The Gene: An Intimate History - Siddhartha Mukherjee Page 0,218

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There is in biology at the moment a sense of barely contained expectations reminiscent of the physical sciences at the beginning of the 20th century. It is a feeling of advancing into the unknown and [a recognition] that where this advance will lead is both exciting and mysterious. . . . The analogy between 20th-century physics and 21st-century biology will continue, for both good and ill.

—“Biology’s Big Bang,” 2007

In the summer of 1991, not long after the Human Genome Project had been launched, a journalist visited James Watson at the Cold Spring Harbor lab in New York. It was a sultry afternoon, and Watson was in his office, sitting by a window overlooking the gleaming bay. The interviewer asked Watson about the future of the Genome Project. What would happen once all the genes in our genome had been sequenced and scientists could manipulate human genetic information at will?

Watson chuckled and raised his eyebrows. “He ran a hand down his sparse strands of white hair . . . and a puckish gleam came into his eye. . . . ‘A lot of people say they’re worried about changing our genetic instructions. But those [genetic instructions] are just a product of evolution designed to adapt us for certain conditions that may not exist today. We all know how imperfect we are. Why not make ourselves a little better suited to survival?’ ”

“That’s what we will do,” he said. He looked at his interviewer and laughed suddenly, emitting that distinctive, high-pitched chortle that had become familiar to the scientific world as a prelude to a storm. “That’s what we will do. We’ll make ourselves a little better.”

Watson’s comment returns us to the second concern raised by the students at the Erice meeting: What if we learn to intentionally alter the human genome? Until the late 1980s, the only mechanism to reshape the human genome—to “make ourselves a little better” in a genetic sense—was to identify highly penetrant and seriously deleterious genetic mutations (such as those that cause Tay-Sachs disease or cystic fibrosis) in utero and terminate the pregnancy. In the 1990s, preimplantation genetic diagnosis (PGD) allowed parents to preemptively select and implant embryos without such mutations, substituting the moral dilemma of the termination of a life with the moral dilemma of choice. Still, human geneticists operated within the aforementioned triangle of boundaries: highly penetrant genetic lesions, extraordinary suffering, and justifiable, noncoerced interventions.

The advent of gene therapy in the late 1990s changed the terms of this discussion: genes could now be changed intentionally in human bodies. This was the rebirth of “positive eugenics.” Rather than eliminating humans carrying deleterious genes, scientists could envision correcting defective human genes, thereby making the genome a “bit better.”

Conceptually, gene therapy comes in two distinct flavors. The first involves modifying the genome of a nonreproductive cell—say a blood, brain, or muscle cell. The genetic modification of these cells affects their function, but it does not alter the human genome for more than one generation. If a genetic change is introduced into a muscle or blood cell, the change is not transmitted into a human embryo; the altered gene is lost when the cell dies. Ashi DeSilva, Jesse Gelsinger, and Cynthia Cutshall are all examples of humans treated with non-germ-line gene therapy: in all three cases, blood cells—but not germ-line cells (i.e., sperm and egg)—were altered by the introduction of foreign genes.

The second, more radical, form of gene therapy is to modify a human genome so that the change affects reproductive cells. Once a genomic change has been introduced into a sperm or egg—i.e., into the germ line of a human being—the change becomes self-propagating. The change is incorporated permanently into the human genome and transmitted from one generation to the next. The inserted gene becomes inextricably linked to the human genome.

Germ-line gene therapy in humans was not conceivable in the late 1990s: no reliable technique existed to transmit genetic changes into a human sperm or egg cell. But even non-germ-line therapy trials had been halted. Jesse Gelsinger’s “biotech death,” as the New York Times Magazine described it, had sent such tremors of anguish through the field that virtually all gene-therapy trials in the United States were frozen. Companies went bankrupt. Scientists left the field. The trial scorched the earth of all forms of gene therapies, leaving a permanent scar on the field.

But gene therapy has returned—step by cautious step. The seemingly stagnant decade between 1990 and 2000 was a decade of introspection and reconsideration. First, the litany of errors