To Resign over an Editorial Decision You Disagree With

What would you do if you were serving on the editorial board of a scientific journal which had just published a manuscript that you knew was seriously flawed. Moreover, you knew that publication of the manuscript might seriously undermine global public health? That was the circumstance of cell biologist Klaudia Brix, Professor of Cell Biology, Jacobs University Bremen, Germany, when, in 2011, the Italian Journal of Anatomy and Embryology (IJAE)—the official publication of the Italian Society of Anatomy and Histology—published a paper by infamous AIDS denialist, Peter Duesberg, which reiterated his already discredited argument that HIV (the human immunodeficiency virus) does not cause AIDS (1). Brix resigned in protest from the IJAE editorial board. But why is that noteworthy? Remarkably, she was, for a time, the only member of the journal’s 13-person editorial board to do so, despite other members having similar misgivings over the decision to publish the paper. Afterwards, Heather Young, an anatomy and neuroscience researcher at the University of Melbourne, likewise resigned from the IJAE editorial board. Here is the background to this state of affairs.

Peter Duesberg is not the only AIDS denialist. However, he has been the most infamous of the AIDS denialists. HIV is a retrovirus, and Duesberg is the only AIDS denialist who also happens to be an expert retrovirologist. In fact, Duesburg was at one time a highly esteemed retrovirologist. In 1985 he was elected to the U.S. National Academy of Sciences; mainly for his 1970 discovery, with Peter Vogt, of the first known retroviral oncogene—the Rous sarcoma virus v-src.

AIDS denialist, Peter Duesberg

Duesberg first put forward his denialist view in a 1987 paper in Cancer Research (2), which asserted that AIDS results from drug abuse, parasitic infections, malnutrition, and antiretroviral drugs. In Duesberg’s assessment, HIV is just another opportunistic infection. He has maintained that view since then, despite overwhelming evidence to the contrary. Consequently, he is looked upon as a pariah by the scientific community.

Even though Duesberg’s denialist views have been rejected by AIDS experts, Duesberg’s standing as a retrovirologist enabled him to yet influence some public health officials. In 2000, Duesberg was serving on a panel advising Thabo Mbeki (President of South Africa after Nelson Mandela) on how to manage the South African AIDS outbreak. Although Mbeki was an able and intelligent leader, he accepted Duesberg’s denialist view that HIV was not the cause of the South African AIDS epidemic. Thus, Mbeki allowed the South African outbreak to get completely out of control (3). Two independent studies later concluded that over 300,000 South African AIDS deaths would not have occurred if the Mbeki government’s public health policy had not followed the denialist view. Many thousands of South African AIDS victims, including infants, would have been spared infection if the government had publicized that AIDS is an infectious disease, and if it had made antiretroviral drugs available, particularly to pregnant women (1).  See Asides 1 and 2.

[Aside 1: The reasons why Mbeki assented to Duesberg’s denialist view are not clear. One possibility is that Mbeki held strong anti-colonialist and anti-West sentiments—born of having come of age during South Africa’s apartheid era—which led him to see his country’s AIDS crisis as a means by which the West sought to exploit his nation. To that point, he may have doubted the efficacy of expensive antiretroviral drugs, which were available only from large Western pharmaceutical companies. Moreover, the cost of treating the 5 million or more HIV-infected South Africans with those drugs would have exceeded the annual health department budget of his poverty-stricken nation by a factor of ten. Mbeki did accept that AIDS is the consequence of a breakdown of the immune system. But he was inclined to believe (or at least claimed) that poverty, bad nourishment, and ill health, rather than a virus, led that breakdown; a stance that enabled him to justify treating poverty in general, rather than AIDS in particular. Duesberg defended Mbeki in his publications, denying that hundreds of thousands of lives were lost in South Africa because of the unavailability of anti-retroviral drugs. But in 2002, after Mbeki suffered political fallout from the consequences of having acceded to Duesberg’s views, he tried to distance himself from the AIDS denialists, and asked that they stop associating his name with theirs.]

[Aside 2: The 2000 International AIDS Conference was taking place in Durban (a city in the South African province of KwaZulu-Natal) at the same time that Mbeki’s AIDS panel was convening in Johannesburg. Consequently, the denialist views expressed by Mbeki’s panel were also being heard in Durban. This prompted the so-called “Durban Declaration,” signed by over 5,000 scientists and physicians, and published in Nature, which proclaimed that the evidence that HIV causes AIDS is “clear-cut, exhaustive and unambiguous”.]

Well before Duesberg submitted his paper to IJAE, the arguments put forward in the paper had already been appraised and rebuffed by the scientific community. Indeed, the paper had previously been rejected by several other journals. The first submission was to the Journal of Acquired Immune Deficiency Syndromes (JAIDS), a peer-reviewed medical journal covering all aspects of HIV/AIDS. The JAIDS editors found that Duesberg’s contentions in the paper were based on a selective reading of the scientific literature, in which he dismissed all the vast evidence that HIV is the etiologic agent of AIDS. Not surprisingly, JAIDS rejected the paper, with one peer reviewer even warning that Duesberg and co-authors could face criminal charges if the paper were published.

After JAIDS rejected the paper, Duesberg  submitted a revised version to Medical Hypotheses (4). Like the original paper sent to JAIDS (as well as the version accepted by IJAE), the paper submitted to Medical Hypotheses contained data cherry-picked to cast doubt on HIV as the cause of AIDS. Nonetheless, Medical Hypotheses accepted the paper. However, the paper never went to press. But first, what was the explanation for the seemingly bizarre decision to accept the paper?

The answer laid in the fact that Medical Hypotheses was the only journal of its parent publisher, Elsevier, that did not use peer review; instead relying on its editorial board to select papers for publication. In any case, before the accepted paper went to press, prominent AIDS researchers, including Nobel laureate Francoise Barre-Sinoussi (co-discoverer that HIV is the cause of AIDS, 5), complained to Elsevier that the paper would have a negative impact on global healthcare, and requested that the paper be withdrawn.

Elsevier responded to these protests by asking the editors of another of its journals, The Lancet, to oversee a peer review of the paper. The Lancet editor sent the paper to five external reviewers, each of whom found that it contained numerous errors and misinterpretations, and that it could threaten global public health if it were published. Elsevier then permanently withdrew the paper.  Elsevier also instituted a peer-review policy at Medical Hypotheses (and fired the journal’s editor, who resisted the change).

The Medical Hypotheses incident resulted in more notoriety for Duesberg when the University of California, Berkley, where Duesberg is still a professor of molecular and cell biology, bought charges of misconduct against him for making false scientific claims in the paper, and for a conflict-of-interest issue. Apropos the latter, Duesberg did not reveal that co-author David Rasnick had earlier worked for Matthias Rath, a German doctor and vitamin entrepreneur, who sold vitamin pills as a therapy for AIDS. Duesberg was later cleared of both charges. But the next iteration of paper, to IJAE, did not respond to these allegations.

Duesberg regarded Elsevier’s actions as another example of “censorship” imposed by the “AIDS establishment.” Undeterred however, he submitted a revision of the paper to IJAE, which that journal then accepted, prompting Klaudia Brix and Heather Young to resign from that journal’s editorial board. The IJAE paper contained the same cherry-picked data and discredited assertions that were rejected earlier by JAIDS and Elsevier.  Moreover, publication of the paper still posed a threat to global public health. What then was behind the IJAE decision to publish?

Here is what happened. The paper was “peer-reviewed” by IJAE, but by only two reviewers; one of whom was Paolo Romagnoli, the IAJE editor-in-chief, who is neither a virologist or an epidemiologist but, instead, a cell anatomist. Consequently, the paper underwent only one external review, and there is no information regarding whether the lone external reviewer was an AIDS expert. One board member (who did not resign) later commented: “Only one [external] reviewer in my mind is not enough for manuscripts of a sensitive nature… (6)” [But this comment too is a bit troubling. Bearing in mind that the paper contained numerous errors and misinterpretations, would those have been okay if the paper were not of a “sensitive nature”?]

One also might ask why a journal that specialized in anatomy and embryology would consider a paper about the cause of AIDS. To that point; Klaudia Beix gave, as a reason for her resignation from the IJAE board, her belief that a journal should function within its scientific “scope” (6). So how did Romagnoli, the IJAE editor-in-chief, justify his decision to consider the paper?  He did so by asserting that it dealt with “issues related to the biology of pregnancy and prenatal development and with the tissues of the immune system (6).” But despite Romagnoli’s contention, the only mention of embryology in the paper was a short comment in the abstract: “We like to draw the attention of scientists, who work in basic and clinical medical fields, including embryologists, to the need of rethinking the risk-and-benefit balance of antiretroviral drugs for pregnant women, and newborn babies (1).”

As for Romagnoli’s reliance on only two reviewers, he justified that stance on the fact that the reviewers had concurring opinions. Moreover, he claimed that his criteria for selecting reviewers—apparently irrespective of their expertise—was to choose individuals (himself included) who he believed would not reject a paper merely because it challenged prevailing opinion.

But is there any possibility that Duesberg might be right? The answer is virtually none whatsoever. An earlier post noted: “…the evidence that HIV causes AIDS is, without exaggeration, overwhelming. Consider just the following. Data from matched groups of homosexual men and hemophiliacs show that only those who are infected with HIV ever develop AIDS. Moreover, in every known instance where an AIDS patient was examined for HIV infection, there was evidence for the presence of the virus. These data have been available for years, and Duesberg should have been aware of them. What is more, there has been the enormous success of antiretroviral therapy in changing AIDS from a nearly invariably fatal disease, into a manageable one, for many HIV-infected individuals (3).”

Even so, Duesberg is not regarded as a pariah by AIDS experts merely because his views concerning the connection between HIV and AIDS challenge accepted wisdom.  Instead, as asserted by Harvard University AIDS epidemiologist, Max Essex, Duesberg has sustained a “dangerous track of distraction that has persuaded some people to avoid treatment or prevention of HIV infection (6)”.

A scientist mounting a long-time challenge to the “establishment,” and being ridiculed for his views, before eventually being vindicated, makes for a very good story. However, such instances are very rare. Exceptions include Howard Temin (7) who hypothesized reverse transcription, and Stanley Pruisner (8) who hypothesized prions—infectious agents that contain no nucleic acid genome. Both researchers had to endure widespread ridicule for several years. But, and importantly, irrefutable evidence eventually accumulated to support their hypotheses. And, finally, both were awarded Nobel Prizes. But Duesberg has not been vindicated and, almost certainly, he  never will be.

References:

1. Duesberg PH, et al., 2011. AIDS since 1984: no evidence for a new, viral epidemic – not even in Africa. Italian Journal of Anatatomy and Embryololgy 116:73–92. http://fupress.net/index.php/ijae/article/view/10336/9525

2. Duesberg P, 1987. Retroviruses as carcinogens and pathogens: expectations and reality. Cancer Res. 47:1199–220. PMID3028606.

3. Thabo Mbeki and the South African AIDS Epidemic, Posted on the blog July 3, 2014.

4. Duesberg PH, et al., 2009. WITHDRAWN: HIV-AIDS hypothesis out of touch with South African AIDS – A new perspective. Medical Hypotheses. doi:10.1016/j.mehy.2009.06.024. PMID19619953.

5. Who Discovered HIV, Posted on the blog, January 24, 2014.

6.  Corbyn Z. 2012. Paper denying HIV–AIDS link sparks resignation: Member of editorial board quits as editor defends publication. Nature doi:10.1038/nature.2012.9926.

7. Howard Temin: “In from the Cold,” Posted on the blog December 14, 2013.

8. Stanley Pruisner and the Discovery of Prions: Infectious Agents Comprised Entirely of Protein, Posted on the blog December 15, 2016.

 

Carlton Gajdusek, Kuru, and Cannibalism

Today’s posting features an especially intriguing infectious disease called kuru, and Carlton Gajdusek, the man who won a Nobel Prize in 1976 for his study of its rather shocking epidemiology, only to have a shadow cast over his reputation when he was later convicted of child molestation.

Carlton Gajdusek in 1997

Gajdusek graduated from Harvard Medical School in 1946 and then carried out postdoctoral studies at Caltech under Linus Pauling and Max Delbruck, and at Harvard under John Enders. [All three of Gajduseks postdoctoral mentors became Nobel laureates. See reference 1 for additional examples of leading scientists who had preeminent scientists for mentors.]

In 1954 Gajdusek was in Melbourne, as a visiting investigator under the direction of another future Nobel laureate, the Australian immunologist Sir Macfarlane Burnet. In 1957 Burnet sent Gajdusek to New Guinea, to take part in a multinational study of disease in the native populations. Thus it came to pass that Gajdusek heard about a mysterious illness called kuru, which affected a tribe of the Fore people of the eastern highlands of New Guinea.

The term “kuru” means “shivering” or “trembling” in the Fore language, reflecting an outward symptom of the disease. In the late 1950s, as the Fore people were just emerging from their Stone Age way of life, stories about their strange disease began to leak out to the modern world. Gajdusek was fascinated by these stories and, accordingly, he traveled to the Fore people to see the disease for himself.

Before continuing our account of Gajdusek and the Fore people, we pause to note that kuru is actually not caused by a virus per se. Instead, kuru, like scrapie in sheep, is caused by a prion (a term derived from “proteinaceous infectious particle.”) Prions, like viruses, pass through filters that block bacteria. However, prions are much smaller than even viruses and, in fact, do not contain genomes! Stanley Pruisner, who coined the term “prion,” won a Nobel Prize in 1997 for his breakthrough studies of the nature of prions and their means of replication (topics for a future posting). Other prion diseases include bovine spongiform encephalopathy (known colloquially as “mad cow disease”) and Creutzfeldt-Jacob disease (CJD) in humans. These diseases are also called transmissible spongiform encephalopathies; reflecting their infectious nature and their characteristic neuropathology. Each is invariably fatal. See Aside 1.

[Aside 1: Bovine spongiform encephalopathy (BSE) was a hot news item several years ago after the disclosure that British health officials allowed BSE-affected cattle to enter into England’s food supply, for as long as two years after those officials knew that BSE was spreading in British cattle. The subsequent discovery, that eating meat from BSE-affected cows can give rise to CJD in humans, led to a panic. Health officials were accused of putting the interests of the British meat industry above those of the public.]

When Gajdusek arrived among the Fore, their population consisted of about 35,000 individuals, about 1% of who were afflicted with kuru. Strangely, the disease was most prevalent in women. In fact, the discrepancy between affected women and affected men was so great that in some Fore villages men outnumbered women by 3 to 1!

Children with kuru were rare. Later, it would be understood that this was because of the long incubation period for kuru; a characteristic of the transmissible spongiform encephalopathies in general. The incubation periods for kuru and CJD can be as long as 30 years. But, once symptoms appear, patients generally succumbed within a year.

A Fore child with advanced kuru in 1957. She was sedentary for
several months and was reaching the terminal stage of the disease.

Gajdusek was fascinated and puzzled by several aspects of kuru, including the strange tendency of the disease to affect women, and its slow progression. Moreover, he observed that there was no inflammation or fever associated with kuru or, indeed, any sign of infection or post-infection phenomena. For these reasons, Gajdusek at first thought that kuru might be caused by a sex-linked genetic factor, or perhaps by malnutrition. See Aside 2.

[Aside 2: Conventional virus infections of the human brain (e.g., subacute sclerosing panencephalitis (measles), progressive multifocal leukoencephalopathy (JC virus), cytomegalovirus brain infection, etc,) are associated with an inflammatory response, a rise in serum protein, and the presence of virus particles in electron micrographs; none of which are seen in the transmissible spongiform encephalopathies.]

Then, in 1959, while Gajdusek was searching for the cause of kuru in New Guinea, William Hadlow fortuitously came on the scene in London. Hadlow was a veterinary pathologist from the United States Department of Agriculture, who, at the time, was studying scrapie in England. By chance, Hadlow was visited in London by his friend, parasitologist William Jellison, from the Rocky Mountain Laboratory in Montana, where Hadlow too had worked before joining the USDA.

During his visit with Hadlow, Jellison casually mentioned an exhibit on the neuropathology of kuru at the Wellcome Medical Museum in London (see Aside 3). Jellison thought that Hadlow might find the exhibit interesting since Hadlow was studying scrapie which, like kuru, is a neurodegenerative disease. Thus, it came to pass that five days later Hadlow visited the exhibit and was struck by the remarkable similarity between the neuropathology of kuru in humans and scrapie in sheep. Importantly, it was already known that scrapie in sheep is a transmissible disease.

[Aside 3: The London exhibit was prepared by Igor Klatzo, Head of the Neuropathology Section of the National Institute of Neurological Diseases at the NIH. Gajdusek sent brains from kuru victims back to the NIH for analysis. That is how Klatzo came to describe the neuropathology of kuru and, in addition, to note its similarity to the more widespread Creutzfeldt-Jakob disease. The importance of Klatzo’s observation concerning CJD and kuru became clearer after Gajdusek discovered that kuru is a transmissible disease (see below). Subsequently, CJD too was found to be transmissible. Later in his career, Klatzo carried out experiments which laid the groundwork for studies of the pathogenesis of Alzheimer’s disease.]

In 1959 Hadlow published a letter in the Lancet noting his observation of the similarities between the neuropathologies of kuru and scrapie (2). Hadlow sent a copy of the letter to Gajdusek, while also suggesting that somebody should inoculate primates with kuru brain tissue to test whether kuru, like scrapie, might be transmissible.

Gajdusek quickly wrote back to Hadlow, telling him that the experiment was underway. However, it was not until 1966 when Gajdusek, now working at the NIH, reported that he indeed succeeded in transmitting kuru to chimpanzees. Perhaps the lag between the start of Gajdusek’s experiment in 1959, and his report of success in 1966, was due in part to the length of the kuru incubation period, which, in chimpanzees, ranges from 14 to 82 months. At any rate, Gajdusek had established that kuru is a transmissible disease. Moreover, the exceptionally long incubation period between inoculation and the first appearance of symptoms, and the absence of fever and inflammation, suggested to Gajdusek that the kuru might be caused by a previously unrecognized class of infectious agents. But, what might account for the predilection of the disease to affect women? The answer would be startling.

In 1961 American anthropologists Ann and J. L. Fischer reported that the Fore people had a custom of eating the corpses of dead relatives (3). In view of the Fischers’ finding, and not yet knowing that kuru is transmissible, in 1963 Gajdusek hypothesized that kuru is a hypersensitivity disease, triggered by consuming human tissue. Gajdusek also proposed that the strange tendency of kuru to strike women might be explained if the tribe’s women consumed more human flesh than the men did. See Aside 4.

[Aside 4: The Fischers were quite prescient in their 1961 report, speculating that kuru is due to a transmissible agent, and that cannibalism might be the way by which it is transmitted between the Fore people. The Fischers also suggested, before Gajdusek did, that more human flesh might have been eaten by women than by men of the tribe, thus accounting for the demographics of kuru.]

The role of cannibalism in kuru was corroborated by a 1967 report by Robert Glasse, an anthropologist at Queens College of the City University of New York, who at the time was working as an anthropologist for the New Guinea Public Health Department. Glasse discovered a striking correlation between the Fore’s practice of “ritual cannibalism” and the incidence of kuru. The Fore people ate their dead relatives as an act of homage during funeral rites. The bodies of the deceased would be cut up into parts. The men took the meatiest parts for themselves, leaving the pancreas, liver, kidneys, and, importantly, the brain for the women and the children. Many of the women would eventually develop kuru after eating the infected brains. When they died, they too were ritually eaten, thereby escalating the epidemic. [See reference 4 for more on the extraordinary observations of Glasse and his colleagues.]

Based on Glasse’s findings, as well as on his own discovery that kuru could be transmitted to chimpanzees; Gajdusek concluded that kuru was caused by an infectious agent, spread by the Fore practice of consuming the brains of deceased relatives. See Aside 5.

[Aside 5: Who, if indeed any one individual, ought to have priority for the discovery of cannibalism as the means by which kuru was transmitted between the Fore people? Hopefully, I’ve credited all the key players. Historian Richard Rhodes’ 1997 letter to Nature contains a short, but likely accurate accounting of this part of our story (5). For more details, see Chapter 6 of Rhodes book, Deadly Feasts: Tracking the Secrets of a Terrifying New Plague (6).]

The incidence of kuru among the Fore declined dramatically in the late 1950s, after the Australian colonial administration put an end to their practice of ritual cannibalism. The very few adults who came down with kuru, as late as 20 years after the government suppressed cannibalism, reflect the fact that the incubation period for kuru in humans could range up to 20 years or longer. [Despite the scientific advances since the 1950s, most Fore people still believed that their kuru was caused by sorcery.]

Next, we consider the allegations of sexual misconduct against Gajdusek. In 1963 Gajdusek began to bring Fore boys back to the US to live with him. To Gajdusek’s credit, he saw to it that all of the boys went through high school, and he paid for some to attend college and even medical school.

In the 1990s a member of Gajdusek’s lab informed the FBI that Gajdusek might be engaging in inappropriate sexual behavior with the boys. The FBI questioned the boys and found one (a 23-year-old, who, at the time, was attending college under Gajdusek’s sponsorship) who claimed that he and Gajdusek had earlier been masturbating each other. None of the other boys would incriminate Gajdusek. On the contrary, several were willing to give evidence in his favor. However, an incriminating, secretly recorded phone conversation sealed the case against Gajdusek.

In 1996 Gajdusek plead guilty to a child molestation charge. Under a plea bargain, he was sentenced to 12 months in prison. In 1998 he was released and moved to Europe, never to return to the US.

Gajdusek’s supporters included leading scientists, as well as some of his adopted children. Pleading for leniency on his behalf, some supporters argued that Gajdusek’s sexual behaviors with the boys were acceptable and, in fact, widespread among the Fore people. Moreover, these supporters took our society to task for not appreciating that different cultures have different attitudes regarding sex. [For more on the sexual outlook and practices Gajdusek encountered among the Fore people, as well as for an assessment of his character from Sir Macfarlane Burnet, see references 7 and 8.] On the other hand, Gajdusek’s detractors maintained that he used his stature as a renowned scientist in order to exploit the boys.

Gajdusek never expressed any remorse over his transgressions. He passed away on December 12, 2008.

References:

(1) Genealogies and a Selective History of Lysogeny: Featuring Friedrich Loeffler, Emile Roux, Andre Lwoff, Elie Wollman, and Francois Jacob, Posted on the blog January 28, 2015.

(2) Hadlow, W.J. (1959) Scrapie and kuru. Lancet 2:289–290.

(3) Fischer, A., and J. L. Fischer. (1961) Culture and epidemiology: A theoretical investigation of Kuru, J Health Hum Behav 2: 16-25.

(4) Lindenbaum, S. (2008) Understanding kuru: the contribution of anthropology and medicine. Philos Trans R Soc Lond B Biol Sci 363:3715–3720.

(5) Rhodes, R. (1997) Gourmet cannibalism in a New Guinea tribe. Nature 389: 11.

(6) Rhodes, R., Deadly Feasts: Tracking the Secrets of a Terrifying New Plague, Simon & Schuster, 1997.

(7) http://www.independent.co.uk/news/the-fall-of-a-family-man-1308277.html

(8) http://www.timeshighereducation.co.uk/…/91481.articl