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Siddhartha Mukherjee’s History of Genomics Is a Story with a Lesson

Siddhartha Mukherjee

Writing history is hard. The details and dates, people and places can tumble over one another, leaving a confusing mess of disjointed stories. Yet in his new book The Gene: An Intimate History, not only does Pulitzer Prize winner and Columbia University cancer researcher Siddhartha Mukherjee successfully tell the hundred-plus year history of genomics. More than that, he explains along the way the science and its significance, in terms non-experts, such as myself, can follow and appreciate. Mukherjee did not write a breezy, short, quick read. His book takes time and requires attention. But it is enriching and worth the effort.

Part of what makes The Gene compelling is Mukherjee’s own story — depression and psychotic illness have skipped along the generations of his family. Grasping how the billions of base-pairs, the letters within our DNA, affects who we are, beyond our height, skin color, and nose size, is, for him, both personal and objective. It clouds his future and drives his curiosity.

the-gene-an-intimate-historyThe issues genomics raises — what we know, what we can do — compels me to look closely at two stories, almost bookends for the larger account. The first is Mukherjee’s depiction of Watson and Crick’s untangling of DNA. The second tells of one of the first families to try gene-therapy.

Watson and Crick are the stuff of science legend. Two mavericks, working through the chemistry, racing against other labs and pioneers of the field, notably Nobel Prize winning Linus Pauling, cracked the chemical structure that codes for life. Since they knew, generally, the chemical composition of DNA, they built towering metal models — precision Tinkertoy-like structures — attempting to fit all the parts into a cohesive whole. A flash of insight, constrained by the physics involved, guided them to success where others failed. (Linus Pauling also drew up DNA models, but his failed to take fundamental physics into account. His proposed structure could not have been stable.) They cracked the code of heredity, winning, along with Maurice Wilkins, who oversaw a lab at King’s College in London, a 1962 Nobel Prize. And although earlier work established the existence of inherited information, their unscrambling of DNA’s structure made tracing, and modifying, that information possible. Without it, there would be no genomic science.

But Mukherjee is careful to tell the whole story. Watson and Crick did not unwind DNA on their own. They conducted no experiments. They took no photographs of DNA (another common research tool). The key to their discovery came through inappropriate access to the X-ray crystallography of another researcher, Rosalind Franklin. X-ray crystallography requires exacting patience, even more when a molecule refuses to sit still. Franklin began refining her methods in 1951, eventually achieving exquisite photographs of DNA. Franklin gave a pre-publication copy of her paper to an oversight committee for review. On that committee was Max Perutz, Watson and Crick’s lab supervisor in Cambridge. Though Perutz claimed innocence, he shared Franklin’s paper with Watson and Crick. Her paper, and the photograph that she worked so hard to obtain, told Watson and Crick all they needed to succeed. Franklin had also critiqued their earlier models, pointing out flaws they should have seen. Yet when Watson and Crick published their paper in 1953, they gave Franklin no credit.

She died, her contributions unknown, in 1958, four years before Watson and Crick received the Nobel Prize. The significance of their discovery cannot overshadow this detail: Depending on how you interpret the chain of events, they either misappropriated work or simply failed to give credit where credit was due. Legends aside, Watson and Crick were human, eager for recognition and success, and that twisted their decisions.

Towards the end of the book Mukherjee unfolds the tragedy of Jesse Gelsinger. In 1999, he took a plane to Philadelphia where he would undergo one of the first gene-therapy treatments. Jesse, 18 years old at the time, suffered from a rare, single-gene disease, ornithine transcarbamylase (OTC) deficiency. The defective OTC gene impairs a critical step in the breakdown of protein, resulting in ammonia accumulating throughout the body. Most people with the condition die in childhood.

As Mukharjee tells it, two eager pediatricians, Mark Batshaw and James Wilson, had developed a gene-therapy they hoped could cure OTC deficiency. Mukherjee describes Wilson as “a former college-level football player” and a “risk taker fascinated by ambitious human experiments.” Batshaw and Wilson’s technique relied on a virus to carry the unmutated OTC gene directly to a patient’s liver from which it would invade the bloodstream, infect the cells, and begin producing the much needed enzyme, or so they reasoned. Gelsinger heard of their work and in June 1999, through his local doctors, contacted Batshaw and Wilson. The following September he caught his plane. On the morning of September 13, 1999, Batshaw and Wilson injected Jesse with the modified virus. The afternoon was “uneventful,” but, by that evening, Jesse had developed a fever of 104 degrees. The next morning, his eyes were a pale yellow, meaning bilirubin, a liver product, was seeping into Jesse’s bloodstream. Something had gone wrong. By eight in the morning the following day, Jesse was no longer coherent and his kidneys were failing. He soon fell into a coma, his body swollen and yellow with jaundice. By Friday, September 17, just four days after his treatment, Jesse was brain-dead and his father agreed to remove life-support.

Mukherjee calls Jesse’s death an experiment gone “so, so wrong.” Investigations found that Wilson had a “financial stake in the biotechnology company that stood to benefit from” the gene-therapy. Protocols were violated. Warning signs ignored. A “pattern of neglect” characterized the entire experiment. As Mukherjee summarizes: “The OTC trial was nothing short of ugly — hurriedly designed, poorly planned, badly monitored, and abysmally delivered. It was made twice as hideous by the financial conflicts involved; the prophets were in it for profits.”

It was not an isolated case. The FDA found problems requiring remediation in other research trials as well. In January 2000, the FDA shut down nearly all gene-therapy trials. Wilson was banned for five years from human clinical trials.

My purpose in highlighting these accounts — and I’ve selected just two from the many Mukharjee reports that touch on the same concerns — is not to disparage scientists. Nor is it to discourage the careful and legitimate hopes of genomic science. The stories do show, however, just how human scientists are. Even on their best days, they, like all of us, make mistakes and misjudge how a treatment might work. Ego and fame can blind them, obscuring important details. They can overreach and suffer conflicts of interest. The popular image of scientists, always clear thinking, objective, pure, driven only by data, is a myth; those men and women do not exist. As paleontologist Niles Eldredge wrote in his book The Monkey Business (pp. 26-27):

Many scientists really do seem to believe they have a special access to the truth…they expect to believed…especially by the public at large. Throwing down scientific thunderbolts from Olympian heights, scientists come across as authoritarian truth givers whose word must be taken unquestioned. That all evidence shows the behavior of scientists clearly to be no different from the ways in which other people behave is somehow overlooked in all this.

Mukharjee makes clear, though he appears conflicted about it, that most scientists want to set their own boundaries and limits, as if, unlike the rest of us, we can trust them to self-guide and do the right thing. In fact, as Mukharjee unintentionally shows, we cannot trust them to make good and right decisions, not all on their own. Scientists will do bad things; sometimes purposely, sometimes mistakenly. They are not super-human.

Scientists also, like everyone else, bring a frame of reference to their work, a view that shapes what they see, how they evaluate risk, and who they elect to reward. Ethics matter; weighing the risks matters. But what matters more is the perspective that informs those ethics and provides weight to the risks.

If the universe is nothing more than a Rube Goldberg machine, an accidental collection of matter pressed through the sieve of survival, you’ll likely make one set of decisions. On the other hand, if the universe is a designed, meant to function and with a purpose behind it all, that’s a very different matter. What researchers believe about the genome can’t help but impact what they see and how they treat it — that is, how they treat other human beings. Since the majority of scientists work within the echo chamber of scientific naturalism, outsiders must establish the boundaries and assess risks. We cannot simply allow genomic researchers to do whatever they believe is best. That is the lesson of Mukharjee’s book, if inadvertently delivered.

Photo: Siddhartha Mukherjee, by ShajiA at ml.wikipedia [CC BY-SA 3.0], via Wikimedia Commons.