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The decoding of success

How to Win the Nobel Prize: An Unexpected Life in Science, J. Michael Bishop, Harvard University Press: 272 pp., $27.95

June 15, 2003|D.T. Max | D.T. Max is a contributing editor to the Paris Review and is working on a book about prion diseases, of which "mad cow" is the best known.

How do you win the Nobel Prize? Despite its title, this book is not going to tell you. More accurate is its subtitle: "An Unexpected Life in Science." Born in rural Pennsylvania in 1936, J. Michael Bishop was not a likely Nobel winner. His science education didn't begin until high school. When he was applying to medical school, he didn't know where Harvard was (ultimately he found out and went there).

Still, he didn't set the world on fire. He met his lifelong collaborator, Harold Varmus, because another researcher didn't want him. This "senior figure in the field ... apparently thought that neither Harold nor I deserved better," he notes. That was in the late 1970s. In 1989, the two, one of the storied collaborations in modern science, shared the Nobel Prize. They had discovered proto-oncogenes, genes that, when damaged, can cause cancer.

To listen to someone explain how things just sort of happened to him is not always encouraging. The accidentalness of life can be dissuasive. The rest of us try so hard. But this memoir manages to be encouraging, thanks to Bishop's disarming, modest and consistently charming tone. And it's interesting to learn that Bishop nearly won two Nobel Prizes.

Early in his career he was studying Rous sarcoma virus, which has long held center stage among biologists because it was one of the first viruses shown to cause cancer in animals. How did it reproduce itself? It did not appear to use DNA. No one had been able to decipher the process. In the late '60s, Bishop was near to discovering that, in Rous sarcoma virus, the RNA made DNA. This is the reverse of the "central dogma" of genes, which is that DNA makes RNA. Unfortunately for Bishop, the idea seemed just too farfetched. He desisted.

The next year, two other research groups made the discovery. "The discovery of reverse transcriptase was a devastating blow to me," he writes. "A momentous secret of nature, mine for the taking, had eluded me." From this debacle, he learned two important lessons: "[T]he scientist must trust his or her imagination," and "most research grants are hunting licenses to bag anything of value."

These lessons helped when Varmus was dumped into Bishop's lab 10 years later. Bishop was now at UC San Francisco. The gene that caused the sarcoma virus had been isolated. But cancer was still a "black box," in Bishop's phrase. The darkest corner was how cells actually became cancerous. Bishop and Varmus were intrigued first by "an evolutionary puzzle. The SRC [sarcoma virus] gene apparently makes no contribution to the welfare of Rous sarcoma virus.... Why then is it there?" One possibility was that it came from an ancient accidental exchange of information with a virus. Was the sarcoma virus a foreign gene, an enemy within? Other researchers had posited this.

What Bishop and Varmus found first is that SRC genes are part of the genetic makeup of normal, healthy mammalian cells. This, unremarkable as it may sound today in an era in which the whole human genome has been sequenced, was a discovery that required painstaking work in the early '70s. Varmus and Bishop had to learn how to detect the presence of the SRC gene. Then they had to test for it in less evolved animals to see when it had come into the genome. What was the most primitive mammal that has the gene? It turned out all mammals have it. Clearly, the gene did one thing when healthy; it did another when sick. But how?

Recombinant DNA techniques later showed that the gene entered the Rous virus "by an accident of nature during the course of viral propagation." In other words, humans hadn't borrowed SRC from viruses -- viruses borrowed SRC from humans. And in borrowing it, they damaged it in ways that made it cause cancerous growth.

SRC was not alone in being able to convert from a normal human gene to one that could cause cancer. A number of genes, dubbed "proto-oncogenes," have this skill. And it turns out that it isn't only viruses that can cause this conversion. Environmental toxins can do it too. Here then were some basic concepts for future cancer researchers, a beginning to the long, still-unfinished attempt to conquer cancer. What Bishop and Varmus did was focus attention on genes as the preeminent center of cancer. Whether offended by viruses or toxins or genetic defects, it was the gene that got the cancer moving.

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