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 than 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.

Nothing had been formalized by the last evening of the conference, until the lawyers took the stage. The five attorneys asked to discuss the legal ramifications of cloning and laid out a grim vision of potential risks: if a single member of a laboratory was infected by a recombinant microbe, and that infection led to even the palest manifestations of a disease, they argued, the laboratory head, the lab, and the institution would be held legally liable. Whole universities would shut down. Labs would be closed indefinitely, their front doors picketed by activists and locked by hazmat men in astronaut suits. The NIH would be flooded with queries; all hell would break loose. The federal government would respond by proposing draconian regulations—not just on recombinant DNA, but on a larger swath of biological research. The result could be restrictions vastly more stringent than any rules that scientists might be willing to impose on themselves.

The lawyers’ presentation, held strategically on the last day of Asilomar II, was the turning point for the entire meeting. Berg realized that the meeting should not—could not—end without formal recommendations. That evening, Baltimore, Berg, Singer, Brenner, and Roblin stayed up late in their cabana, eating Chinese takeout from paper cartons, scribbling on a blackboard, and drafting a plan for the future. At five thirty in the morning, disheveled and bleary-eyed, they emerged from the beach house smelling of coffee and typewriter ink, with a document in hand. The document began with the recognition of the strange parallel universe of biology that scientists had unwittingly entered with gene cloning. “The new techniques, which permit combination of genetic information from very different organisms, place us in an arena of biology with many unknowns. . . . It is this ignorance that has compelled us to conclude that it would be wise to exercise considerable caution in performing this research.”

To mitigate the risks, the document proposed a four-level scheme to rank the biohazard potentials of various genetically altered organisms, with recommended containment facilities for each level (inserting a cancer-causing gene into a human virus, for instance, would merit the highest level of containment, while placing a frog gene into a bacterial cell might merit minimal containment). As Baltimore and Brenner had insisted, it proposed the development of crippled gene-carrying organisms and vectors to further contain them in laboratories. Finally, it urged continuous review of recombination and containment procedures, with the possibility of loosening or tightening restrictions in the near future.

When the meeting opened at eight thirty on the last morning, the five members of the committee worried that the proposal would be rejected. Surprisingly, it was near unanimously accepted.

In the aftermath of the Asilomar Conference, several historians of science have tried to grasp the scope of the meeting by seeking an analogous moment in scientific history. There is none. The closest one gets to a similar document, perhaps, is a two-page letter written in August 1939 by Albert Einstein and Leo Szilard to alert President Roosevelt to the alarming possibility of a powerful war weapon in the making. A “new and important source of energy” had been discovered, Einstein wrote, through which “vast amounts of power . . . might be generated.” “This new phenomenon would also lead to the construction of bombs, and it is conceivable . . . that extremely powerful bombs of a new type may thus be constructed. A single bomb of this type, carried by boat and exploded in a port, might very well destroy the whole port.” The Einstein-Szilard letter had generated an immediate response. Sensing the urgency, Roosevelt had appointed a scientific commission to investigate it. Within a few months, Roosevelt’s commission would become the Advisory Committee on Uranium. By 1942, it would morph further into the Manhattan Project and ultimately culminate in the creation of the atomic bomb.

But Asilomar was different: here, scientists were alerting themselves to the perils of their own technology and seeking to regulate and constrain their own work. Historically, scientists had rarely sought to become self-regulators. As Alan Waterman, the head of the National Science Foundation, wrote in 1962, “Science, in its pure form, is not interested in where discoveries may lead. . . . Its disciples are interested only in discovering the truth.”

But with recombinant DNA, Berg argued, scientists could no longer afford to focus merely on “discovering the truth.” The truth was complex and inconvenient, and it required sophisticated assessment. Extraordinary technologies demand extraordinary caution, and political forces could hardly be trusted to assess the perils or the promise of gene cloning (nor, for that matter, had political forces been particularly wise about handling genetic technologies in the past—as the students had pointedly reminded Berg at Erice). In 1973, less than two years before Asilomar, Nixon, fed up with his scientific advisers, had vengefully scrapped the Office of Science and Technology, sending spasms of anxiety through the scientific community. Impulsive, authoritarian, and suspicious of science even at the best of times, the president might impose arbitrary control on scientists’ autonomy at any time.

A crucial choice was at stake: scientists could relinquish the control of gene cloning to unpredictable regulators and find their work arbitrarily constrained—or they could become science regulators themselves. How were biologists to confront the risks and uncertainties of recombinant DNA? By using the methods that they knew best: gathering data, sifting evidence, evaluating risks, making decisions under uncertainty—and quarreling relentlessly. “The most important lesson of Asilomar,” Berg said, “was to demonstrate that scientists were capable of self-governance.” Those accustomed to the “unfettered pursuit of research” would have to learn to fetter themselves.

The second distinctive feature of Asilomar concerned the nature of communications between scientists and the public. The Einstein-Szilard letter had been deliberately shrouded in secrecy; Asilomar, in contrast, sought to air the concerns about gene cloning in the most public forum possible. As Berg put it, “The public’s trust was undeniably increased by the fact that more than ten percent of the participants were from the news media. They were free to describe, comment on, and criticize the discussions and conclusions. . . . The deliberations, bickering, bitter accusations, wavering views, and the arrival at a consensus were widely chronicled by the reporters that attended.”

A final feature of Asilomar deserves commentary—notably for its absence. While the biological risks of gene cloning were extensively discussed at the meeting, virtually no mention was made of the ethical and moral dimensions of the problem. What would happen once human genes were manipulated in human cells? What if we began to “write” new material into our own genes, and potentially our genomes? The conversation that Berg had started in Sicily was never rejuvenated.

Later, Berg reflected on this lacuna: “Did the organizers and participants of the Asilomar conference deliberately limit the scope of the concerns? . . . Others have been critical of the conference because it did not confront the potential misuse of the recombinant DNA technology or the ethical dilemmas that would arise from applying the technology to genetic screening and . . . gene therapy. It should not be forgotten that these possibilities were still far in the future. . . . In short, the agenda for the three-day meeting had to focus on an assessment of the [biohazard] risks. We accepted that the other issues would be dealt with as they became imminent and estimable.” The absence of this discussion was noted by several participants, but it was never addressed during the meeting itself. It is a theme to which we will return.

In the spring of 1993, I traveled to Asilomar with Berg and a group of researchers from Stanford. I was a student in Berg’s lab then, and this was the annual retreat for the department. We left Stanford in a caravan of cars and vans, hugging the coast at Santa Cruz and then heading out toward the narrow cormorant neck of the Monterey Peninsula. Kornberg and Berg drove ahead. I was in a rental van driven by a graduate student and accompanied, improbably, by an opera-diva-turned-biochemist who worked on DNA replication and occasionally burst into strains of Puccini.

On the last day of our meeting, I took a walk through the scrub-pine groves with Marianne Dieckmann, Berg’s long-term research assistant and collaborator. Dieckmann guided me through an unorthodox tour of Asilomar, pointing out the places where the fiercest mutinies and arguments had broken out. This was an expedition through a landscape of disagreements. “Asilomar,” she told me, “was the most quarrelsome meeting that I have ever attended.”

What did these quarrels achieve? I asked. Dieckmann paused, looking toward the sea. The tide had gone out, leaving the beach carved in the shadows of waves. She used her toe to draw a line on the wet sand. “More than anything, Asilomar marked a transition,” she said. “The capacity to manipulate genes represented nothing short of a transformation in genetics. We had learned a new language. We needed to convince ourselves, and everyone else, that we were responsible enough to use it.”

It is the impulse of science to try to understand nature, and the impulse of technology to try to manipulate it. Recombinant DNA had pushed genetics from the realm of science into the realm of technology. Genes were not abstractions anymore. They could be liberated from the genomes of organisms where they had been trapped for millennia, shuttled between species, amplified, purified, extended, shortened, altered, remixed, mutated, mixed, matched, cut, pasted, edited; they were infinitely malleable to human intervention. Genes were no longer just the subjects of study, but the instruments of study. There is an illuminated moment in the development of a child when she grasps the recursiveness of language: just as thoughts can be used to generate words, she realizes, words can be used to generate thoughts. Recombinant DNA had made the language of genetics recursive. Biologists had spent decades trying to interrogate the nature of the gene—but now it was the gene that could be used to interrogate biology. We had graduated, in short, from thinking about genes, to thinking in genes.

Asilomar, then, marked the crossing of these pivotal lines. It was a celebration, an appraisal, an assembly, a confrontation, a warning. It began with a speech and ended with a document. It was the graduation ceremony for the new genetics.