Peter Duesberg has grown accustomed to all of the slights that come with a life in intellectual exile. The 72-year-old molecular biologist no longer expects an invitation to present his research at the big conferences in his field or to meet with any of the scientists who visit the University of California, Berkeley, where he works. Nor is he surprised when his manuscripts are inexplicably rejected. But in an open lecture this past May, when a visiting scientist claimed that practically no one had investigated the role chromosome damage plays in cancer, it was a step too far. Duesberg himself has been hammering away at that very question for years. He's published peer-reviewed papers on the topic, given a recent talk at the National Cancer Institute (his first there in 15 years), even hosted two small conferences of his own. So when the speaker solicited audience feedback, he jumped up immediately. "Excuse me," he said into the microphone. "But I am nobody."
He wasn't always. In the past three decades, Duesberg has been described as a genius, a martyr, and a genocidal lunatic—often by the same person, usually amid the fierce debates and international headlines that come with major scientific breakthroughs. In 1971, at the age of 33, he became the first scientist to identify a cancer-causing gene—a biological holy grail that secured his place among an elite group of the country's top researchers. Tenure at Berkeley and a coveted spot in the National Academy of Sciences followed. So did rumors of a Nobel and millions in grant money from the National Cancer Institute.
Then in 1988, Duesberg broke ranks with his colleagues and postulated that the newly discovered human immuno-deficiency virus (HIV) was not the cause of AIDS. Rather, he declared, it was a harmless passenger virus, found by coincidence in patients whose illnesses stemmed from a constellation of other factors including malnutrition and substance abuse. For this, he was summarily cast out of Eden: Grant money evaporated. Graduate students disappeared. Nobel laureates stopped inviting him to dinner. Of course, he might have been forgiven—or at least forgotten—were it not for his consultation with Thabo Mbeki in 2000. When Duesberg advised the South African president not to bother with antiretroviral medication programs (he still believes the drugs are more toxic than the virus), his adversaries say he condemned hundreds of thousands of the world's most vulnerable people to death. Consorting with Mbeki to such disastrous ends fixed Duesberg as more than a mere pariah. From then on, he was Duesberg the mass murderer.
Since then, the fallen hero has toiled in what amounts to scientific purgatory—a smaller lab with private funding where he continues his cancer research. The shadows have proved both a refuge and a prison for Duesberg—freeing him to pursue less conventional ideas, but preventing his colleagues from taking those ideas seriously. His stubbornness has made him one of science's most disturbing paradoxes—a self-avowed outsider searching desperately for a way back in. While he implores his colleagues to open their minds about cancer, he continues to keep his own closed about HIV, insisting still that the virus does not cause AIDS. To honestly evaluate his latest work, we will have to separate science from scientist.
For decades now, researchers have been operating (to the tune of billions of dollars) under the assumption that cancer is the work of oncogenes: human genes that have mutated or viral genes that insert themselves into the host's DNA. According to current dogma, oncogenes cause cells to divide uncontrollably, spurring a cascade of additional mutations that eventually results in a tumor. So far, this hypothesis has led to a number of apparent cul-de-sacs: some faltering attempts at gene-replacement therapy, a growing roster of targeted drugs that work only for some patients (and usually not for very long), and, more recently, the Cancer Genome Atlas—a concerted effort by the National Cancer Institute to sequence the genomes of 10,000 tumor samples, described by more than a few insiders as a colossal waste of time and money.
Duesberg has a different hypothesis. According to him, tumors are created not by the accumulation of individual mutations, but by wholesale changes in the structure and arrangement of a cell's chromosomes. "It's the difference between changing a couple of words in a sentence and ripping the entire set of encyclopedias apart," he says. The upheaval is so great that a tumor effectively constitutes a new species—one that grows like a parasite inside its host. Duesberg says that characterizing these upheavals is the best way to understand how cancer begins. Two decades into his scientific exile, some scientists think he might actually be on to something. Something big enough to change the way we look at cancer.
The defining trait of any given species—the thing that distinguishes it from all other species—is not so much its genetic code as its karyotype: the number and size of chromosomes into which that code is organized. Humans and cats and worms all share numerous genes in common, but each has a different karyotype: cats have a total of 38 chromosomes, worms 12. And with a few rare exceptions, humans have two copies each of 23 different chromosomes. Cells that deviate significantly from this blueprint—by making five copies of one chromosome, for example, or only one copy of another—usually die pretty quickly. But sometimes, Duesberg says, a cell will chance upon a new karyotype that doesn't kill it. These cells are called aneuploid, and they tend to grow and divide in rapid and unstable fashion. Eventually, he says, they evolve into something that can grow uncontrollably anywhere in the body.
It turns out that almost all solid tumors are aneuploid, and this little-examined fact may have implications for the way some cancers are diagnosed and treated. For example, the karyotypes of prostate and cervical tumors can be used to predict whether a given lesion is likely to become malignant, and thus help determine whether surgery is warranted. Swedish doctors are beginning to make use of this information, but aneuploidy receives little attention in the U.S., where the vast majority of funding still goes toward oncogene research. Part of the problem may be entrenched viewpoints that hinder innovation. But another problem may be Duesberg himself.
For five minutes, at least, the embattled scientist can be charming. When I met him at the Caffe Strada just a few blocks east of Berkeley's Telegraph Avenue, he rode up on an old -Schwinn, gave me a hug, and bought me a scone. He is loquacious and grandfatherly. He has bright blue eyes, a warm smile and a thick German accent that makes him endearingly difficult to understand. It's at 10 minutes that he begins to betray himself. In explaining the impact chromosome changes can have on health, he lumps being a woman and having Down syndrome into the same category. "One happens when you add an extra copy of chromosome 21, and the other," he says, half joking, "when you take away the Y chromosome and put an X in its place; you lose all the IQ genes." He calls black people Schwarzes, and gay people homos, and as an example of how evolution can go awry, he compares Nobel laureate James Watson to E. coli. His assistant, Josh Nicholson, describes these constant gaffes as fingernails-on-a-blackboard irksome. "But he's not racist," Nicholson says. "He's just from a different era, when people actually talked like that."
In fact, Duesberg grew up during World War II, a Catholic in Nazi Germany. Both parents were prominent doctors; his father volunteered as a medic in the Nazi Army to avoid being forced into the Nazi political party. And Allied forces firebombed his house one Christmas Eve while his family huddled in a shelter. He recalls his formative years fondly, but it's clear that that time still hangs over him: in casual conversation, Duesberg repeatedly refers to the war, the Holocaust, and the idea of being a "good German"—almost always in some comparison to his current situation. Being cast out of the mainstream, for example, is like being herded onto a train by the Gestapo, never to be seen again.
At Berkeley, Duesberg has long since been relegated to the small, cluttered corner of a decaying building, where he and Nicholson have done their best to conduct research on a shoestring. For a recent series of tumor experiments, Nicholson bought mice from a pet shop in downtown Berkeley and snuck them into the lab. (Lab animals are supposed to be housed in a separate veterinarian-run animal facility, and only by investigators who have obtained the necessary approvals, but all of that costs money.) Campus officials found them out halfway through the six-month project. Despite Duesberg's pleas to let them finish up, the mice were confiscated and killed. The data were lost. "We are the pauper scientists," he says, recalling the incident. "Always begging on our knees. Ever since HIV."
In truth, Duesberg had marked himself as an iconoclast even before the discovery of HIV. He came to Berkeley in 1964, after finishing his Ph.D. in chemistry at the University of Frankfurt. Back then, scientists still believed that yet-to-be-discovered viruses were the root cause of all cancers, and Duesberg quickly joined the likes of David Baltimore and Robert Gallo in the hunt for these viruses. Duesberg was the first to score a win. He sequenced the entire genome of RSV—a chicken virus believed to trigger tumor growth—and identified the offending gene, called src, which was thought to cause rapid, unchecked cell growth when it inserted itself into the host genome. Soon after, Michael Bishop and Harold Varmus found an analogous src gene in human cells that, when mutated, did the same as the viral form of the gene. Almost immediately, the tribe of cancer researchers split into two factions: one continued searching for cancer viruses; the other turned its attention to human oncogenes. Duesberg had already begun to suspect that neither was the smoking gun.
For starters, some known carcinogens like arsenic and asbestos did not seem to cause mutations. On top of that, no single mutation was enough to turn a normal cell cancerous. Over the years, researchers have accounted for this by expanding the list of required mutations. In breast cancer alone, some 250 mutations are now thought to play a role. But several researchers have noted that a cell's chances of hitting on the exact combination of required mutations would make cancer a rare event, not a common disease.
In his quest for another instigator, Duesberg stumbled upon aneuploidy, something almost all tumors had in common. The aneuploidy nature of cancer was no secret—German scientist Theodor Boveri first noted it in 1914—but it had long since been written off as a consequence of cancer, not a cause. In 1984 Duesberg began to question this presumption. Doing so meant trivializing two decades' worth of his own oncogene research, but he says that was fine by him. "Science is a game," he says." And I was prepared to lose." But just as he was fleshing out his new hypothesis, a mystery epidemic seized the nation; the towns and cities surrounding Berkeley's campus were at its very epicenter.
Duesberg concocted his AIDS hypothesis in the frenetic early days of the epidemic, when the balance of evidence had not yet tipped in favor of HIV. At first, he proceeded along perfectly respectable avenues of inquiry—mapping out the epidemic use of poppers, a nitrite drug that had become a cheap and popular way of getting high—and showing that it correlated strongly with the AIDS epidemic. His results were published in Science and Nature, and for a brief moment it appeared that his hypothesis was at least plausible.
But as a consensus formed around HIV as the cause of AIDS, Duesberg refused to budge. He clung to the outliers: HIV-positive patients who never developed full-blown AIDS, and patients with all the symptoms of AIDS but no detectable HIV. When his colleagues offered potential explanations for each, he challenged their interpretations of the data. Before long, the so-called golden boy had alienated himself from all but a few friends. "He was irritating too many people at once," says George Miklos, an Australian scientist who helped map the human genome. "He was challenging the HIV work and raising all these uncomfortable questions about oncogenes. Nobody wanted to hear it. So they wrote him off as crazy."
Experts who have followed Duesberg's career say he is not so much crazy as pathologically stubborn. "He is like a big-game fisher who loves the fight too much," says Seth Kalichman, a social psychologist whose recent book on HIV-deniers included a whole chapter on Duesberg. "He's destined to lose because he won't give any slack. It's tragic because he's clearly a brilliant thinker and could have had much more to offer." While it's clear that Duesberg craves a return to respectability, he refuses to cede any ground to his adversaries. "If you go on your knees," he says, "then they say, 'We knew you were wrong all along—now you've admitted it!' "
In recent years, cancer researchers have begun to take up the questions that Duesberg laid out 25 years ago—reexamining the role of aneuploidy and other forms of chromosome instability in tumor formation, and figuring out how they tie into the mutation model. "The relative contribution of each is now one of the biggest questions in cancer," says Thomas Ried, a scientist at the National Cancer Institute who recently invited Duesberg to present his aneuploidy research.
But even as some of his ideas rise to the top, Duesberg himself remains stuck at the bottom. Few scientists who have turned their attention to aneuploidy bother to cite Duesberg's work. His lab is down to its last $50,000, and this past year Berkeley officials relieved him of his only remaining teaching duty. Even some scientists who don't agree with Duesberg say that he has been treated unfairly. "The ideological assassinations that he has undergone will remain an embarrassing testament to the reactionary tendencies of modern science," Richard Horton, editor of The Lancet, wrote in 1996.
Duesberg's old life still haunts him at every turn. At an opera this past spring, he spotted Jay Levy, a friend from the good old days who has since become a laboratory director and lead HIV researcher at the University of California, San Francisco. "I called over to him, and I think at first he was trying to pretend he didn't hear me," Duesberg says. "And I think he was looking over his shoulder the whole time—afraid someone would see us together." But the two men talked through the intermission, mostly about the fun they used to have. "He used to throw these fantastic parties," says Duesberg. They also talked science, sparring a bit over Levy's latest work on latent HIV infection. Recalling the evening weeks later, Duesberg admits that he misses his old friends and the intellectual rigor of their exchanges. "The whole dissident idea attracts a lot of crazies," he says, his voice trailing off into a sigh. "And then all of a sudden, without realizing it, you've become one of them."