued to smoke, with the droplet of virus disintegrating into ash.
The Asilomar conference produced an important book, Biohazards in Biological Research, but its larger conclusion was in the negative. As Berg described it, “What came out of it, frankly, was the recognition of how little we know.”
Concerns about gene cloning were further inflamed in the summer of 1973 when Boyer and Cohen presented their experiments on bacterial gene hybrids at another conference. At Stanford, meanwhile, Berg was being flooded with requests from researchers around the world asking for gene recombination reagents. One researcher from Chicago proposed inserting genes of the highly pathogenic human herpes virus into bacterial cells, thereby creating a human intestinal bacterium loaded with a lethal toxin gene, ostensibly to study the toxicity of herpes virus genes. (Berg politely declined.) Antibiotic-resistance genes were routinely being swapped between bacteria. Genes were being shuffled between species and genera, leaping across a million years of evolutionary rift as if casually stepping over thin lines in sand. Noting the growing swirl of uncertainties, the National Academy of Sciences called on Berg to lead a study panel on gene recombination.
The panel—eight scientists, including Berg, Watson, David Baltimore, and Norton Zinder—met at MIT, in Boston, on a chilly spring afternoon in April 1973. They instantly got to work, brainstorming possible mechanisms to control and regulate gene cloning. Baltimore suggested the development of “ ‘safe’ viruses, plasmids and bacteria, which would be crippled”—and thereby be unable to cause disease. But even that safety measure was not foolproof. Who would ensure that “crippled” viruses would remain permanently crippled? Viruses and bacteria were, after all, not passive, inert objects. Even within laboratory environments, they were living, evolving, moving targets. One mutation—and a previously disabled bacterium might spring to virulent life again.
The debate had gone on for several hours when Zinder proposed a plan that seemed almost reactionary: “Well, if we had any guts at all, we’d just tell people not to do these experiments.” The proposal created a quiet stir around the table. It was far from an ideal solution—there was something obviously disingenuous about scientists telling scientists to restrict their scientific work—but it would at least act as a temporary stay order. “Unpleasant as it was, we thought it might just work,” Berg recalled. The panel drafted a formal letter, pleading for a “moratorium” on certain kinds of recombinant DNA research. The letter weighed the risks and benefits of gene recombination technologies and suggested that certain experiments be deferred until the safety issues had been addressed. “Not every conceivable experiment was dangerous,” Berg noted, but “some were clearly more hazardous than others.” Three types of procedures involving recombinant DNA, in particular, needed to be sharply restricted: “Don’t put toxin genes into E. coli. Don’t put drug-resistant genes into E. coli, and don’t put cancer genes into E. coli,” Berg advised. With a moratorium in place, Berg and his colleagues argued, scientists could buy some time to consider the implications of their work. A second meeting was proposed for 1975, where the issues could be debated among a larger group of scientists.
In 1974, the “Berg letter” ran in Nature, Science, and Proceedings of the National Academy of Sciences. It drew instant attention around the globe. In Britain, a committee was formed to address the “potential benefits and potential hazards” of recombinant DNA and gene cloning. In France, reactions to the letter were published in Le Monde. That winter, François Jacob (of gene-regulation fame) was asked to review a grant application that proposed inserting a human muscle gene into a virus. Following Berg’s footsteps, Jacob urged tabling such proposals until a national response to recombinant DNA technology had been drafted. At a meeting in Germany in 1974, many geneticists reiterated a similar caution. Sharp constraints on experiments with recombinant DNA research were essential until the risks had been delineated, and recommendations formalized.
The research, meanwhile, was steamrolling ahead, knocking down biological and evolutionary barriers as if they had been propped up on toothpicks. At Stanford, Boyer, Cohen, and their students grafted a gene for penicillin resistance from one bacterium onto another and thereby created drug-resistant E. coli. In principle, any gene could be transferred from one organism to the next. Audaciously, Boyer and Cohen projected forward: “It may be practical . . . to introduce genes specifying metabolic or synthetic functions [that are] indigenous to other biological classes, such as plants and animals.” Species, Boyer declared jokingly, “are specious.”
On New Year’s Day 1974, a researcher working with Cohen at Stanford reported that he had inserted a frog gene into a bacterial cell. Another evolutionary border was casually crossed, another boundary transgressed. In biology, “being natural,” as Oscar Wilde once put it, was turning out to be “simply a pose.”
Asilomar II—one of the most unusual meetings in the history of science—was organized by Berg, Baltimore, and three other scientists for February 1975. Once again, geneticists returned to the windy beach dunes to discuss genes, recombination, and the shape of the future. It was an evocatively beautiful season. Monarch butterflies were migrating along the coast on their annual visit to the grasslands of Canada, and the redwoods and scrub pines were suddenly alit by a flotilla of red, orange, and black.
The human visitors arrived on February 24—but not just biologists. Cannily, Berg and Baltimore had asked lawyers, journalists, and writers to join the conference. If the future of gene manipulation was to be discussed, they wanted opinions not just from scientists, but from a much larger group of thinkers. The wood-decked pathways around the conference center allowed discursive conversations; walking on the decks or on the sand flats, biologists could trade notes on recombination, cloning, and gene manipulation. In contrast, the central hall—a stone-walled, cathedral-like space ablaze with sepulchral California light—was the epicenter of the conference, where the fiercest debates on gene cloning would soon erupt.
Berg spoke first. He summarized the data and outlined the scope of the problem. In the course of investigating methods to chemically alter DNA, biochemists had recently discovered a relatively facile technique to mix and match genetic information from different organisms. The technology, as Berg put it, was so “ridiculously simple” that even an amateur biologist could produce chimeric genes in a lab. These hybrid DNA molecules—recombinant DNA—could be propagated and expanded (i
.e., cloned) in bacteria to generate millions of identical copies. Some of these molecules could be shuttled into mammalian cells. Recognizing the profound potential and risks of this technology, a preliminary meeting had suggested a temporary moratorium on experiments. The Asilomar II meeting had been convened to deliberate on the next steps. Eventually, this second meeting would so far overshadow the first in its influence and scope that it would be called simply the Asilomar Conference—or just Asilomar.
Tensions and tempers flared quickly on the first morning. The main issue was still the self-imposed moratorium: Should scientists be restricted in their experiments with recombinant DNA? Watson was against it. He wanted perfect freedom: let the scientists loose on the science, he urged. Baltimore and Brenner reiterated their plan to create “crippled” gene carriers to ensure safety. Others were deeply divided. The scientific opportunities were enormous, they argued, and a moratorium might paralyze progress. One microbiologist was particularly incensed by the severity of the proposed restrictions: “You fucked the plasmid group,” he accused the committee. At one point, Berg threatened to sue Watson for failing to adequately acknowledge the nature of the risk of recombinant DNA. Brenner asked a journalist from the Washington Post to turn off his recorder during a particularly sensitive session on the risks of gene cloning; “I believe in the inalienable right of all adult scientists to make absolute fools of themselves in private,” he said. He was promptly accused of “being a fascist.”
The five members of the organizing committee—Berg, Baltimore, Brenner, Richard Roblin, and Maxine Singer, the biochemist—anxiously made rounds of the room, assessing the rising temperature. “Arguments went on and on,” one journalist wrote. “Some people got sick of it all and went out to the beach to smoke marijuana.” Berg sat in his room, glowering, worried that the conference would end with no conclusions at all.