The Gene: Part Three

But before he could envision modifying the human genome, Berg had to confront a technical challenge: he needed a method to insert a foreign gene into a viral genome. He would have to artificially engineer a genetic “chimera”—a hybrid between a virus’s genes and a foreign gene.

Genes, Lobban argued in his proposal, were no different from steel girders; they could also be retooled, altered, shaped to human specifications, and put to use.

They use DNA-cutting enzymes, like switchblades, to slice open the DNA of invaders, thereby rendering their hosts immune to attack.

The result was a strange chimera: genes from far branches of the evolutionary tree stitched together to form a single contiguous piece of DNA.

Berg called the hybrids “recombinant DNA”. It was a cannily chosen phrase, harkening back to the natural phenomenon of “recombination,” the genesis of hybrid genes during sexual reproduction.

Tenacious, unabashedly vocal about her opinions—“smart as all hell,” as Berg described her—Mertz was an anomaly in the world of biochemists: the second woman to join Stanford’s biochemistry department in nearly a decade.

But with his feet slung on the edge of a potential precipice, Berg could not afford to be cavalier. He wrote to several cancer biologists and microbiologists, asking them for independent opinions of the risk.

Until he had determined the precise nature of the risk, and made a plan for containment, Berg placed a self-imposed moratorium.

The initial cutting and pasting of DNA, as envisaged by Berg and Jackson, required six tedious enzymatic steps.

Mertz’s discovery, made with Ron Davis, involved a fortuitous quality of enzymes such as EcoR1.

Dinner had ended, but Cohen and Boyer were still hungry. With Stan Falkow, a fellow microbiologist, they strolled out of the hotel toward a quiet, dark street in a commercial strip near Waikiki beach. A New York-style deli, with bright flashing signs and neon-lit fixtures, loomed providentially out of the shadows of the volcanoes, and they found an open booth inside it.

Evolution would be conscripted to help their experiment. Natural selection, deployed in a petri dish, would naturally select their hybrid plasmids.

Genetics, like any language, is built out of basic structural elements—alphabet, vocabulary, syntax, and grammar.

Every experimental science depends, crucially, on the capacity to perturb a system intentionally, and to measure the effects of that perturbation.

In 1955, two years after his discovery of the structure of DNA, Watson had moved to the Department of Biology at Harvard and instantly raised the hackles of some of its most venerated professors.

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.”

By 1979, that same gene could be shuttled into bacteria, spliced into a viral vector, delivered into the genome of a mammalian cell, cloned, sequenced, and compared to the normal form.

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.

Berg was inundated with questions, as he had expected—but the direction of the conversation surprised him.

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.

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.

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.

Sharp constraints on experiments with recombinant DNA research were essential until the risks had been delineated, and recommendations formalized.

“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.”

“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.”

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.

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.

The federal government would respond by proposing draconian regulations—not just on recombinant DNA, but on a larger swath of biological 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).

“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.

Later, Berg reflected on this lacuna: “Did the organizers and participants of the Asilomar conference deliberately limit the scope of the concerns?...."

Joshua Lederberg, the Nobel Prize-winning biologist and Cohen’s colleague at Stanford, was among the few who wrote, presciently, that the experiment “may completely change the pharmaceutical industry’s approach to making biological elements, such as insulin and antibiotics.”

During their experiments, they had not even broached the idea that recombinant DNA techniques could be “patentable,” or that the technique could carry future commercial value.

Two decades later, two surgeons, Oskar Minkowski and Josef von Mering, had surgically removed the pancreas from a dog to identify the function of the organ. The dog was struck by an implacable thirst and began to urinate on the floor.

But the hormone was notoriously difficult to work with: insoluble, heat-labile, temperamental, unstable, mysterious—insular.

Swanson and Boyer suspected ruefully that they had taken a wrong turn and been left behind in the insulin race.

Dyspeptic even during the best of times, Swanson edged toward another bout of anxiety and indigestion.

Ironically, it was Asilomar—the very meeting that Boyer had so vociferously disparaged—that came to their rescue.

The conditions in the military facility were absurdly stringent. “You totally change your clothes, shower in, shower out, have gas masks available so that if the alarm goes off you can sterilize the entire laboratory,” Gilbert recalled.

At the CDC in Atlanta, a technician was asked to fill nine requests for pentamidine, an unusual antibiotic reserved to treat Pneumocystis pneumonia. These requisitions made no sense: PCP was a rare infection that typically afflicted cancer patients with severely depleted immune systems.

These were fulminant, aggressive cancers that spread rapidly through the skin and into the lungs, and they seemed to have a predilection for gay men living in New York and San Francisco.

Noting the preponderance of gay men afflicted, doctors began to call it GRID—gay-related immune deficiency.

The paucity of medicines has one principal reason: specificity.

Nearly every drug works by binding to its target and enabling or disabling it—turning molecular switches on or off. To be useful, a drug must bind to its switches—but to only a selected set of switches; an indiscriminate drug is no different from a poison.