By Kevin E. Noonan --
Peter Duesberg is at it again. Pioneering virologist and molecular biologist, purported genius, and member of the U.S. National Academy of Science, Professor Duesberg is predominantly and (in)famously a scientific contrarian, quick, even eager to tell other scientists that they are wrong - not just wrong about a particular experiment or line of inquiry, but utterly, irredeemably wrong about fundamental explanations for biological phenomena.
Professor Duesberg (at right), who is on the faculty at the University of California at Berkley in the Department of Molecular and Cell Biology, began to develop his dissenting style over the issue of oncogenes - cellular genes believed to be involved in causing cancer. The genesis for the idea came from Duesberg's own area of study - using molecular biology to sequence avian and mammalian retroviruses which were associated with cancer in many animal species (except, with one rare exception, man). One of the biggest surprises to come out of this work is that the viral genes responsible for making the viruses cancer-causing - called oncogenes - had related homologues in vertebrate genomic DNA. This led to a large field of endeavor to identify these human proto-oncogenes and to determine the differences between the viral genes and the vertebrate genes to understand why the viral genes caused cancer.
Professor Duesberg began to take exception to the interpretation of the results of these studies when Robert Weinberg (at MIT; left), Mariano Barbacid (at the NIH), and Michael Wigler (at Cold Spring Harbor) all independently showed that a proto-oncogene, c-ras, could transform a mouse fibroblast cell line (NIH 3T3 cells) to display cancer-cell associated properties, including growth in serum-depleted media and soft agar, and tumorigenicity in experimental animals. Demonstrations (some that turned out to be unreliable) of the same capacity were published for other cellular proto-oncogenes. This resulted in the theory that such proto-oncogenes, and mutation or dysregulation of proto-oncogene expression, were involved in naturally-occurring tumorigenesis in humans.
Professor Duesberg vigorously challenged these results, basing his objections on the artificiality of the transformation system used and the structural differences between proto-oncogenes and retroviral oncogenes. The latter, according to Professor Duesberg, were in every case dramatically-changed molecules, exhibiting deletions, truncations, and mutations that distinguished the viral genes from their cellular progenitors. Professor Duesberg accepted that the viral genes had been selected by evolutionary pressures to act as tumor-causing genes, but did not agree that cellular genes played the same role. Rather, Professor Duesberg believed that loss-of-function mutations, particularly among tumor suppressor genes (which at the time were mainly hypothetical) were responsible for human cancer. At times, his was one of the few voices making this argument, and although no one today doubts that oncogenes are involved in human cancer, the role of mutant tumor suppressor genes has also been recognized in the years since Professor Duesberg's original objections. Tellingly, however, Professor Duesberg's objections were based at least in part on his conviction that the phenomenology of classical cancer cell biology did not comport with (or was relegated to a mere consequence by) the ascendant molecular biology of cancer.
Professor Duesberg is most famous, of course, for challenging the hypothesis that human immunodeficiency virus causes acquired immune deficiency syndrome (AIDS). Again, the basis for Professor Duesberg's objections were based on classical epidemiology: according to Professor Duesberg, the HIV hypothesis did not fulfill Koch's postulates for identifying a microorganism responsible for disease. The postulates, developed by Robert Koch (at right) during his investigations in the late 19th century resulting in identifying many disease-causing microorganisms, are:
1. The microorganism must be found in all organisms suffering from the disease, but not in healthy organisms.
2. The microorganism must be isolated from a diseased organism and grown in pure culture.
3. The cultured microorganism should cause disease when introduced into a healthy organism.
4. The microorganism must be reisolated from the inoculated, diseased experimental host and identified as being identical to the original specific causative agent.
According to Professor Duesberg, HIV did not fulfill these criteria: HIV was not always detectable in AIDS patients, and HIV infected individuals could appear healthy, for example. Unfortunately, the universality of the postulates is not absolute, a fact recognized by Koch himself. For example, asymptomatic "carriers" of disease exist, contravening the first postulate (for example, in typhoid), and the capacity of a cultured microorganism to cause disease according to the third postulate is dependent on a great many other factors, including individual susceptibility of the host organism. Undeterred, Professor Duesberg attributed AIDS to a general depletion of the immune system caused by, among other things, promiscuous sex and amyl nitrate abuse. While these theories may have had some attractiveness, particularly among those ready and willing to blame homosexual behavior for the AIDS epidemic, it had much less relevance to the crisis in places like sub-Saharan Africa, but that did not deter Professor Duesberg from promoting his unorthodox theories.
Professor Duesberg's insistence that he was right and everyone else wrong about the "AIDS hypothesis" soon turned to accusations by him that those advocating that HIV causes AIDS were motivated not by the evidence but by a desire to secure research funding. In the political climate of the times, where AIDS sufferers, mostly homosexual American men, were suspicious of the intentions and motivations of the Reagan administration, Professor Duesberg's accusations had some traction. They also led to his rapid expulsion from whatever reasoned debate occurred about AIDS in those years, and he was marginalized along with other "HIV deniers." While Professor Duesberg's position has not affected clinical care for AIDS patients in the West, the most persistent and deleterious effects have been in Africa, where charlatans and corrupt politicians have seized upon his notoriety to use his statements to support policies that do not address the crisis, including everything from folk remedies to neglect (see, e.g., abstract for "The Denialists").
Professor Duesberg paid a personal price for his stridency regarding AIDS: after many years of consistent funding for his own research, he lost most federal funding in the aftermath of the AIDS controversy.
In his later years, Professor Duesberg has once again returned to the question of what causes cancer in humans, and in a recent article in Drug Resistance Updates, he once again maintains that those advocating a mutation-based cause are wrong. This time, he believes that what causes cancer is not mutation, but aneuploidy - the disruption in the number and integrity of the chromosomes in cancer when compared with normal cells. This phenomenon is well-known, both for the existence of specific, diagnostic chromosomal abnormalities (such as the Philadelphia chromosome associated with chronic myelogenous leukemia, named for the city where Peter Nowell and David Hungerford first identified it), as well as a more pervasive loss of ploidy found in many types of cancer. According to Professor Duesberg, it is this dysregulation of the physical structure of genomic DNA that "causes" cancer, and which explains why despite great advances in understanding mutations associated with cancer, science has discovered neither the "cause" or the cure. Professor Duesberg asserts that because this chromosomal disruption is causative, each cancer is unique and uniquely caused by changes in any number of genes. Professor Duesberg also contends that his theory explains why cancer cells become resistant to anti-cancer drugs, and why drug resistance develops in cancer cells rapidly, while cancer itself takes many years to develop (years when the cells accumulate the changes resulting an anueploidy). He is currently promoting aneuploidy screening to detect early stage cancer, and one of his collaborators has started a company marketing a device for such screening. His work is being funded by private sources.
Professor Duesberg's theories are not unanswered, even in the pages of Drug Resistance Updates. Tito Fojo, an NIH researcher, in an article in the same issue sets out several reasons why mutations can explain the development of drug resistance; indeed, there are several well-recognized cellular genes whose inactivation (topoisomerase II) or increase expression (P-glycoprotein) provide conventional molecular explanations for drug resistance.
Perhaps the biggest flaw in Professor Duesberg's theory - and one that illustrates his penchant for classical biological explanations that eschew the illumination provided by molecular analyses - is that it simply begs the question. It is recognized that in large part the complicated cellular machinery of replication (which is the time and the place where chromosomal aberrations arise) is mediated by the controlled expression of a set of cellular genes. Indeed, the machinery has a number of checkpoints and failsafes, where cells that have accumulated a mutation or other injury that has disrupted normal mitosis are shunted into repair, senescence, or apoptosis pathways which prevent (or at least reduce the frequency) with which chromosomally-abnormal cells survive. Professor Duesberg's theory may well have more than a germ of truth to
it, in view of recent findings that genomic transcription is more
global and less confined to discrete genes than was the leading
paradigm in the past (see "What's ENCODE'd in Your Genome Isn't a Simple Collection of Genes"). It is certainly possible, and indeed likely, that even if chromosomal abnormalities play a bigger causative role than now recognized in tumorigenesis, how these abnormalities arise is based on mutation, inappropriate expression, or some other deficiency in the genes responsible for maintaining chromosomal integrity. Viewed in this light, Professor Duesberg has just changed the focus of which genes, and mutations of those genes, should be studied. In truth, it doesn't even do that, since some of these genes have been identified in certain contexts as oncogenes, and in any event, cell cycle and replication control (and disruptions thereof) have been understood to be involved in tumorigenesis for some time. And in view of the tone of his latest article, it appears Professor Dueserg continues to be more comfortable in the role of someone who sees more clearly than others in these matters, and has no time for determining whether there are any giant's shoulders on which he may be standing. This attitude is likely to have the most unfortunate consequence of making it easier to dismiss his ideas, or at best to miss the germ of truth and clearer understanding that they may provide. Pity.