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-reviewedmedical 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.
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. CorbynZ. 2012. Paper denying HIV–AIDS link sparks resignation: Member of editorial board quits as editor defends publication. Nature doi:10.1038/nature.2012.9926.
Ebola, MERS, and Hepatitis C viruses dominated virology news during the past year (2015). Now, early in 2016, Zika virus has taken center stage. The reasons are clear. This once seemingly innocuous virus, initially restricted to Equatorial Africa, has of late spread to the Western Hemisphere, and is now suspected (but not proven) to cause microcephaly—an otherwise rare condition in which babies have unusually small heads and incomplete brain development—in transplacentally infected fetuses of infected pregnant woman. Moreover there is evidence which links Zika virus to Guillain–Barré syndrome—a potentially severe autoimmune attack on peripheral nerves that may occur after signs of a viral infection. We begin with some background.
Zika virus is a member of the flavivirus family of plus-strand RNA viruses. The family also includes several notable human pathogens, including yellow fever, dengue, hepatitis C, and West Nile viruses. Like most other flaviviruses, Zika virus too is spread by an arthropod vector; in this instance Aedes mosquitoes. 80% of Zika virus infections are asymptomatic and, prior to recent developments, symptomatic infections were seen as mild, acute febrile illnesses, similar to dengue.
Zika virus was discovered by accident in the Zika Forest of Uganda in 1947. The discovery was made by scientists who had been studying yellow fever. They isolated Zika virus from one of their rhesus macaques, which was suffering from an unknown fever. The following year the same virus was found in Aedes mosquitos from the same Ugandan forest, thus identifying the mosquito as a vector for Zika virus. Zika virus was detected for the first time in humans in 1954, in Nigeria.
The Aedes aegypti mosquito, the Zika virus vector
Until recently, Zika virus infections were rare and were reported only within equatorial Africa and Southeast Asia. Then, in 2007, an outbreak occurred in Yap Island, Micronesia. The Yap Island Zika outbreak was the first one outside of Africa and Asia. None of the Yap Island cases, which included 49 in which Zinka virus was confirmed by the presence of Zinka RNA, resulted in either hospitalization or death.
The Yap Island outbreak was followed by epidemics in Polynesia, Easter Island, the Cook Islands and New Caledonia. The Polynesian outbreak was notable for being the first in which Zika infection was associated with Guillain–Barré syndrome.
Concern over Zika virus was heightened, particularly in the Americas, when, in April 2015, a large and still ongoing outbreak of Zika virus occurred in Brazil. The Brazilian outbreak marked the first appearance of Zika virus in the Western Hemisphere. It is not clear how Zika virus made its way to Brazil, but it is widely believed that the virus made the leap from Polynesia to Brazil during the 2014 World Cup soccer tournament.
Apprehension over Zika virus increased in November 2015 when the virus was isolated from a Brazilian newborn with microcephaly. By December 2015 many more cases of this generally rare disorder were reported. The European Center for Disease Prevention and Control then warned of a possible association between Zika virus infection and congenital microcephaly, and with Guillain–Barré syndrome as well.
More than a million Brazilian people since been infected with Zika virus, and the number of Brazilian children born with microcephaly jumped from 147 in 2014 to nearly 4,000 in 2015. There is no anti-Zika vaccine, nor is there an effective therapy.
The first Zika virus-associated case of microcephaly in the United States occurred in early January 2016 in a baby born in Oahu, Hawaii. The baby and its mother each tested positive for a past Zinka infection; probably acquired in May 2015 when the mother, then pregnant, had been traveling in Brazil.
On January 24, 2016 the World Health Organization warned that Zika virus will likely spread to every nation in the Western Hemisphere (possibly excepting Canada and Chile), since its Aedes aegypti vector can thrive in tropical and sub-tropical climates here. The Aedes mosquito has long been present in the United States, ranging as far north as New York and west into Indiana and Illinois. [An earlier posting reported that Aedes aegypti may have been brought from Africa to the New World by slave ships in 1596 (1). Mosquito larvae, present in the water casks of the sailing ships of the day, also carried yellow fever to the New World.]
Global concern over the Brazilian Zika outbreak was heightened by the fact that Brazil is scheduled to host the Olympic Games this summer, and about 500,000 people are expected to attend from all over the world, including 200,000 Americans. Some of these attendees will, of course, be bringing the virus back to their home countries.
Brazilian officials no doubt are concerned that their Zika outbreak will affect attendance at the upcoming Olympic Games. Consequently, commercial considerations may be one of the motives behind Brazil’s extensive campaign to eradicate its mosquitoes. Unfortunately, standard approaches, such as using insecticides and removing standing water where mosquitoes breed, have not done the job. Thus, the Brazilian Zika outbreak may not be under control by the start of the Olympic Games. [Brazil also experienced more than 1.6 million cases of dengue during 2015, with 863 people dying from the disease, underscoring that the Aedes mosquito vector is not well contained in that country.]
The failure of Brazilian vector-control approaches suggests that new strategies may be needed to contain the outbreak. Apropos that, this past January Colombia began releasing mosquitoes treated with bacteria, which are hoped might limit the mosquitoes’ capacity to spread disease. Note that insecticides have limited effectiveness. Not only are they toxic to humans, but after decades of overexposure to them, many mosquitoes are now resistant.
Zika virus is now present in the continental United States. Thus, it is timely to consider how grave a threat Zika virus might impose here. To that point, consider that yellow fever, dengue and chikungunya viruses are dangerous pathogens that also are spread by Aedes mosquitoes. Yet these viruses are not regarded as important threats in the United States. That is so because our vector control measures have thus far been able to contain them. Those measures might likewise be expected to contain local transmission of Zika virus here.
But, what if Zika virus has a mode of transmission other than via its mosquito vector? To that point, there is a single reported case of Zika transmission via a blood transfusion. Also, it was suggested that Zika virus might have a sexual route of transmission, as per the finding of high levels of the virus in the semen of a man from French Polynesia. In addition, there is a report of an American scientist, Brian D. Foy, who contracted Zika virus while working in Senegal in 2008, and who transmitted the virus to his wife after returning home (2). Serologic analyses of the couple’s convalescent serum confirmed that they had been infected with Zika. Sexual transmission is implicated in this instance since neither Foy nor his wife passed the infection to their children or to other close relatives. Moreover, Foy and his wife observed signs of hematospermia (red–brown fluid in his ejaculate).
Foy notes in his scientific report (2), “If sexual transmission could be verified in subsequent studies, this would have major implications toward the epidemiology of Zika virus and possibly other arthropod-borne flaviviruses.” [Human sexual transmission of an arthropod-borne virus has not yet been documented.] Foy has been trying to get funds to investigate sexual transmission of Zika. However, according to a January 26, 2016 article in the N.Y. Times, the CDC says that the “theoretical risk” of sexual transmission in the above instances is insufficient to justify a warning (and funding?). But, see the following paragraph.
As I’m sitting at my computer on the evening of February 2, 2016, NPR, CNN, BBC News, the N.Y. Times, etc., are reporting a case of Zika virus infection in Texas that appears to have been sexually transmitted. According to the Dallas County Health and Human Services Department, a patient with the Zika virus was infected after having sex with someone who returned from Venezuela, where Zika is circulating. The CDC appears to give credence to the Texas report, since it quickly responded to it by advising men having sex after traveling to these areas to “consider” wearing condoms, and advised pregnant women to avoid “contact with semen” from men recently exposed to the virus.
Sexual transmission will probably account for only a very small fraction of Zika cases, but that isn’t known for certain. As in instances of mosquito-borne transmission, its contribution will depend in part on how long the virus might persist in infected individuals.
Since the vast majority of Zika virus infections are likely transmitted via its mosquito vector, and since Zika virus mainly threatens fetuses infected in utero, the most severe consequences of Zika virus infection can be largely avoided if pregnant women, or women planning to become pregnant, avoid traveling to places where Zika virus remains prevalent (a fact which doesn’t help individuals living in those regions). For that reason, on January 15, 2016, the United States Centers for Disease Control and Prevention (CDC) released a list of countries—Brazil, Colombia, El Salvador, French Guiana, Guatemala, Haiti, Honduras, Martinique, Mexico, Panama, Paraguay, Suriname, Venezuela, and Puerto Rico—where mosquitoes are spreading the Zika virus, and which pregnant women should avoid at this time. On February 1, 2016, the World Health Organization added Costa Rica and Jamaica.
Political and commercial considerations may have been behind the Brazilian minister of tourism taking exception to the CDC’s warning, claiming that measures adapted by Brazilian health authorities are bringing the Zika outbreak under control, and that Brazil is, in fact, a safe destination for pregnant women. The Brazilian health minister added, “Zika virus doesn’t worry us…,” calling it a “benign disease.” Those pronouncements were made despite the fact that Brazilian health authorities were at the same time investigating more than 3,500 cases of microcephaly. But at least some Brazilian health professionals did endorse the CDC announcement.
On February 1, 2016 the World Health Organization took the further step of declaring that Zika virus and its suspected link to birth defects constitute an international public health emergency. Yet the WHO stopped short of advising pregnant women not to travel to affected regions. Some public health experts claimed that the WHO’s silence on that point was more about politics than public health. Any travel ban—even one aimed only at pregnant women—would be embarrassing and costly to Brazil, which is moving ahead with its plans to host the Olympic Games this summer. And, while there have been calls to cancel, postpone, or move the Rio games, the International Olympic Committee (IOC) hasn’t expressed any concerns over the Games taking place as planned.
Meanwhile, the governments of Columbia, El Salvador, Ecuador, and Jamaica have taken the rather extraordinary step of recommending that women avoid getting pregnant until the Zika outbreak might be brought under control in their countries. This advisory was not well received by many El Salvadoran women, especially in view of the strict abortion laws and high levels of sexual violence against women in that country.
And, as I’m putting the final touches on this piece, an article in today’s (February 4, 2016) N.Y. Times reports that the Zika virus/microcephaly link is causing a fierce debate in Brazil over its strict abortion laws; under which abortion is illegal under most circumstances. [Remarkably, Brazil’s strict abortion laws are actually less restrictive than those in other Latin American countries.] Some Brazilian doctors are already seeing pregnant women who are seeking abortions because they fear microcephaly. Yet conservative Brazilian lawmakers actually want to make the restrictions against abortion more stringent than they already are. [The Times article says that their position reflects “the influence of Roman Catholic leaders and the increasingly powerful preachers at the helm of a growing evangelical Christian movement.”] Regardless, individuals on both sides of the debate might be troubled by the fact that microcephaly can not be detected by ultrasound scans until the end of the second trimester, when the “child” is already very much formed. Moreover, the criteria for diagnosing microcephaly are rather non-specific, and it is difficult to predict what its consequences might be.
A crucially important question regarding Zika virus concerns determining its true pathologic potential, particularly its role in microcephaly—a role that is strongly inferred (but not proven) by the geographic and temporal relationship between microcephaly and Zika infection. To that point, no increase in microcephaly has been linked to Zika virus outside of Brazil. For instance, Colombia is the second-most Zika-affected country, with around 20,000 confirmed cases. More than 2,000 of the Columbian cases have been pregnant women. Yet none of their fetuses have been diagnosed with microcephaly.
Did Zika virus become an etiologic agent for microcephaly only after reaching Brazil? If so, how did that happen? Was it because of the emergence of a new strain of the virus? Or, does Zika virus cause microcephaly only if the mother has had a previous infection, like dengue? Alternatively, was the link simply missed in the past because, until now, the virus has not invaded a country where there are a large enough number of non-immune individuals, who also are living under conditions that are ideal for the virus to spread? Or, were previous cases merely under-reported, such that the 147 Brazilian cases in 2014 were a vast underestimate?
The flip side is that the current extraordinarily high number of reported cases of microcephaly in Brazil might merely be due to a heightened awareness of that condition; a possibility that is favored by some Brazilian officials. A supporting argument is that the criteria for diagnosing microcephaly are relatively unspecific. However, others point out that physicians were reporting a rise in cases as early as November 2015, before the increased attention from health authorities and the media.
Another unexplained yet key factor is the unusually severe congenital deformities—extensive loss of brain tissue, unusually smooth, wrinkleless brains, many calcium deposits, and smaller cerebellums—seen in the Brazilian microcephaly cases. These features are not characteristic of microcephaly caused by other pathogens, such as toxoplasmosis, cytomegalovirus, or rubella.
And, presuming that Zika virus indeed causes microcephaly, how or why is it able to cross the human placenta and enter the fetal brain? [In December 2015, the Pan American Health Organization reported that Zika virus RNA was identified by reverse transcription-polymerase chain reaction (RT-PCR) in amniotic fluid samples from two pregnant women whose fetuses were found to have microcephaly by prenatal ultrasound. Moreover, Zika virus RNA was identified in multiple fetal body tissues, including the brain of an infant with microcephaly (3).] Remarkably, only a handful of viruses cross the human placenta and infect the fetus with any notable frequency (4). These include rubella virus, cytomegalovirus, and HIV; none of which is related to Zika virus. Yellow fever, dengue, and West Nile viruses, which are related to Zika virus, are not known to harm embryos.
Since most Zika virus infections are either asymptomatic, or present with flu-like symptoms that mimic other infections, a rapid diagnostic test for Zika infection is needed to accurately measure the prevalence of the virus in a population, and to measure its spread. Such a test might also help sort out whether the Brazilian microcephaly cases indeed have been due to Zika, rather than to another virus, such as the related dengue virus. Efforts are currently underway to develop Zika-specific immunological reagents for these purposes.
Vaccine researchers say that a vaccine against Zika virus may be available for testing by the end of 2016. But, even if the vaccine were effective, how long might it take for it to gain approval?
Meanwhile, an increasing, but still small number of Zika virus infections are being detected in the continental United States. With the exception of the Texas case noted above, all cases have thus far involved travelers who recently returned from overseas. Thus, with the exception of the Texas case, there is no evidence yet for local transmission here. But that well might change as summer approaches.
So, Zika now joins Lyme, West Nile, Chagas, dengue, and chikungunya on the list of recently emergent arthropod-borne diseases. Still, as we’ve noted, it is not yet clear how much of a threat Zika virus actually poses. Regardless, until that is known, it will be necessary to prepare for the worst. Even if the threat of Zika has been vastly overblown, progress towards its containment will pay important dividends in the containment of established threats, such as dengue and chikungunya.
And, if Zika is indeed a dangerous pathogen that is responsible for severe birth defects, then current conditions—global warming, more people traveling worldwide on jet airliners, cities in tropical countries becoming larger and ever more crowded—don’t portend well for the future. Stand by for new developments.
References:
1. The Struggle Against Yellow Fever: Featuring Walter Reed and Max Theiler, Posted on the blog May 13, 2014.
2. Foy, B.D., K. C. Kobylinski, J.L. Foy, et al., 2011. Probable Non–Vector-borne Transmission of Zika Virus, Colorado, USA, Emerg Infect Dis.17: 880–882.
3. Pan American Health Organization. Neurological syndrome, congenital malformations, and Zika virus infection. Implications for public health in the Americas—epidemiological alert. Washington DC: World Health Organization, Pan American Health Organization; 2015. This paper is in Spanish.
Harold Varmus and J. Michael Bishop changed cancer research in a fundamental way in the 1970s, when they discovered proto-oncogenes at the University of California at San Francisco (UCSF). Proto-oncogenes are cellular genes that normally play an important role in controlling cell division and differentiation. However, Varmus and Bishop found that proto-oncogenes can be altered by mutation, to become oncogenes that contribute to cancer. When Varmus and Bishop first began their collaboration in 1970, cancer research was, for the most part, focused on epidemiology (e.g., studies linking smoking to lung cancer) and empirical approaches to therapy (e.g., radiation and chemotherapy).
Harold Varmus, Cancer Researcher, Nobel Laureate, Director of the NIH
The discovery of proto-oncogenes is a pertinent topic for our Virology blog because it depended crucially on Varmus and Bishop’s earlier finding that retroviral oncogenes are mutated versions of cellular genes that retroviruses “captured” from their host cells. Varmus and Bishop hypothesized and then demonstrated that since retroviral oncogenes are versions of genes that actually are part of a normal cell’s genetic makeup, mutations in those genes, or their inappropriate expression, can lead to cancer. The v-src gene of Rous sarcoma virus was the first retroviral oncogene that Varmus and Bishop showed is derived from a cellular genome (1).
Varmus and Bishop continued searching for proto-oncogenes in the 1980s. Varmus also began investigating HIV (also a retrovirus and the cause of AIDS). In 1989 Varmus and Bishop were awarded the Nobel Prize in Physiology or Medicine for their discovery of proto-oncogenes.
In the early 1990s Varmus stepped out from his role as a research scientist to take up the cause of public funding for biomedical research. In 1993 President Bill Clinton acknowledged Varmus’ efforts in that regard, as well as his stature as a scientist, by appointing him to serve as Director of the National Institutes of Health (NIH). Thus, Varmus became the first Nobel laureate to head the NIH.
In 2000 Varmus left the NIH to accept the presidency of the Memorial Sloan-Kettering Cancer Center in New York. In 2010 Varmus returned to the NIH, this time appointed by President Barak Obama to serve as director of the National Cancer Institute (NCI). In 2015 Varmus was back again in New York where he is the Lewis Thomas University Professor of Medicine at Weill-Cornell Medical College.
Varmus was featured in two earlier blog postings. The first of these described how he mediated the dispute between Robert Gallo and Luc Montagnier over the right to name the AIDS virus (2). The second posting covered some of the political and social dilemmas Varmus faced during his days leading the NIH (3).
Here, we relate first how Varmus opted for a career in biomedical science and, second, how his collaboration with Bishop came about. This is an interesting tale because Varmus’ remarkable career as a science researcher, administrator, and spokesperson happened despite his initial intention to become a teacher of English literature. Indeed, his career in science did not begin until after he earned an M.A. degree in English from Harvard University, and then spent four years in medical school preparing for a career in clinical medicine.
We begin our story in 1950 as Varmus recounts how, as a ten-year-old, he witnessed his physician father receive a call that conveyed shocking news: “one of my mother’s favorite cousins, a robust man in the middle of his life, had just been diagnosed with leukemia. Of course, I did not know very much about leukemia, but I did know immediately from my parents’ expressions–and within a few weeks, from our cousin’s death—that his disease was a veritable tidal wave.” [All quotations are from Varmus’ book The Art and Politics of Science (4), in which he reflects back on his entire career.]
His cousin’s leukemia actually resulted from a mutation in one of the genes that Varmus would discover more than two decades later. And Varmus notes just how far the science in general had progressed during that 25-year interim: “…when my father heard about our cousin’s leukemia, biologists were not even sure that genes were made of DNA, had no idea how genetic information could be encoded in genes, and, of course, had no way of knowing that cancers are driven by mutations.”
Varmus was urged by his father to prepare for a career in medicine. Nonetheless, when Varmus enrolled as a freshman at Amherst College he strongly favored studying the humanities. Thus, he “toyed with the idea of majoring in philosophy (ultimately too abstract), physics (ultimately too hard), and English literature (ultimately selected).”
Throughout his undergraduate days, Varmus envisioned preparing for an academic career teaching literature. Still, he dutifully fulfilled premed requirements to keep open the possibility of obliging his father’s wishes that he become a medical doctor. Yet he never considered majoring in biology. “I couldn’t understand how some of my close friends (among them, some now distinguished scientists) could spend long afternoons and evenings incarcerated in a laboratory, when they could be reading books in a soft library chair or reciting poetry on Amherst’s green hills.”
Varmus began having doubts about his career choice when his Amherst College classmate Art Landy (later a well-known molecular biologist at Brown University) won an Amherst biology prize that allowed him to attend a 1961 international biochemistry meeting in Moscow. Importantly, Landy invited Varmus to accompany him to the Moscow meeting, where Varmus learned that Marshal Nirenberg had deciphered the genetic code. “Even though I did not understand its meaning or its importance at the time, I was not oblivious to the excitement around me…Scientists seemed likely to discover new, deep, and useful things about the world, and other scientists would be excited by these discoveries and eager to build on them. Would this be true of literary critics and teachers?”
Notwithstanding these misgivings, Varmus continued on his path to a career in English literature after graduating from Amherst College in 1961, earning an M.A. in English from Harvard in 1962 (his focus was on Anglo-Saxon poetry). But his uncertainties about his future only grew stronger. “Despite outward signs that I had chosen a life of studying and teaching literature, soon after starting my graduate work at Harvard I began to suffer some further internal doubts about abandoning medicine. The graduate curriculum in English literature was not especially onerous, but it felt like a prolongation of college. Most of my courses were heavily populated with Harvard and Radcliff undergraduates.” Varmus leaves the impression that he looked upon much of his course work at Harvard as a tiresome chore.
Varmus was also aware of the enthusiasm of former Amherst College classmates who were then studying at Harvard Medical School. “Occasionally, on Saturday mornings, I traveled across the Charles River to join some Amherst classmates at Harvard Medical School, while they sat in the Ether Dome at Massachusetts General Hospital, entranced by diagnostic dilemmas discussed at the weekly pathology conference. These stories struck me as far more interesting than those I was reading, and my medical school friends expressed general excitement about their work. They also seemed to have formed a community of scholars, with shared interests in the human body and its diseases and common expectations that they would soon be able to do something about those diseases…These Saturday excursions probably account for an influential dream I had one night about my continuing indecision. In that dream, my future literature students were relieved when I didn’t turn up to teach a class, but my future patients were disappointed when I didn’t appear. It seemed I wanted to be wanted.”
So, Varmus finally came to grips with his qualms about a career teaching English literature, hastily preparing an application to Harvard Medical School and biking across the frozen Charles River to deliver it just in time to meet the deadline. But it was to no avail, since the dean of admissions thought Varmus was “too inconstant and immature” for medical school.
Varmus next sent off an application to Columbia University’s College of Physicians and Surgeons (P&S). His interviewer at Columbia was an esteemed physician named David Seegal, who also happened to be rather literate. Seegal asked Varmus if he might translate the Anglo Saxon phrase Ich ne wat. “This was easy; it simply means ‘I don’t know.’” Seegal used his question as a lead-in to discuss why a physician might admit fallibility to a patient. In any case: “By the fall of 1962, I was happily enrolled at P&S, helped for the first, but not the last, time by someone’s exaggerated appreciation of my competence in two cultures.”
Now ensconced at P&S, Varmus thought he might become a psychiatrist; an ambition stoked by an interest in Freud and by his winning of an essay prize at P&S in psychiatry. But, he found his “first hour alone in a room with a psychotic patient to be more difficult and less interesting than an hour reading Freud.” So, Varmus’ interests in medical school turned from the “elusive mind” to the physical brain and then, more generally, to diseases that might be explained by known physiology and biochemistry.
When graduation from medical school was impending, Varmus had to consider his career options more deliberately than he had in the past. A key factor was the Vietnam War, which was in progress, and which he and many others of that era vehemently opposed. “I was determined not to serve in it. Medical graduates were subject to the draft; however, we did have the more palatable option of two years training at one of the agencies of the Public Health Service. For most of my classmates with academic ambitions similar to my own, the NIH was the favored choice. As the largest biomedical research campus in the world, it offered unequaled opportunities to learn virtually any form of biomedical research…”
Varmus confesses that he had a “woeful lack of laboratory credentials.” Nonetheless, he entered the competition for one of the coveted research slots at the NIH. But, because of his lack of research experience, he was not encouraged by most of the NIH laboratory chiefs who interviewed him. However, one of them, endocrinologist Jack Robbins, suggested to Varmus that he speak to Ira Pastan; a young endocrinologist who, at that time, was interested in the production of thyroid hormones.
As Varmus relates, “The recommendation proved to be wise and fateful. My schooling in literature turned out to be more important than my interest in endocrinology, Ira’s field, because Ira’s wife Linda, a poet, had often complained that Ira’s colleagues seldom talked about books…When matches were announced I was told I would become Ira’s first clinical associate, having been passed over by the more senior investigators. This outcome could not have been more fortunate.”
But, before Varmus could take up his position at the NIH, he received a “shocking phone call” from Pastan, to the effect that he (Pastan) was giving up his work on thyroid hormones because he and colleague Bob Perlman “had made a shocking discovery about gene regulation in bacteria.” Pastan and Perlman found that cyclic AMP is a major regulator of bacterial gene activity, and that it plays a similar role in animal cells—findings which led Pastan to pioneer the field of receptor biology in animal cells.
The discovery by Pastan and Perlman had important consequences for Varmus. First, it immediately forced him to give up his plan to train in endocrinology. Instead, Pastan assigned Varmus to find out whether cyclic AMP augments bacterial gene expression by increasing transcription of mRNA. Second, as explained below, Pastan’s new research direction led to Varmus’ introduction to and fascination with virology.
So, Varmus was now a budding molecular biologist. But, since he had no prior research experience, his first days in the Pastan lab were a near disaster, leading Pastan to half jokingly ask, “Now remind me why I took you into the lab.”
In any case, Varmus worked closely with Pastan to develop a molecular hybridization assay to measure transcription of E. coli lac mRNA. [Their specific the goal was determine whether the mechanism by which cyclic AMP reverses catabolite repression of the E. coli lac operon is by enhancing transcription of lac mRNA.] And, they used an E. coli phage, which had incorporated the lac operon into its genome, as their source of isolated lac operon DNA. Thus, Varmus was introduced to virology. [Aficionados, note, “These experiments with the lac operon proved to be analogous in several ways to experiments that revealed the first proto-oncogene a few years later.”]
The satisfaction that Varmus derived from his research in Pastan’s lab caused him to reconsider his aspirations for a career in clinical medicine, and instead to think about a future in biomedical research. He thought he might next try his hand at cancer research, motivated in part, by his mother’s breast cancer, first diagnosed in 1968, to which she succumbed two years later. But there were other factors at work as well. In particular, Varmus’ use of the E. coli phage in Pastan’s lab led to his fascination with virology. And his interest in virology was relevant to his new plans because the DNA and RNA tumor viruses held immense potential for cancer research. 1970s technology could not identify which one of the tens of thousands of cellular genes might have mutated to result in a cancer. However, that technology was potentially able to identify which of the handful of a tumor virus’ genes might underlie its ability to transform a normal cell into a tumor cell.
That line of thought led Varmus to apply for a research position in Renato Dulbecco’s lab at the Salk Institute. [Dulbecco would win a share of the 1975 Nobel Prize in Physiology or Medicine for his pioneering studies of the DNA tumor viruses (5).] However, reminiscent of Varmus’ unsuccessful application to Harvard Medical School, he was “rebuffed by not one but two letters from his (Dulbecco’s) secretary.”
While the rejection from Dulbecco was a disappointment, it would be another of the seemingly providential happenings in Varmus’ career. In the summer of 1969 he chanced to visit Harry Rubin, an eminent Rous sarcoma virus researcher at U Cal Berkeley. Rubin, who had earlier introduced Howard Temin to virology (another auspicious happening; see reference 6), told Varmus about a new group at UCSF that had begun to study retroviruses. Importantly, the goal of the UCSF group was to discover cancer-causing genes. Thus, Varmus stopped over at UCSF, where he met members of the group, including a smart young virologist named Mike Bishop. Varmus reports, “we recognized from the first moments that we were destined to work together.”
Varmus came to Bishop’s lab in 1970 as a postdoctoral fellow. However, their relationship quickly evolved to one of equals, and they made all of their major discoveries in the 1970s and 1980s as a team, and they rose together through the UCSF academic ranks. Bishop relates that their bond formed not just by a shared fascination with cancer viruses but “by our mutual love of words and language.” Varmus, for his part, notes that “after many years of ambivalence and indecision…I appeared to be headed in a clear direction, even if not towards medicine or literature.”
References:
1. Stehelin D, Varmus HE, Bishop JM, Vogt PK., 1976. DNA related to the transforming gene(s) of avian sarcoma viruses is present in normal avian DNA. Nature 260:170-173.
2. How the Human Immunodeficiency Deficiency Virus (HIV) Got Its Name, posted on the blog February 4, 2014.
3. The Politics of Science: Vignettes Featuring Nobel Laureate Harold Varmus during his Tenure as Director of the NIH, posted on the blog June 2, 2014.
4. Varmus, H. 2009. The Art and Politics of Science, (W. W. Norton & Company).
5. Renato Dulbecco and the Beginnings of Quantitative Animal Virology, posted on the blog December 3, 2013.
6. Howard Temin: “In from the Cold”, posted on the blog December 14, 2013.
Peter Piot co-discovered Ebola virus in a laboratory in Belgium in 1976. Two weeks after the discovery, he risked his life in Zaire, now the Democratic Republic of the Congo, studying the Ebola outbreak at its source.
Piot went on to have a distinguished career and is now best known for his advocacy of HIV/AIDS control and prevention, particularly in Africa. Toward that end, Piot participated in the first international project on AIDS in Africa, leading the way to understanding the African AIDS epidemic. He helped found and then served as Executive Director of the Joint United Nations Program on HIV/AIDS (UNAIDS) and then as Assistant-Secretary-General of the United Nations. It is safe to say that Piot helped to save hundreds of thousands, and perhaps even millions of lives. He currently serves as director of the London School of Hygiene & Tropical Medicine.
As a boy growing up in Belgium, Piot fantasized of having exotic adventures. One of his dreams was to travel to Africa, where he might lend a hand to underprivileged people. A more mature Piot, aware that infectious diseases caused most deaths in the developing world, thought that medicine might be an ideal means of fulfilling his fantasies. But, in medical school, one of his professors emphatically advised him: “There’s no future in infectious diseases…Just don’t do that, that’s a waste of time, we have antibiotics, we have vaccines, it’s all solved.”
However, Piot chose to ignore his professor’s advice. “But I wanted to go to Africa. I wanted to help save the world. And it seemed to me that infectious disease might be just the ticket and full of unresolved scientific questions. So I ignored him.”
[Aside 1: The view expressed by Piot’s professor was not altogether rare in the day. As noted in Virology: Molecular Biology and Pathogenesis (1), “Shortly before the emergence of HIV/AIDS in 1981, many health professionals held the opinion that the development of antibiotics against bacteria, and vaccines against poliovirus and other viruses, relegated the threat of infectious disease epidemics to history. Indeed, in 1962, Sir MacFarlane Burnet, who won the Nobel Prize in 1960 for his work on immunological tolerance, stated “…one can think of the middle of the 20th century as the end of one of the most important social events in history; the virtual elimination of the infectious disease as a significant factor in social life.”
AIDS and Ebola were not the only “new” infectious diseases to shatter the kind of optimism voiced by Burnet and others. There was also Lyme disease (caused by the bacterium Borrelia burgdorferi), Legionnaires’ disease (caused by the bacterium Legionella pneumophila), SARS, and West Nile virus. What’s more, rotaviruses are now a major cause of death, especially in children in the developing world, and hepatitis C virus may now affect more people worldwide than even HIV. Moreover, earlier pathogens, such as Mycobacterium tuberculosis, Corynebacterium diphtheriae, the dengue hemorrhagic fever virus, and yellow fever virus, have reemerged over the past 30 years. Making matters worse still, increasing resistance of bacterial pathogens to antibiotics, due in part to misuse of these once “miracle” drugs, is now a major threat to public health.]
The following, sometimes spine-tingling excerpts from Piot’s 2012 memoir, No Time to Lose (2), tell how 27-year-old Piot, two years out of medical school, helped to discover Ebola virus in a laboratory in Antwerp in 1976.
“On the last Tuesday in September 1976 my boss at the microbiology lab was alerted that a special package was on its way to us from Zaire. It was flying in from Kinshasa: samples of blood from an unusual epidemic that seemed to be stirring in the distant Équateur region, along the river Congo.”
[My notes: The blood sample was from a Flemish nun who had been carrying out missionary work in Zaire. She was stricken with a mysterious illness that was killing scores of people there. Piot was then working towards a PhD in Microbiology, awarded to him in 1980 by the University of Antwerp.]
“Nothing quite like this had happened in the two years I had so far been working in a junior position at a lab at the Prince Leopold Institute of Tropical Medicine in Antwerp, Belgium. But I knew it was part of the job. We sometimes took in strange samples of bodily fluids and tried to work out what they were. Our lab was certified to diagnose all kinds of diseases, including arbovirus infections like yellow fever, and the working hypothesis for this epidemic was reported to be “yellow fever with hemorrhagic manifestations.”
“I never actually worked with any suspected yellow fever. It wasn’t every day we received samples from as far away as equatorial Zaire. And it was clear this was an unusual sample, and that something pretty curious had occurred, because several Belgian nuns apparently died of the disease even though their vaccinations were completely up to date.”
“The next day—September 29—the package arrived: a cheap plastic thermos flask, shiny and blue. I settled down with Guido Van Der.” [The italics here, and in the following excerpts, are mine, for emphasis.]
“Groen—a shy, funny, fellow Belgian aged about thirty, a few years older than I—and René Delgadillo, a Bolivian postdoc student, opened it up on the lab bench. Nowadays it makes me wince just to think of it. Sure, we were wearing latex gloves—our boss insisted on gloves in the lab but we used no other precautions, no suits or masks of any kind.”
“We didn’t even imagine the risk we were taking. Indeed, shipping those blood samples in a simple thermos, without any kind of precautions, was an incredibly perilous act. Maybe the world was a simpler, more innocent place in those days, or maybe it was just a lot more reckless.”
“Unscrewing the thermos, we found a soup of half-melted ice: it was clear that subzero temperatures had not been constantly maintained. And the thermos itself had taken a few knocks, too. One of the test tubes was intact, but there were pieces of a broken tube—its lethal content now mixed up with the ice water—as well as a handwritten note, whose ink had partially bled away into the icy wet.”
“It was from Dr. Jacques Courteille, a Belgian physician who worked at the Clinique Ngaliema in Kinshasa. He described the thermos’s contents as two vials, each containing 5 milliliters of clotted blood from a Flemish nun who was too ill to be evacuated out of Zaire. … She was suffering from a mysterious epidemic that had so far evaded identification, possibly yellow fever.”
“I was still trying to find my way in the labyrinth of infectious diseases research, and this kind of thing made my heart beat faster. Guido and René picked out the one remaining test tube of blood from the thermos and set to work. We needed to look for antibodies against the yellow fever virus, and other causes of hemorrhagic or epidemic fever such as typhoid. To isolate any virus material, we injected small amounts of the blood samples into VERO cells, an easily replicable cell lineage that is used a lot in labs. We also injected some into the brains of adult mice and newborn baby mice. (I never liked this aspect of the work. Sometimes we needed to inject patient tissue into the testicles of rats, to isolate Mycobacterium ulcerans, the cause of Buruli ulcers, and it made me cringe.)”
“All this work was done with no more precautions than if we had been handling a routine case of salmonella or tuberculosis. It never occurred to us that something far more rare and much more powerful might have just entered our lives.”
[Aside 2: The italicized excerpts take me back to my postdoctoral days in the early 1970’s, when my colleagues and I routinely mouth-pipetted the much less (but still) dangerous SV40 (3), and the monkey kidney cell cultures that the virus was grown in. Indeed, we were more concerned with contaminating our cultures with mycoplasma, than with infecting ourselves with a simian virus.]
“In the next few days, the antibody tests for yellow fever, Lassa fever, and several other candidates all came up negative, and it seemed likely that the samples had been fatally damaged by their transportation at a semi-thawed temperature. We bustled nervously around the mice and checked our cell cultures four times a day instead of two. On the weekend, each of us popped in to check the samples. All of us, I think, were hoping something would grow.”
“Then it happened. On Monday morning, October 4, we found that several adult mice had died. Three days later all the baby mice had also died—a sign that a pathogenic virus was probably present in the blood samples that we had used to inoculate them.”
“By this time our boss, Professor Stefaan Pattyn, had also gleaned a little more information about the epidemic in Zaire. It seemed to be centered on a village called Yambuku, where there was a mission outpost run by Flemish nuns—the Sisters of the Sacred Heart of Our Lady of s’Gravenwezel. (S’Gravenwezel is a small town north of Antwerp.) The epidemic had been raging for three weeks, since September 5, and at least 200 people had died. Although two Zairean doctors who had been to the region had diagnosed the malady yellow fever, the patients suffered violent hemorrhagic symptoms, including extensive bleeding from the anal passage, nose, and mouth as well as high fever, headache, and vomiting.”
“Previously I had been excited about the work we were doing; now I was inflamed. If we were hunting for signs of a hemorrhagic virus, this was outbreak investigation of the most stirring variety. I truly loved the detective thrill of working in infectious disease. You came in and figured out what the problem was. And if you managed to figure it out quickly enough—before the patient died, basically—then you could almost always solve it, because, just like my medical school professor of social medicine had said, solutions had by this time been found for almost every kind of infectious illness.”
Piot relates that Pattyn “ knew we were not equipped to do the work in safety. In 1974 there were only three labs outside the Soviet Union that could handle hemorrhagic viruses: Fort Detrick, a military lab in Maryland that did high-security bioterrorism work on anthrax and other highly lethal diseases; the Army High Security Laboratory in Porton Down, in England; and the so-called hot lab at the Centers for Disease Control (CDC), in Atlanta.”
“Nonetheless, we continued to bustle around like amateurs in our cotton lab coats and latex gloves, checking our VERO cell lines. The cells began detaching from the glass sides of their containers: it was either a toxic effect or an infection, but either way, cytotoxicity had kicked in. That meant we might be close to isolating a virus, and we began extracting cells to cultivate them in a second line of VERO cells. And Pattyn had been told we should expect more samples from Zaire in the next few days.”
At this point in the story, Pattyn received a message from the Viral Diseases Unit of the World Health Organization (WHO), instructing him to ship all of the Belgium lab’s samples of the mysterious new virus to Porton Down in Britain.
“Pattyn was furious, and I too was upset. It looked as though our outbreak investigation was over before it had even begun. Glumly, we prepared to pack everything in tightly sealed containers: the patient serum, the inoculated cell lines, and the autopsied mouse brains and samples. But then Pattyn told us to keep some of the material back. He claimed that we needed a few more days to ready it for transport. So we kept a few tubes of VERO cells, as well as some of the newborn mice, which were dying. Perhaps it was a stubborn rebellion against the whole Belgian history of constantly being forced to grovel to greater powers. That material was just too valuable, too glorious to let it go. It was new, it was exciting—just too exciting to hand it over to the Brits or, in particular, to the Americans.” [A few days after Porton Down received the samples from Antwerp, the British lab passed a portion on to the CDC in Atlanta, which was the world’s reference lab for hemorrhagic viruses.]
So, with some of their sample material held back, the misadventures in the Antwerp lab kept on. “There was a rack of secondary tubes in the lab, which we had inoculated after the first VERO cell line was killed. We knew there was something in there—something that was trouble—but still, we had taken out the rack so we could examine the tubes under the microscope. Doing that kind of work wasn’t Pattyn’s job. He was a micro-manager but he wasn’t a technician, and in fact he could be rather clumsy. But impulsively he reached for one of the precious tubes, to check it out himself under the scope, and as he did so it slipped from his hand and crashed on the floor.”
“Little René Delgadillo was the one who got his shoes splashed. They were good, solid leather shoes but René bleated, “Madre de Dios” (Mother of God!) while Pattyn swore, “Godverdomme” (Goddamn!)—and there was a moment, just a beat, of blank fear. Immediately we whisked into action: the floor was disinfected and the shoes removed. It was just a small incident. But it struck me only then how lethal this thing really might be and the huge risks we had been taking in handling it so cavalierly.”
Piot then relates that electron micrographs of the new virus, prepared at the university hospital, showed it to be strikingly similar morphologically to the Marburg virus.
“Marburg was clearly a very scary illness, and as we did not have Marburg virus–specific antibodies, we could not definitely conclude whether our isolate was Marburg. Perhaps it was a different virus with similar morphology.”
“Pattyn was not suicidal. Once he had established that ‘our’ virus was—at the very least—closely related to the terrifying Marburg, he had the sense to shelve all further work on it and sent the remaining samples directly to the high-security lab at the CDC.”
Shortly afterwards, the CDC informed the Belgium lab that the mystery virus did not react with Marburg antibodies, and was indeed a new, previously unknown agent. Recalling the earlier advice from his medical school professor, Piot remarked, perhaps with some satisfaction, “… my professors were wrong.”
Piot then tells us, “I was still very excited. It felt as though my childhood fantasy of exploration was almost within my reach. I kept arguing that we had to follow up our work, go to Zaire and check out the epidemic. I felt strongly that we shouldn’t hand this world-class discovery over to some other team. We had identified this virus, after all, so we should be the ones to establish its lethality and its real effects on the ground.”
Piot then relates the political machinations that enabled him to fulfill his dream of going to Africa, where he would help to analyze and contain the deadly epidemic. In Zaire, in the quarantine zone, Piot lived among dying Zairians, repeatedly risking his life collecting blood samples from victims and gradually helping put together a picture of how the virus (eventually known as Ebola, after the river where its first outbreak occurred ), was transmitted.
Piot’s experience in Zaire led him to believe that he might benefit from additional training in infectious diseases. So, he came to the United States to receive further training on sexually transmitted diseases. Upon returning to Belgium, he became the go-to doctor for people arriving from Africa with exotic tropical infections. The emergence of the African AIDS epidemic led Piot back to Africa. He was now well prepared to lead the world’s response against the newer and eventually much graver HIV/AIDS epidemic there (4, 5).
(1) Virology: Molecular Biology and Pathogenesis, by Leonard C. Norkin, ASM Press, 2010.
(2) No Time to Lose: A Life in Pursuit of Deadly Viruses, by Peter Piot, W. W. Norton & Company, 2012.
(3) SV40-Contaminated Polio Vaccines and Human Cancer, posted on the blog, July 24, 2014
(4) The American Public’s Response to the 2014 West African Ebola Outbreak, posted on the blog, August 10, 2014.
(5) Thabo Mbeki and the South African AIDS Epidemic, posted on the blog, July 3, 2014.
The American media has been extensively covering the current West African Ebola outbreak. Consequently, the American public is anxious that the epidemic might spread to the United States; a worry likely fueled by Ebola’s horrible symptoms, which can include extensive internal and external bleeding (although not the liquefying of internal organs depicted in disaster movies), and by a fatality rate that has been as high as 90% in the developing world.
Yet aside from two American medical workers, Dr. Kent Brantly and missionary Nancy Writebol, who were infected in Africa, and returned to the United States for treatment at Emory University Hospital, no other Americans have been infected with Ebola. Moreover, public health experts, speaking through the media, have repeatedly assured the American public that the chance of an Ebola epidemic here at home is extremely slight. [One reason is that Ebola is not highly contagious, as it is transmitted only by direct contact with body fluids from an infected person. Moreover, infected individuals cannot transmit Ebola to others until they begin to express symptoms themselves. For these reasons, an Ebola outbreak in the United States should be quickly contained by isolating infected individuals. What’s more, supportive care in American hospitals would dramatically decrease the likelihood of any infection being fatal.]
Consider the following facts. By August 6, the current Ebola outbreak was estimated to have killed about 1,000 persons. The largest previous Ebola outbreak, which occurred in Uganda in 2000, claimed 244 lives, and Ebola has killed a total of about 2,000 people since it first emerged in 1976. All Ebola outbreaks occurred in Africa, and no Ebola infection has ever occurred in the United States. In each of the previous Ebola outbreaks, the virus ran its destructive course and then “disappeared.”
In contrast, consider that seasonal influenza claims on average about 40,000 lives annually in the United States alone, and 500,000 lives worldwide. And, the influenza virus reappears in a somewhat different immunological guise each and every year. Yet with the exception of those occasions when a seemingly exotic new influenza strain emerged (e.g., the H1N1 swine flu of 2009), the public seems rather indifferent to influenza. Indeed, even the 1918 influenza pandemic (which claimed 196,000 American lives in the single month of October, 1918, and 50,000,000 lives worldwide) did not cause any panic. And, despite the fact that a vaccine is available to prevent the flu, all too many individuals pass up that opportunity to protect themselves.
So, how might we account for the disparity between public apprehensions regarding an Ebola outbreak in Africa, versus public complacency regarding influenza here at home? Perhaps we simply take for granted that influenza will appear every year, and afterwards we forget about it. We even confuse influenza with the much less severe common cold, saying we have the flu, when we are merely experiencing the sneezes and sniffles of a cold.
We might think that the public is more worried by newer emerging viruses (e.g., West Nile virus, the SARS virus, and Ebola), than by actually more dangerous older ones (e.g., measles and influenza), at least in part because the newer viruses are relatively unfamiliar. Also, the current spate of post-apocalyptic movies, the 24-hour news coverage on cable television, and continuous commentary on social media, have each fostered public concern over new emerging infectious agents. But, that can’t be all, since it does not explain the intense fear that polio elicited in America until the Salk and Sabin polio vaccines appeared in the mid to late 1950s; decades before cable television and social media? I was a young teenager in the early 1950s, and remember well the panic that set in every summer when the newspapers reported the first polio cases of the season. What’s more, panic increased dramatically if a neighbor or schoolmate were stricken. You were kept home from school, and couldn’t even play outside. Yet the number of poliomyelitis cases was on average “only” about 20,000 per year, which was about half the average number of influenza fatalities. [The peak year for poliomyelitis was 1952, when there were 57,879 cases.]
So, how might we account for the difference in the public’s concern for polio, versus its relative lack of concern for influenza? A possible reason for the greater fear engendered by poliomyelitis was that the paralytic disease struck mainly children, adolescents and young adults, whereas influenza threatens mainly the elderly. People are usually much more emotionally invested in their children’s well being than in their parents or even themselves.
Yet the public did worry about influenza on occasions when a novel new influenza strain appeared (e.g., the H1N1 swine flu strain that emerged in 2009). Here is another situation in which influenza caused alarm. Unusual circumstances led to flu vaccine shortages in the United States during the winter of 2004/2005. When news of the vaccine shortage first broke in October 2004, there was panic as many individuals clamored for the limited vaccine dosages then available, which, as a matter of policy were being reserved for people at highest risk (e.g., the elderly and the immunologically compromised). But, as small numbers of extra doses began to trickle in from outside sources, demand for the vaccine suddenly disappeared. Indeed, there actually was a surplus, with many doses going to waste.
The outbreak of HIV/AIDS in the early 1980s was one of the defining moments of our time, and merits a longer posting of its own. In brief, because of the association of AIDS with human sexuality in all its forms, the media of that more prudish time had difficulty speaking openly and frankly about the disease. For instance, it used the term “body fluids” to avoid mentioning “semen,” leading to misinformation regarding how the then invariably fatal disease is transmitted. Also, AIDS was associated with intravenous drug abuse. That fact, together with homophobia, resulted in infected individuals (including hemophiliacs who were infected via the contaminated blood supply) being blamed for their illness, and there was blatant discrimination against them. About 15,000 Americans still die from AIDS each year.
The above examples, taken together, point up that the public’s response to infectious disease is shaped by a variety of factors. Furthermore, we might expect that as more and more people crowd into urban areas, and also intrude into once remote areas, new exotic viruses, as well as the older familiar ones, will continue to threaten the human population.
One final point: Whereas the American media has extensively discussed the risk (or non-risk) to Americans from the West African Ebola outbreak, it has barely mentioned America’s responsibility to the West African nations attempting to deal with the outbreak there. And aside from the moral issue, it is clearly in our own self interest to address an epidemic early, at its source, rather than to allow it to spread. [Donald Trump praised Brantly and Writebol for helping out in Africa, but argued that they should not be brought back for treatment because of the risk imposed. He said, “People that go that far away to help are great but must suffer the consequences!”]
The subject of this short posting is a public figure, Colin Powell, rather than a scientist. It deals with Powell’s strong support of condom usage by sexually active young people, so that they might protect themselves against contracting HIV/AIDS. In 2002, at the time of this particular incident, Powell was serving as Secretary of State in the George W. Bush administration. Importantly, Powell’s advocacy of condoms to prevent sexual transmission of HIV was contrary to the Bush administration’s strongly held abstinence-only approach. Powell, a Republican, previously served as a four-star general in the U.S. Army and as Chairman of the Joint Chiefs of Staff.
[Aside: This incident was brought to mind by the recent “Hobby Lobby” case, in which the conservative majority of the U.S. Supreme Court ruled by a 5-4 vote that certain so-called “closely held” corporations do not have to provide contraceptive coverage to their employees under the Affordable Care Act (“Obama care”), if providing that coverage violates the religious beliefs of the corporation’s owners.]
Powell made his remarks during an interview concerning the spread of AIDS that was broadcast on the MTV network. Among Powell’s comments, he said “It is important that the whole international community come together, speak candidly about it, forget taboos, and forget about conservative ideas about what you should tell young people about. It’s the lives of young people that are put a risk by unsafe sex.”
While the interview took place in a Washington D.C. studio, it was transmitted via satellites to studios worldwide, and Powell took questions from young listeners both at home and abroad. A young Italian Catholic woman asked Powell, through an interpreter, to specifically state his position regarding condoms. Powell replied “I certainly respect the position of the Holy Father and the Catholic Church. In my own judgment, condoms are a way to prevent infection. Therefore, I not only support their use, I encourage their use among people who are sexually active and need to protect themselves. I think it’s important for young people especially to protect themselves from the possibility of acquiring any sexually transmitted disease, but especially to protect themselves from HIV/AIDS, which is a plague that is upon the face of the earth.”
Not surprisingly, Powell’s statements generated an angry response from some of the President’s closest supporters, as well as from conservative politicians and right-wing religious groups. Most criticism took Powell to task on “moral” grounds. For example, the president of Concerned Women for America stated, “He undercut the moral authority of all parents, he embarrassed President Bush and undercut the Administration’s policies, and he needs to retract these statements immediately.”
Others of Powell’s detractors added that condom usage is not 100% effective at preventing sexual transmission of HIV. To that point, it is difficult to accurately measure the effectiveness of condoms, since that assessment involves looking into people’s private behaviors. Nevertheless, the U.S. Centers for Diseases Control and Prevention states: “The body of research on the effectiveness of latex condoms in preventing sexual transmission of HIV is both comprehensive and conclusive. The ability of latex condoms to prevent transmission of HIV has been scientifically established in ‘real-life’ studies of sexually active couples as well as in laboratory studies.” And, since condoms need to be used consistently and correctly to be maximally effective, it is important that sex education programs speak to these points. For, as Powell said, “It’s the lives of young people that are put at risk by unsafe sex.”
White House spokesman Ari Fleischer attempted to calm matters stating, “Colin Powell takes a back seat to no one when it comes to abstinence and abstinence education.”
I recently watched the fact-based 2009 movie Endgame, which depicts the final days of apartheid in South Africa. The movie focused on how a young Thabo Mbeki facilitated the late 1980s secret talks between Afrikaner leaders and the about-to-be freed Nelson Mandela’s African National Congress. The purpose of these talks was to arrange negotiations between de Klerk’s apartheid government and the ANC, in order to facilitate the stable transition of South Africa from apartheid.
Thabo Mbeki with Nelson Mandela
Mbeki is portrayed in the film as a wise, compassionate, and respected political activist. Moreover, all commentary on the movie that I’ve read is consistent with it having accurately depicted people and events. Here then is Mbeki in a different guise, when dealing with the South African AIDS epidemic, after succeeding Mandela as the nation’s president. As usual, we begin with some background.
The South African AIDS outbreak may well have been the most devastating of all the world’s AIDS epidemics. Consider the following statistics. By 2007, more than one in five South African adults (approximately 5 million people) were living with HIV, and the disease claimed nearly 1,000 lives daily. Shockingly, 71% of all deaths among individuals between 15 and 49 years of age were due to AIDS. Moreover, a 15-year old South African had a 50:50 chance of dying of AIDS before his or her 30th birthday.
Yet despite these statistics, South Africa escaped the initial HIV/AIDS epidemic of the 1980’s. Why then did HIV/AIDS get so out of hand in South Africa in the early 21st century? One reason is that it was a time when the government was preoccupied with the nation’s poverty and its transition from apartheid. Moreover, and importantly, any rational efforts to deal with the South African HIV/AIDS epidemic were severely compromised when, in 2001, President Mbeki embraced the “denialist” view that AIDS is not caused by HIV. [See the addendum on the AIDS denialists at the end of this posting.]
Mbeki’s “denialist” position on AIDS dates back to 2001, when his minister of health convened a 36-member international panel of supposed AIDS experts to advise Mbeki on how best to confront the nation’s AIDS crisis. Regrettably, the14 known HIV/AIDS denialists, who were invited by the health minister to join Mbeki’s AIDS Advisory Panel, convinced Mbeki to adopt their denialist point of view.
Afterwards, Mbeki and his administration were repeatedly accused of improperly dealing with their nation’s AIDS epidemic. Noting that AIDS patients succumb to the opportunistic infections that appear following the HIV-caused breakdown of their immune systems, South African AIDS patients, who used the public health system, were able to get treatment for their opportunistic infections. However, the Mbeki government prevented those patients from receiving antiretroviral therapy, which might have prevented the breakdown of their immune systems in the first place.
Governmental restrictions against the use of antiretroviral drugs remained in place until August 2003, when the South African Cabinet overruled Mbeki, and declared as Cabinet policy that HIV is the cause of AIDS. Moreover, the cabinet promised to formulate a national treatment plan that would include antiretroviral therapy. Yet despite the efforts of the cabinet to make antiretroviral drugs the mainstay of the country’s treatment plan, the health minister continued to promote nutritional approaches to treating AIDS, while also proclaiming the toxicity of the antiretroviral drugs.
The continued unwillingness of the Mbeki administration, to acknowledge that HIV is the cause of AIDS, prevented the cabinet’s more enlightened AIDS policy from being fully realized. By the end of 2007, only about 28% of South Africa’s AIDS patients were able to obtain antiretroviral therapy. And, since many HIV-infected pregnant women were not getting the antiretroviral drugs that might have prevented transmission of the virus to their babies, HIV remained tragically common among South African children. In this regard, in 2007, UNAIDS reported that there were about 280,000 children under 15 years of age who were living with HIV in South Africa. Moreover, AIDS-related adult deaths resulted in 1.4 million South African children becoming orphans in 2007; a rise from the 780,000 new orphans reported in 2003.
A 2008 report from the Harvard School of Public Health estimated that Mbeki’s denialist stance caused an estimated 330,000 or more preventable AIDS-related deaths in South Africa. That estimate was based on comparing the effect of antiretroviral therapy in neighboring Botswana and Namibia, to the state of affairs in South Africa, during the period from 2000 to 2005.
Mbeki resigned the presidency in September 2008, after losing the support of his party. His resignation was not related to his AIDS denialism. Rather, it involved his alleged interfering with the country’s National Prosecuting Authority in a political matter.
Following Mbeki’s resignation, his successor, Kgalema Motlanthe, fired health minister Manto Tshabalala-Msimang, who, like Mbeki, was an AIDS denialist. South Africa then initiated the largest antiretroviral therapy roll-out program in the world, resulting in a 5-year jump in life expectancy to a current 36 years-of age. Moreover, in 2011, there were 100,000 fewer AIDS-related deaths in South Africa than occurred in 2001, and over 300,000 fewer than occurred in 2006. Still, about 5.6 million South Africans were estimated to be infected with HIV in 2011; the highest number of infected people in any country! Almost one-in-three women aged 25-29, and over a quarter of men aged 30-34, were HIV-positive
Considering the prevalence of HIV in South Africa, it may surprise some readers that there is widespread prejudice in the country against those living with AIDS. With that in mind, we note Nelson Mandela’s action when his son died of AIDS in 2005. Mandela deliberately revealed the cause of his son’s death to the public. His purpose was to countermand the stigma associated with being infected with HIV and, also, as a “political statement designed to… force the President [Mbeki] out of his denial.” Earlier, in 2002, South African politicians, who were loyal to Mbeki, attacked Mandela for questioning the government’s AIDS policy.
Bearing in mind that Mbeki was a respected and intelligent leader, how might we explain his rejection of the orthodox view, based on indisputable evidence, that HIV is the cause of AIDS? Could he simply have been taken in by the AIDS denialists? Or, might there be more? A likely possibility is as follows. Mbeki was known to harbor strong anti-colonialist and anti-West sentiments, born of having come of age during South Africa’s apartheid era. Perhaps his earlier experiences caused him to see his country’s AIDS crisis as a means by which the West sought to exploit his nation’s people.
In the same vein, Mbeki was acutely conscious of South Africa’s poverty and, consequently, was likely affected by the huge expense of antiretroviral drugs. In that regard, his health minister advised him that the cost of treating the 5 million or so HIV-infected South Africans with AZT would exceed the annual health department budget by a factor of ten. And, given Mbeki’s anti-West sentiments, he was particularly sensitive to the fact that antiretroviral drugs were made and sold by powerful Western pharmaceutical companies. Additionally, Mbeki may have been skeptical of the efficacy of those drugs; an attitude reflecting the fact that the health policies of the colonial and apartheid governments in South Africa indeed were often self-serving and manipulative.
Mbeki indeed accepted that AIDS results from the collapse of the immune system. Nevertheless, he believed (or at least claimed) that the cause of that collapse was poor nutrition and poor health resulting from poverty, rather than from a virus. Thus, he argued that he needed to attend to poverty in general, rather than to AIDS in particular.
Treating HIV/AIDS has indeed been expensive for South Africa. Additionally, the more than $1 billion that the nation now spends annually on its HIV/AIDS program has been largely financed from its own domestic resources. Yet, South Africa is still desperately trying to emerge from the poverty of its former oppression. So, if you were in Mbeki’s position as the President in 2001, would you have chosen to support AIDS therapy, which might have exceeded the limits of your financial resources for the foreseeable future or, instead, would you invest in water systems, housing, schools, and hospitals? And what of other crucial social and medical problems that still abound in South Africa, such as malaria, tuberculosis, and violence against women? You cannot have it all. And even if Mbeki and his government had believed in and fully supported antiretroviral therapy, impediments to its effectiveness would still have remained. These comment are not meant to defend Mbeki, but, instead, to point up the complexity of the AIDS problem in a poverty-stricken nation emerging from apartheid.
Addendum: The AIDS denialsts: While some AIDS denialists had legitimate scientific credentials, none, except Peter Duesberg, was an expert retrovirologist. Indeed, before Duesberg emerged as an AIDS denialist, he made important contributions to the retrovirus field, including his finding that Rous sarcoma virus contains an oncogene (1). For this contribution, and others, Duesberg was elected to the prestigious U.S. National Academy of Sciences. However, once Duesberg broke ranks with other scientists over AIDS, he became a scientific outcast, no longer receiving invitations to scientific conferences and no longer able to obtain research grants.
Duesberg advocated the belief that AIDS results from drug abuse, parasitic infections, and malnutrition, rather than from a retrovirus, and that HIV itself is just another opportunistic infection. He stated that if he discovered that he was HIV antibody-positive, he would take that as an encouraging sign that his immune system was working.
Yet Duesberg was never able to offer any plausible evidence that might substantiate his dissident views. Moreover, he repeatedly ignored the numerous rebuttals of his claims that appeared in the scientific literature. [Kary Mullis, who was awarded the Nobel Prize for inventing the polymerase chain reaction (PCR), is another AIDS denialist with legitimate, indeed prestigious scientific credentials. But, unlike Duesberg, Mullis has no expertise that might be relevant to HIV/AIDS.]
In an interesting aside, in 2009, Duesberg published a paper in Medical Hypotheses, which defended Mbeki and disputed the 2008 study which reported that hundreds of thousands of lives were lost in South Africa because antiretroviral drugs were not available to AIDS patients there. Prominent AIDS researchers, including Nobel laureate Francoise Barre-Sinoussi (2) then complained to the journal’s publisher, Elsevier, asking that the paper (which had not yet been printed) be withdrawn.
Since Medical Hypotheses was the only Elsevier journal to have a policy against peer review, Elsevier then asked the editors of another of its journals, The Lancet, to oversee review of Duesberg’s paper. After The Lancet reviewers found that the paper contained numerous errors and misinterpretations, Elsevier permanently withdrew it. What’s more, Elsevier then forced Medical Hypotheses to introduce peer review. [On the one hand, the editorial policy of Medical Hypotheses, to “consider radical, speculative and non-mainstream scientific ideas,” may well have provided a means for airing new, potentially important premises. On the other hand, publication of Duesberg’s denialist notions, in what is nominally a scientific journal, would have given those notions an air of credibility, potentially impairing worldwide efforts against AIDS.]
Far from conceding his position, Duesberg claimed that Elsevier’s measures are the latest example of “censorship” imposed by the “AIDS establishment.” He then published a revised version of the paper in the Italian Journal of Anatomy and Embryology, causing further controversy.
So, taking into account Duesberg’s very real expertise as a retrovirologist, can he possibly have been right about HIV and AIDS, and is his alternative view helpful in the fight against the disease? It would make for a fascinating story if the answers were yes, or just even maybe. But, 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 well 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.
It is not known how many people might have been infected with HIV, or might not have benefited from effective antiretroviral therapy, because they heeded the arguments of the AIDS denialists. These individuals continue to tout their notions, to the detriment of the millions of HIV-infected individuals who listen to them.
1. The relevance of retroviral oncogenes is discussed in: The Politics of Science: Vignettes Featuring Nobel Laureate Harold Varmus during his Tenure as Director of the NIH, posted on the blog, June 2, 2014.
2. see: Who Discovered HIV, posted on the blog, January 24, 2014
This story began with the clash between Luc Montagnier and Robert Gallo over priority of discovery and, with it, the right to name the virus. In the midst of this controversy, Harold Varmus seized the initiative to find a universally accepted name for the virus that causes AIDS.
Our previous posting (Who Discovered HIV?) told how Robert Gallo, at the U.S. National Institutes of Health (NIH), and Luc Montagnier, at the Pasteur Institute in Paris, vied to be recognized as the sole discoverer of the AIDS virus. Montagnier named his isolate of the virus “lymphadenopathy associated virus” or LAV, because it came from a patient presenting with lymphadenopthy. 1 Gallo, in contrast, named the virus “human T-cell lymphotropic virus III” or HTLV-III, based on his belief that it was a variant of the human T-cell leukemia viruses-I and –II, which were isolated earlier in his laboratory.
It soon became clear that LAV was quite distinct from HTLV-I and –II. 2 Moreover, and improbably, HTLV-III was found to be identical to another LAV isolated in Montagnier’s laboratory. What’s more, Montagnier had sent a sample of his virus to Gallo before Gallo reported isolating HTLV-III. These events led to recriminations flying back and forth between Montagnier and Gallo, and, not surprisingly, to a bitter rivalry between them, as each held fast to his claim for priority of the discovery.
For the sake of completeness, Jay Levy, at the University of California, San Francisco (UCSF), was also among the first to isolate the AIDS virus, which he named the “AIDS-associated retrovirus” or ARV. Levy did not take part in the dispute between Gallo and Montagnier and, consequently, did not receive the publicity that they did. And, while Levy did not contend for recognition with the fervor of Gallo and Montagnier, his designation for the AIDS virus, and other proposals as well, also had to be considered in the deliberations described below.
The discoverer of a new virus is generally accorded the privilege of naming it. Consequently, the name that the scientific community might ultimately adopt for the AIDS virus could have implications beyond merely providing an appropriate designation for it. Specifically, if the scientific community were to acknowledge LAV or HTLV-III as the name for the virus, it would have been tantamount to recognizing Montagnier or Gallo, respectively, as its discoverer. Thus, any individuals entrusted with resolving the naming issue had to be wary of inadvertently advancing the claims of one, or the other, of the two main protagonists. There was even more at stake for Gallo, since his integrity was being called into question and, consequently, his reputation as well. Moreover, the national pride of both the United States and France were also at issue, as well patent rights to the blood test for the virus.
Although it was clear to all that HTLV-III (or LAV) is distinct from HTLV-I and –II, and that HTLV-III and LAV are one and the same virus, Gallo still went all-out to preserve HTLV-III as the designation for the virus. So, for a time, the awkward solution of the scientific community was to call the virus LAV/HTLV-III, as was recommended by the World Health Organization, or HTLV-III/LAV, as preferred by the U.S. government.
Harold Varmus now steps up to become the key player in the resolution of the naming dispute. But first, here is his bio in brief. Varmus, born in 1939, shared a 1989 Nobel Prize with Michael Bishop for demonstrating that retroviral oncogenes (e.g., v-src) have their counterparts (proto-oncogenes; e.g., c-src) in normal cells. 3 In turn, this led to the realization that mutations in particular host genes, or the inappropriate expression of those genes, might be the underlying basis for human cancers.
Harold Varmus (1981)
To appreciate the huge significance of Varmus’ and Bishop’s 1976 findings, bear in mind that most of the scientific community of the day were skeptical of the notion that cancer had a genetic basis, until Varmus and Bishop provided direct evidence in its support. Moreover, as Varmus later stated: “In recent years, after our prize was awarded, mutant proto-oncogenes and the proteins they encode have become critical tools for the classification of cancers and promising targets for drugs and antibodies-treatments that have, in some cases, proven to be effective for a significant and growing number of cancers, including leukemias and lymphomas, lung, gastrointestinal, and kidney cancers: and cancers of the breast.” 4
Varmus was a professor at UCSF during the happenings recounted here. Later, between 1993 through 1999, he served as Director of the U.S. National Institutes of Health, and from 2000 through 2010, as President of the Memorial Sloan Kettering Cancer Center. He is currently Director of the National Cancer Institute. On a personal note; I got the idea for this posting from Varmus’ brief account in his book, The Art and Politics of Science (2009). This is a marvelous book that I strongly recommend to all readers of this blog.
At the time of our story, Varmus also was serving as chairman of the Retrovirus Study Group of the International Committee on Taxonomy of Viruses (ICTV). [The ICTV, through its various study groups, has the task of developing and maintaining the commonly accepted virus taxonomy.] As chairman of his study group, Varmus assumed responsibility for resolving the AIDS virus naming dispute. To advise him in that effort, he created an international panel of eminent retrovirologists, which included Howard Temin, 5 Peter Vogt, Myron Essex, Ashley Haase, Steven Oroszlan, Natalie Teich, Kumao Toyoshima, Robin Weiss, John Coffin, and Jay Levy, as well as Gallo and Montagnier. Moreover, Varmus solicited written opinions from more than fifty additional prominent scientists and clinicians, not on his panel.
The panel was soon considering more than a dozen names. Some of these were suggested within the panel, while others were suggested by Varmus’ outside correspondents.
After the panel invested more than a year deliberating these proposed names, which included the two that Montagnier and Gallo originally adopted, it finally settled on “human immunodeficiency virus,” or HIV, as the AIDS virus is now universally known. In reaching its conclusion, the panel considered many issues, including the controversy over priority of discovery, the phylogentic relationship between the AIDS virus and HTLV-I and -II, 2 the immunosuppressive properties of the virus, and the desirability of including the term “AIDS” in its designation. Finally, the panel considered how its preferences squared with established naming conventions and precedent. Varmus, of course, mediated all discussions within his panel.
Notwithstanding all the arguments and compromises that the panel considered, Gallo was not satisfied when all was said and done, nor did the outcome end his dispute with Montagnier. 6 Although the panel’s end result essentially nullified the right of Montagnier and his group to name the virus which they believed they had discovered, Montagnier was already prepared to accept an alternative name, although not HTLV-III. In contrast, since the panel rejected Gallo’s claim that the virus was a variant of HTLV, he, unlike Montagnier, would not sign-off on the May 1986 letter the panel sent to Nature, whichproposed that the AIDS virus be called human immunodeficiency virus, or HIV. [The panel also recommended subcategories of HIV. HIV-1 designates the more common type of HIV, which Gallo and Montagnier each claimed to have discovered. HIV-2 designates the less common variety seen in West Africa, which Montagnier is acknowledged to have discovered. 6]
As Varmus later related, “However difficult this process was-with leaks to the press by Montagnier, belligerent letters to me from Gallo that were copied to most of our nation’s leaders, surly and aggressive behavior by the two rivals, and refusals to sign the final statement by Gallo and his close colleague Max Essex, a virologist at Harvard’s School of Public Health-it was interesting intellectually and socially.” 4 [It’s been said that the diplomatic skills, which Varmus acquired while leading the effort to solve the AIDS virus naming dispute, served him well later in his role as Director of the NIH. For much more on Varmus in that later role see: Varmus, H. 2009. The Art and Politics of Science. Norton Books, New York, NY.]
Some of the thorny issues that Varmus’ panel had to come to grips with with were enumerated above. Those issues and additional others, were also discussed in Varmus’s written correspondences with members of his panel, as well as with the outside experts whom he consulted. 7 We now draw on those communications to glimpse the multiple points of view that Varmus and his panel had to wrestle with.
We begin by considering why the term “AIDS” was not included in the panel’s designation for the virus. This is particularly interesting, especially in view of the naming precedent for viruses such as poliovirus, hepatitis A virus, hepatitis B virus, and the influenza viruses; all cases where the virus is designated by the clinical syndrome that it is associated with. Moreover, that naming convention is generally accepted, despite the fact that in these and other such instances, only a small minority of infected individuals ever manifest the disease. What is more, taking the cases of Hepatitis A and B viruses as an example; these are two phylogenetically unrelated viruses that have nothing whatsoever in common, other than that each causes liver disease. And, as Varmus, himself, noted: “Traditional retroviral nomenclature has worked well in this regard. The convention has been to name viruses according to the host species and the prominent pathology associated with the prototypic isolate of a single type; two examples of such names are ‘feline leukemia virus’ and ‘mouse mammary tumor virus.’” 8 And, even more to the point, there are the examples of the human T-cell leukemia viruses, which have already featured prominently in this tale, and in our previous one (Who Discovered HIV?). So, why then did the panel not choose to simply call the etiologic agent of AIDS “the AIDS virus”?
Michael Gottlieb was one of Varmus’ correspondents who spoke out strongly on this issue. He, and his colleagues at UCLA, command our attention, since, in 1981, they were the first to realize that individuals suffering from persistent infections with the protozoan Pneumocystis carinini, and those with the rare cancer, Kaposi’s sarcoma, were all afflicted with the same underlying disease that specifically targeted their CD4 T cells for destruction. That is, they were the first to recognize and report the existence of the disease that subsequently was named AIDS. Here, then, is an excerpt from Gottlieb’s April 25, 1985 letter to Varmus.
“I am writing to convey my concerns as a clinician about sentiment for nomenclature which would identify the agent as the ‘AIDS virus.’ I believe that this nomenclature would be unfortunate. It is estimated that over one million persons in the U.S. alone have serum antibodies. The fully expressed AIDS syndrome is well publicized to be a lethal intractable illness associated with considerable suffering. In my view the term ‘AIDS virus’ would create considerable distress among all individuals found to have previous exposure…I am hopeful that your Study Group will also wish to avoid creating widespread social distress…” [My note: Gottlieb’s comments, as well as others quoted below, reflect that it was not yet appreciated that virtually all HIV-infected individuals would eventually succumb to AIDS. That disheartening state of affairs would begin to change dramatically with the development of antiretroviral therapy. 6]
Mark Kaplan (North Shore University Hospital), Jerome Groopman (New England Deaconess Hospital), and several other clinicians spoke on the same issue in their April 29, 1985 letter to Varmus:
“The last major aspect to consider in determining the nomenclature of this virus must be the emotions of the patient who is infected with this agent. Patients told that they have infection with the AIDS virus develop devastating psychological symptoms that have been witnessed by all clinicians dealing with these patients and their families. It is a cruel name for the virus for it leaves no hope for the patient, implying that the patient will inevitably develop and die from AIDS. If we were to have called the EB virus by the disease it was first felt to produce, it would have been called the Burkitts Lymphoma virus. By analogy, one can imagine the distress caused to a patient with EBV if told that he had the Burkitts lymphoma virus…” [My note: EBV, for the Epstein-Barr virus, is a ubiquitous herpesvirus that occasionally causes the non-fatal illness, infectious mononucleosis. It also is associated with Burkitt’s lymphoma, a malignant B-cell lymphoma seen in children living in equatorial Africa and New Guinea.]
Addressing the same issue in her April 22, 1985 letter to Varmus, panel member Natalie Teich, at the Imperial Cancer Research Fund Laboratories, wrote the following :
“Poliovirus was acceptable even though the vast majority of infected persons remained asymptomatic. However, with AIDS, the social and economic implications and stigma may be too overriding.”
Yet in the case of this issue, and others as well, there was no immediate consensus among those contributing to the discussion. Here is what Jay Levy, also a panel member, wrote in his May 10, 1985 letter to Varmus:
“The concern about frightening individuals with the term ‘AIDS’ virus should not be a consideration…no matter what term is given to the AIDS retrovirus, individuals will easily recognize its connotation.”
Levy adds the following: “I favor classifying the AIDS virus in a category by itself. It is most likely the prototype of a human lentivirus and should not be confused with other human retroviruses. My group prefers to maintain our initial nomenclature, that of AIDS-associated retrovirus (ARV) as it best defines the agent linked to this distinct clinical disease.”
Irrespective of whatever scientific merits Levy’s proposal may have brought to the table, it was not seriously considered by the discussants. For example, Natalie Teich dismissed it as follows: “With due regard for Jay, this was clearly a ‘johnny-come-lately’ claim.”
And, William Haseltine, at the Dana-Farber Cancer Institute, wrote the following in his August 7, 1985 letter to Varmus. “…Dr. Jay Levy’s proposed name has no merit as his report merely repeated the original isolations using previously published methods.”
Notice that both Teich and Haseltine rebuff Levy’s preference solely on the basis of right-of-discovery. With that in mind, here is Haseltine’s take on the appropriateness of calling the virus HTLV-III:
“I strongly favor the name HTLV-III for the virus. I would not oppose the name HTLV-III/LAV or LAV/HTLV-III. My reasons are as follows:…Unless there is good reason to the contrary, the original discoverers of the virus should have the right to call the virus the name they chose. Both the laboratories of Drs. Gallo and Montagnier have valid claims to be original discoverers of the virus. Although the Paris laboratory published first, I am convinced that Gallo had, in fact, isolated the virus at or before late 1982 to very early 1983 as did the Paris Laboratory…Given what must be considered to be a lack of consensus of the committee on the appropriate nomenclature, there is no compelling reason not to abide by the choice of the discoverers themselves…HTLV-III is a far better name than LAV. LAV refers to a specific disease state. HTLV-III does not.” [My note: This passage underscores that the controversy between Montagnier and Gallo, over priority of discovery, was still very much alive at this time.]
Anthony Fauci, as Director of the National Institute of Allergy and Infectious Diseases, also commanded attention. In his May 3, 1985 letter to Varmus, Fauci noted that he typically refers to the virus as the “AIDS retrovirus.” However, he argues against adopting that name, not quite for the reasons expressed above, but seemingly because of the mistaken belief at the time that many infected individuals will not develop AIDS. Nevertheless, even if that belief were correct, the very vast majority of individuals infected with poliovirus, and the hepatitis A and B viruses, and other viruses likewise named for the pathology with which they are associated, do not develop those diseases, as was noted above.
Fauci’s most interesting comments may be those concerned with naming the virus either “LAV” or “HTLV-III.” Regarding “LAV,” he says: “…I do believe it would be inappropriate to call this the lymphadenopathy-associated virus (LAV). The reasons for this should be obvious. First, the virus causes more than lymphadenopathy…”
Regarding “HTLV-III,” he says: “Although there are accumulating data, of which you are aware or more aware than I am, that there are significant dissimilarities between this virus and HTLV-I and –II, I still believe that there is enough reason to maintain this virus within the HTLV nomenclature that this should be continued. The reasons for this are that it surely is a human virus (H), it is a T-lymphotropic virus (TL), and it is a virus (V). Therefore, I would think that HTLV itself is a reasonable abbreviation for the virus. For that reason I would suggest naming it either HTLV-III alone or HTLV-III/LAV. However, for reasons given above concerning the disadvantage of using the terminology LAV, I would elect to call it HTLV-III.”
Fauci does not neglect to point out: “I am well aware of all the difficulties and the emotional issues that are interjected into this vis-à-vis who will get more credit related to the name that is chosen. I will try to disassociate myself from any of that and give you as objective a viewpoint as I possibly can concerning the nomenclature….”
The above comments are from but a small subset of Varmus’ correspondences. And, the comments cited above are merely a subset of the positions and arguments stated in them. Yet they enable us to better appreciate Varmus’ accomplishment in arriving at an acceptable and appropriate name for the AIDS virus, and one which did not stir up further discord. As he succinctly stated in his January 17, 1986 memorandum to his panel: “I and several committee members have come to favor HIV: it is simple; it is novel (and hence does not inflame controversies); and it is based upon the name of the disease with which the virus is readily identified, without including the term AIDS.”
I end this posting with the text of a December 19, 1984 letter from Varmus to David Kingsbury at Oxford, in which Varmus informs Kingsbury of the progress of his ICTV Retrovirus Study Group towards revising the retrovirus phylogeny. Varmus’ letter is followed by a portion of Kingsbury’s January 4, 1985 response. [Kingsbury is best known for his research on influenza viruses. I presume that Varmus was corresponding with Kingsbury here, in part because of the latter’s stature within the ICTV, which put Kingsbury in a position to help Varmus gain approval from the ICTV’s higher leadership for his study group’s recommendations.]
“Dear David:
Thanks for your newsletter. As you probably know, we have updated the summary of Retroviridae for Intervirology (a minor task), and we are anticipating some difficulty with finding a suitable name for the AIDS virus. I am waiting for the dust to settle from the nucleotide sequencing (done or almost done in four labs at least) before convening a subcommittee. But it is clear that the AIDS virus is no more related to HTLV-I than to any other retrovirus on the basis of sequence comparison. Would you like to tell Bob Gallo it shouldn’t be called HTLV-III?
Best regards,
Harold E. Varmus, M.D.”
And Kingsbury’s reply:
“Dear Harold:
….The news about the AIDS virus is startling! Another family of human retroviruses? When you have adequate data to take a firm position on this I will be happy to tell Bob Gallo the facts. I have no vested interest in the matter.
With best wishes,
David”
Footnotes:
1. As noted in Who Discovered HIV?, before Montagnier began his search for the AIDS agent, a group of French physicians and scientists suggested to him that the best chance to find and isolate it might be at the start of the disease, before the patient’s T cells had severely declined.The reasoning was that if a virus were found at this early stage of the disease, then it would more likely be its cause, rather than merely a consequence of the immune depression. So Montagnier and co-workers looked for a retrovirus in a lymph-node biopsy from a patient with persistent lymphadenopathy (swollen lymph glands); an early sign in patients progressing towards AIDS, but with little sign yet of the impending severe immunodeficiency.
2. The following statement appears in Harold Varmus’ draft report (Naming the AIDS Virus), which reviews the deliberations of his panel to find a suitable name for the retrovirus that causes AIDS.
“If an evolutionary tree is established for retroviruses by comparing the order of amino acids in the protein most characteristic of retroviruses, the enzyme that converts RNA to DNA, it is apparent that the AIDS virus is most closely related to the sheep lentivirus, called visna, whereas the human T cell leukemia viruses are in another limb of the tree, more closely related to other oncogenic viruses, leukemia and sarcoma viruses of various animals, particularly the bovine leukemia virus.”
3. Stehelin, D., H.E. Varmus, M. Bishop, and P.K. Vogt. 1976. DNA related to transforming gene(s) of avian sarcoma viruses is present in normal avian DNA. Nature 260:170-173.
4. Varmus, H. 2009. The Art and Politics of Science. Norton Books, New York, NY.
5. For more on Temin, see: Howard Temin: In From the Cold, on the blog.
6.Who Discovered HIV? On the blog.
7. The Harold Varmus Papers, AIDS and HIV: Science, Politics, and Controversy, 1981-1993: Documents
8. Harold Varmus’ April 10,1986 draft of his report, Naming the AIDS Virus, which reviews the deliberations of his panel to find a suitable name for the retrovirus that causes AIDS.
The Nobel Committee rewarded Luc Montagnier and Françoise Barré-Sinoussi for the discovery, but passed over Robert Gallo, who did much of the basic research that made the discovery possible.
Our story mainly involves two research groups; Robert Gallo and his colleagues at the U.S. National Institutes of Health, and Luc Montagnier and his colleagues at the Pasteur Institute in Paris. But first, we begin with a few tangential personal recollections, followed by relevant background to provide the setting for our tale.
The herpes simplex viruses and Epstein-Barr virus were the viruses that most excited the interest of my students in the 1970s, almost certainly because of their association with genital infections and infectious mononucleosis (the “kissing disease”), respectively. But, the major interest that these herpesviruses held for my students changed suddenly and dramatically in 1983 with the discovery of HIV as the cause of AIDS. In the more straitlaced early 1980s, excitement over HIV/AIDS was at least in part due to its association with human sexuality in all its forms.
HIV remains a hot topic. Nevertheless, the attention that HIV initially garnered has to some extent diminished as new emerging viruses, such as West Nile Virus, the SARS coronavirus, and the avian and swine influenza viruses arrived to replace the already familiar HIV as the most interesting of viruses. Another development which somewhat diminished concern over HIV is that while a positive HIV diagnosis in the 1980’s was essentially a “death sentence,” the development of new antiretroviral drugs has since turned AIDS into a manageable chronic infection for many HIV-infected individuals. And, in our less prudish times, the association of AIDS with sex may now rouse less interest than it did in earlier times.
The somewhat ephemeral nature of what is trendy in science, as illustrated here by the declining interest in HIV/AIDS, perhaps reflects the short-lived nature of what is hot in contemporary culture in general. This may help to explain my experience of only a few years ago when I began to excitedly recount for my virology class, comprised mostly of microbiology majors, how Robert Gallo and Luke Montagnier vied to be recognized for the discovery of HIV. I was most surprised to realize that not any of my students had ever heard of Gallo and Montagnier. This disquieting experience compels me to tell this story here. It is rich in human, scientific, political and, perhaps now, historic interest, and needs to be told.
Before beginning the story of the discovery per se, it would be good to recount again the extent of human suffering wrought by the AIDS epidemic. It was indeed enormous, especially in its early years when there were no therapies to treat what was then an almost invariably fatal infection. Indeed, the emergence of HIV/AIDS was by some criteria the worst outbreak of an infectious disease in history. Approximately 65 million people in the world were infected by the fall of 2007, and the rate of new infections remains at several million per year. Of these, 50,000 HIV infections still occur annually in the United States, and these disproportionally involve African-Americans and other minorities.
In view of the above, the unearthing of HIV as the cause of AIDS can well be regarded as one of the great discoveries of medical science. First, it led to the development of sensitive tests for HIV infection, which made it possible to asses the effectiveness of world-wide prevention efforts. And, by identifying those who might be infected, the tests significantly slowed the spread of the infection. What’s more, the tests also made the world’s blood supply safe from the virus. Second, and critically, the identification of a retrovirus as the cause of AIDS opened up the use of antiretroviral therapy to treat AIDS patients, thereby dramatically reducing morbidity and death. In fact, current antiretroviral regimens can lower viral levels in some HIV-positive patients to the point where even the risk of transmission is negligible. And, pre-exposure prophylaxis (PrEP) may soon be available, in the form of a single pill (e.g., Truvada, a combination of the antiretrovirals, tenofovir disoproxil fumarate and emtricitabine). [Nevertheless, bear in mind that even now, with the availability of effective antiretroviral drugs, the virus is still present and ready to multiply if treatment is interrupted. Furthermore, many patients, particularly in the developing world, do not have access to these therapies. And, an HIV vaccine remains problematical. The reasons for the latter are discussed in Virology: Molecular Biology and Pathogenesis.]
Precious little was known about the underlying basis of AIDS before HIV was isolated and confirmed as its cause. Consequently, many wrongheaded hypotheses were put forward to explain the origin of the disease. For example, since AIDS first appeared among cohorts of gay men, some researchers proposed that the disease might be caused by sperm in the male bowel. And, since AIDS is characterized by a severe immunodeficiency, others suggested that it might be caused by excess stress that some individuals placed on their immune systems. Yet some investigators did suggest that AIDS might be caused by a virus. Thus, cytomegalovirus, Epstein-Barr virus, hepatitis B virus, and the herpes simplex viruses were all investigated as the possible cause of AIDS.
Interestingly, very few biomedical scientists thought that AIDS might be caused by an as yet unknown infectious agent (based on the conceit that all infectious agents had already been identified), much less a retrovirus. Indeed, prior to the discovery of HIV, it was generally thought that there are no human retroviruses; a view based on previous failed attempts to find retroviruses in human cancers. In this regard, it had been the hope of many an ambitious retrovirologist to find an oncogenic human retrovirus.
As it was, the two research groups featured here were among the very few that persisted in the search for retroviruses in human cancers. And, it was fortunate that their searches focused on leukemias in one laboratory, and T lymphocyte cultures from breast cancer patients in the other. As a consequence of their ongoing efforts, when the first patients with AIDS were identified in 1981, one of these groups was able to provide the conceptual and technical tools to isolate the AIDS virus, which the other group used to actually isolate the virus.
The stage is now set for Robert Gallo to play a key part in our story. In 1980, just before the first patients with AIDS were recognized, Gallo and his associates discovered the first known human retroviruses. These were two closely related viruses, isolated from patients with an unusual adult T-cell leukemia. Accordingly, Gallo originally named them “human T-cell leukemia virus I and –II” (HTLV-I and –II). These viruses are also known as the human T-lymphotropic virus I and –II. [See below regarding the origin of the second meaning of “L” in the acronym.]
Bearing in mind that all earlier efforts to isolate a human retrovirus were unsuccessful, why was Gallo able to isolate HTLV-I and -II in 1980? Part of the answer is as follows. During the previous 15 years, Gallo had been studying other mammalian leukemogenic retroviruses. To facilitate those studies, Gallo’s group developed methods for growing T lymphocytes in culture for extended periods. This advancement depended on the earlier discovery by Doris Morgan in Gallo’s laboratory of the T-cell growth factor, now known as IL-2.1 Importantly, the ability to grow T lymphocytes in cell culture, which enabled Gallo to grow the HTLVs, would be a critical breakthrough with regard to isolating HIV, since HIV specifically targets CD4 helper T lymphocytes in vivo. Moreover, it would be a key to developing the blood tests that detected the virus.
Other investigators also made significant advances. One of these was the discovery only ten years earlier of reverse transcriptase by Howard Temin and David Baltimore. 2 The availability of reverse transcriptase made it possible to develop highly sensitive PCR-based assays for detecting a retrovirus. These developments, taken together, enabled Gallo’s group to isolate HTLV-I and –II in 1980. And, consequently, when AIDS emerged, tools were already in place to search for a retrovirus as its causative agent.
When AIDS then suddenly appeared on the scene, Gallo saw several clues which hinted to him that its etiologic agent might be a retrovirus similar to the HTLVs.3 First, AIDS is characterized by a severe loss of CD4 CD4 helper T lymphocytes, and HTLV was already known to target T cells. Second, HTLV was known to be transmitted via blood and sexual activity, and from mother to infant; the very modes by which AIDS was proving to be transmitted. Third, a high incidence of AIDS was being reported in Haiti, a region in which HTLV is endemic. Thus, Gallo’s premise was that AIDS is caused by a variant of HTLV. That premise would prove to be incorrect, but Gallo was indeed correct in hypothesizing that it is caused by a retrovirus.
Now we turn to Luc Montagnier, a retrovirus researcher at the Pasteur Institute, who was at the time of the AIDS outbreak investigating the possible involvement of retroviruses in human breast cancers. Toward that end, Montagnier was cultivating T cells from breast cancer patients,and assaying the culture medium for reverse transcriptase activity.
In 1982, influenced by Gallo’s arguments, Montagnier set out to isolate a retrovirus as the possible etiologic agent of AIDS. As Montagnier noted, “At that time there were only a few cases in France, but they attracted the interest of a group of young clinicians and immunologists. They were looking for virologists, especially retro-virologists, as a likely hypothesis was that HTLV – the only human retrovirus known so far, recently described by R. C. Gallo – could be involved.” 4
Before Montagnier began his search for the AIDS agent, a group of French physicians and scientists suggested to him that the best chance to find and isolate it might be at the start of the disease, before the patient’s T cells had severely declined. Their reasoning was that if a virus were found at this early stage of the disease, then it would more likely be its cause, rather than merely a consequence of the immune depression. So, Montagnier and co-workers looked for a retrovirus in a lymph-node biopsy from a patient with persistent lymphadenopathy (swollen lymph glands), an early sign in patients progressing towards AIDS, but with little sign yet of the impending severe immunodeficiency. [In their later joint report, Gallo and Montagnier noted: “The idea that the causative agent of AIDS should be sought in swollen lymph nodes was partly right, since we now know that lymph nodes are the main site where the virus hides during the presymptomatic phase.” 3] Cells from this patient were cultivated in the presence of IL-2, as per Gallo’s earlier finding, as well as anti-interferon antiserum. The latter was an innovation of Montagnier, based on the earlier finding in Paris that interferon repressed the replication of retroviruses in cell culture. Two weeks later, in early January 1983, Montagnier’s research group detected the first evidence of reverse transcriptase activity in the cell culture medium.
Contrary to expectations, the new retrovirus detected in Montagnier’s laboratory was not an HTLV. This was initially shown by the fact that it did not react with anti-HTLV antibodies that were provided by Gallo. Moreover, when Montagnier’s isolate was viewed by electron microscopy, its morphology was clearly different from that of an HTLV. The difference between these viruses was further confirmed by sequence analysis. However, and crucially important, antibodies against Montagnier’s new virus were later found to be present in serum from most AIDS patients, and the virus was shown to have a tropism for CD4 T cells.
Since Montagnier’s new virus came from an AIDS patient with lymphadenopathy, he dubbed it “lymphadenopathy-associated virus” or LAV. This particular isolate of LAV was named “Bru.” Interestingly, Montagnier later obtained a biopsy from another AIDS patient who was infected with HTLV, as well as with the virus that he called LAV. If this had been the first patient sample, results might have been very confusing indeed.
Returning now to Gallo, concurrently and independently of Montagnier, he too was attempting to isolate a retrovirus from biopsies of AIDS patients. The sequence of events which then transpired was truly bizarre, beginning with the fact that while Gallo was seeking to isolate an AIDS retrovirus, he received a sample of Bru from Montagnier. Shortly afterwards, Gallo announced that he had isolated a retrovirus from an AIDS patient pool in his laboratory. 5 Moreover, Gallo’s isolate had somewhat different properties from those earlier ascribed to Bru. For example, unlike Bru, which grew only in fresh T cell cultures, Gallo’s isolate also grew in permanent T-cell lines. Bearing in mind Gallo’s premise that AIDS is caused by an HTLV variant, he reported that he had isolated a second type of AIDS retrovirus, which he named HTLV-III.
Here now is the crucial part of our story. When the nucleotide sequence of HTLV-III was determined afterwards, it turned out to be essentially identical to that of another LAV sample that had been isolated earlier in Montagnier’s laboratory. This finding was remarkable since HIV has an extraordinarily high mutation rate. And, since an untreated HIV-infected individual can produce between 108 and 1010 new virus particles each day, it would be extremely improbable to obtain virtually identical isolates from two different patient samples.
Considering the enormous importance of the discovery of the virus responsible for AIDS, and the resultant accolades that would surely go to its discoverer, the fact that Gallo’s HTLV-III was identical to a LAV isolate from Montagnier’s laboratory resulted in accusations flying back and forth between the two men. And, in part because of the sensational nature of AIDS itself, the competing claims of Gallo and Montagnier led to likewise sensational accounts of their controversy in the media of the day.
Now might be a good time to comment on the fact that Montagnier and Gallo gave different names to their AIDS isolates; LAV and HTLV-III, respectively. Importantly, the discoverer of a new virus is generally accorded the privilege of naming the virus. So bearing in mind the competing claims of Gallo and Montagnier, if the scientific community were to designate the AIDS virus as either LAV or HTLV-III, it would have been tantamount to recognizing Montagnier or Gallo, respectively, as its discoverer.
Harold Varmus, as chairman of the Retrovirus Study Group of the International Committee on Taxonomy of Viruses (ICTV), was mainly responsible for arriving at an outcome to the naming dispute that was acceptable to both protagonists, settling on “human immunodeficiency virus,” or HIV, as the AIDS virus is now universally known. [The story of how the naming issue was resolved will soon be covered in a separate posting.]
The fact that HTLV-III was identical to LAV, taken together with subsequent events, ultimately resulted in Gallo’s integrity being questioned and his reputation being compromised. We begin this part of our tale at a September 1983 Cold Spring Harbor meeting, ostensibly organized to discuss retroviruses in human leukemias. At this meeting, Montagnier reported isolating LAV from three AIDS patients; a homosexual, a hemophiliac, and a Haitian. Moreover, Montagnier also pointed up key differences between LAV and HTLV-I and -II. As for Gallo’s response to Montagnier’s presentation, some conference attendees described it as scornful and arrogant. In addition, in the introduction to the conference proceedings, which Gallo wrote, he brought up HTLV-III, although he never actually spoke about HTLV-III at the meeting. And, apropos the two meanings of “L” in the HTLV acronym noted above, it was in Gallo’s introduction to these proceedings that he subtly changed the meaning of “L” from “leukemia” to “lymphotropic.”
Next, in April 1984, Margaret Heckler, President Ronald Reagan’s Health and Human Services Secretary, hastily called a press conference to publicly announce that Gallo had discovered the AIDS virus. Heckler then introduced Gallo, who confirmed the discovery, while neglecting to mention that Montagnier had isolated the same virus. Gallo also managed to avoid questions from reporters who were primed to raise this issue. [In an interesting sidelight, Heckler confidently announced to the press that an AIDS vaccine would be available within two-years-time, leaving every scientist in the room aghast. Her rash optimism regarding an AIDS vaccine may well have been based on the earlier successes of Jonas Salk and Albert Sabin, who developed the killed and attenuated polio vaccines, respectively. (Salk and Sabin, like Gallo and Montagnier, were also bitter rivals; the topic of a future post.) Some have suggested that Heckler’s prediction of the vaccine was meant to distract attention from Reagan’s earlier silence on AIDS. The U.S. government indeed appeared to be indifferent to what was perceived by the public as a gay disease.6]
On the same day that Gallo announced his discovery of the AIDS virus at the press conference noted above, he also filed a U.S. patent application for a blood test that would detect signs of the virus in people. Gallo’s patent application became another sore point in his controversy with Montagnier, since the latter charged that Gallo’s blood test made use of a virus that was isolated at the Pasteur Institute. And, considering that the patent was estimated to be worth about $100 million per year, even the governments of the United States and France weighed in on the dispute. In fact, to end the disagreement over patent rights to the blood test, and so enable the U.S. and France to share proceeds from the patent equally, U.S. President Ronald Reagan and French Prime Minister Jacques Chirac signed a declaration that Gallo and Monatagnier were co-discoverers of the virus.
Here now is an example of politics intruding on science. As a condition of the agreement signed by Reagan and Chirac, Gallo and Montagnier had to write a history of the discovery of HIV that was in the accord with the agreement. What’s more, Gallo and Montagnier were forbidden from later publishing any statement that might undermine the agreement. Nevertheless, and irrespective of the political settlement of the patent rights to the blood test, the patent dispute also worked to undermine Gallo’s standing, not only because of persisting questions regarding the origins of the virus on which the test was based, but also because some of Gallo’s critics contend that his patent claim delayed use of the blood test for a year.
Considering that the undermining of Gallo’s standing began with the finding that his HTLV-III was virtually identical to a virus isolated in Montagnier’s laboratory, how did it happen that isolates of a highly mutable virus, from laboratories more than 3,000 miles apart, were virtually identical? Here is what many believe to have been the likely scenario. After Montagnier isolated Bru in Paris, he then isolated HIV from biopsies of several other AIDS patients. One of these isolates, called “Lai,” replicated much more rapidly than Bru, as well as other HIV isolates, in cell culture. Unbeknownst to Montagnier, Lai then contaminated and overgrew stocks of Bru in his laboratory. Then, Montagnier sent a sample of Bru to Gallo that unknowingly was contaminated with Lai. Next, Lai contaminated the culture that Gallo’s research group thought contained a virus that originated in their pool of AIDS patient biopsies. 7
Apropos the above, such mix-ups are not uncommon (a warning to beginning researchers). In fact, Montagnier also sent Lai-contaminated LAV samples to several other laboratories, and Lai likewise contaminated cell cultures in those laboratories. But, before entirely absolving Gallo of any culpability, we well might ask why he did not compare his HTLV-III to the sample that Montagnier had sent him, before announcing that he had discovered a new virus.
The virtual certainty, that a Nobel Prize would go to the scientist recognized as the discoverer of the AIDS virus, was for sure a major factor behind the bitter rivalry between Gallo and Montagnier. As it was, in 2008, 25 years after the first article describing HIV and its causal link to AIDS, 8 the Nobel Prize for Physiology or Medicine was awarded to Luc Montagnier and his co-worker, Francoise Barre-Sinoussi, for discovering the AIDS virus. Harold Zur Hausen shared in the award for his work identifying human papilloma viruses as the cause of cervical carcinoma. Gallo was not included in the award.
Was the decision of the Nobel Committee to exclude Gallo from the award correct? The Committee stated that Barre-Sinoussu and Montagnier “made the most important contributions to the discovery.” The Committee did acknowledge Gallo’s “detection of a novel…virus from a vast number of patients with AIDS or pre-AIDS in 1984…[which] showed considerable similarity with LAV-1.” Those findings of Gallo, taken alone, may not have justified a Nobel award. Importantly, however, the Nobel Committee did not acknowledge that Gallo’s group had been responsible for much of the basic research that made the discovery of HIV achievable. As noted above, Gallo’s group discovered IL-2, which made it possible to grow T cells in culture and, consequently, HIV as well. [One source I came across claimed that Gallo himself was unimpressed by Doris Morgan’s discovery of IL-2, and discouraged her from working on it, and that Gallo did not see any value in growing T cells.] Moreover, these breakthroughs enabled Gallo’s group to also isolate HTLV-1 and HTLV-II, thereby demonstrating the existence of human retroviruses and, what’s more, the feasibility of isolating them. And it was Gallo who first suggested that AIDS might be caused by a retrovirus. Furthermore, Gallo’s group was also the first to grow HIV in an established T-cell line, which was crucial to the development of the blood test for HIV. Additionally, Gallo’s group provided the more definitive evidence that HIV is indeed the etiologic agent of AIDS, as based on their repeated isolation of HIV from patients with AIDS and, subsequently, by means of the blood test. Also note that Montagnier was quick to acknowledge that Gallo deserved the award as much as he and Barre-Sinoussi.
Gallo said it was a “disappointment” not to be included in the Nobel award, but he affirmed that all three of the recipients deserved the honor. Jay Levy, at the University of California, San Francisco (UCSF), is also recognized as a co-discoverer of HIV, which he originally termed the AIDS-associated retrovirus, or ARV. Levy is not as well known as Gallo and Montagnier, in part because he was not involved in their controversy. Levy reacted to being passed over by the Nobel Committee with the gracious comment: “In the end, what they (the Nobel Committee) did was quite, quite fair…And I congratulate them (Montagnier, Barre-Sinoussi, and Zur Hausen).”
Considering the importance of Gallo’s ground-breaking work, what might really have been behind the Nobel committee’s decision to exclude him from the award? Even if the Nobel committee did not regard Gallo’s contributions as equal to those of Montagnier and Barre-Sinoussi, weren’t they still worthy of the Nobel Prize?
Questions concerning Gallo’s integrity may have worked against him in the eyes of the Nobel committee; most importantly those arising from the virtual identity of Gallo’s HTLV-III and Montagnier’s earlier LAV-1 isolate. Other researchers also had concerns regarding Gallo’s ethics. Consequently, in 1990, to get to the bottom of the origin of HTLV-III, the Office of Scientific Integrity at the National Institutes of Health authorized a group at Hoffmann-La Roche to analyze HIV samples isolated in the laboratories of Gallo and Montagnier between 1983 and 1985. The conclusion of the Roche group, published in Nature in 1993, was that Gallo’s HTLV-III indeed had originated in Montagnier’s laboratory. 9 But, the group also concluded that the initial mix-up, Lai in place of Bru, occurred in Montagnier’s laboratory. The Lai-contaminated sample that Montagnier then sent to Gallo subsequently may have contaminated the culture that Gallo was working with in his laboratory.
In the end, the Roche investigating team dropped all charges against Gallo. However, before publication of their findings, Gallo’s group was found guilty of “minor misconduct” by the Office of Scientific Integrity in 1991. Thus, while the Roche team cleared Gallo of all charges of misconduct, his reputation had already been tarnished by the accusations against him. Moreover, questions still remained, particularly those pertaining to Gallo having grown Montagnier’s LAV in his own laboratory, before he reported isolating HTLV-III. What’s more, there is evidence that a micrograph published by Gallo that is said to show HTLV-III, actually depicts Montagnier’s LAV.
A second reason suggested for the Nobel committee’s slight to Gallo concerns his ego and fiercely competitive nature. Still, while Gallo’s personality may not have endeared him to the Nobel committee, it most certainly should not have precluded his contributions from being recognized by them.
Here then is another possible take on the Nobel committee’s decision to leave Gallo out of the award, as noted at the time by Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases. “The committee has a long history of awarding the prize to the person or group that makes the first seminal observation or discovery, and they did that in this case.” Hence, in the end, it may simply have come down to who the committee considered to be the actual discoverer of HIV.
So, who actually discovered the AIDS virus? The answer is that HIV was first isolated by Françoise Barré-Sinoussi in Montagnier’s laboratory at the Pasteur Institute, in collaboration with other French clinicians and researchers, including Jean-Claude Chermann, Willy Rozenbaum, David Klatzmann and, of course, Montagnier. They published their findings in Science, in May 2003; about a year before anyone else. 8 Jean Claude Chermann, the second author of the Science paper, is considered by many to be equally deserving of the Nobel Award. Chermann supervised Barre-Sinoussi in Montagnier’s laboratory, and had the idea of focusing efforts to isolate HIV on patients with lymphadenopathy.
This remarkable photograph was taken in the park of the Institut Pasteur Annex in Garches, near Paris, during a break of a “100 guards meeting” in 1987. From left to right: Jonas Salk, Jean- Claude Gluckman, Jean-Claude Chermann, Luc Montagnier, Robert Gallo, Françoise Barré-Sinoussi, Willy Rozenbaum, and Charles Mérieux.
Also note that, in 1985, Montagnier’s research group, in collaboration with physicians in Lisbon and virologists from Hopital Claude Bernard in Paris, also discovered HIV-2 (which they initially dubbed LAV-II) in West African patients with AIDS. Concurrent with the above efforts, Jay Levy and colleagues at UCSF demonstrated that HIV is present in AIDS patients and in healthy carriers as well.
Still, consider the following. First, the issue of which research group was the first to isolate HIV was resolved by the early 1990s. Second, Howard Temin and David Baltimore had to wait a mere five years after announcing their discovery of reverse transcriptase before receiving their Nobel Prizes. 2 So, bearing in mind the enormous significance of the discovery of HIV, why did 25 years elapse before the Nobel committee rewarded that discovery? Can it be that it was concerned with, and needed to resolve some of the ethical issues noted above? Or, was it simply that the Nobel committee tends to steer clear of controversies? Since the Nobel committee’s deliberations are shrouded in secrecy, we can only speculate on the reason for the 25-year hiatus, and why Gallo was excluded from the prize.
Next, bearing in mind Gallo’s extensive experience as a retrovirologist and that only his group had ever isolated a human retrovirus, as well as all of the resources available to him at the NIH, why didn’t he succeed in isolating the AIDS virus ahead of Montagnier? Was it because he was fixed on the notion that AIDS is caused by a virus closely related to HTLV-I and –II? Indeed, until May 1983, Gallo was looking only for, and reporting only isolates that were like the HTLVs. So, perhaps there is the irony that if Gallo’s group had not discovered HTLV-I and -II, it might well have been the first to discover HIV.
The controversy between Gallo and Montagnier has long since subsided (although some sources state that the animosity between them remains), and they appear to be in agreement on all major issues. For his part, Gallo has stated that he never claimed to have discovered HIV, but rather claims credit for demonstrating that it is the cause of AIDS. Montagnier concedes that Gallo’s evidence in that regard was more convincing than his own. Regardless, efforts of these two individuals resulted in the identification of a new retrovirus as the cause of AIDS, and made it possible to grow large enough amounts of the virus to enable further studies. Moreover, their discovery quickly resulted in a blood test for HIV, and opened up the development of anti-retroviral drug therapies for HIV-positive individuals.
One fundamental lesson learned from these experiences was well stated in a report jointly written by Gallo and Montagnier: “Our experience with AIDS underscores the importance of basic research, which gave us the technical and conceptual tools to find the cause less than three years after the disease was first described.” 3
1 Doris Morgan, working in Gallo’s laboratory, discovered a T-cell growth factor that enabled her to grow T lymphocytes in culture for extended periods. Kendall Smith, at Dartmouth, followed up Morgan’s observations, isolating interleukin-2 (IL-2) as the T-cell growth factor that Morgan detected.
2 Howard Temin: In from the Cold (on the blog)
3 Gallo, R C., and L. Montagnier, (2003) The Discovery of HIV as the Cause of AIDS, N. Engl. J. Med.349:2283-2285.
4 Luc Montagnier-Biographical, at Nobelprize.org, The official web site of the Nobel Prize.
5 Mikulas Popovic, in Gallo’s laboratory, proposed isolating the virus from a pool of 10 different AIDS patient biopsies. His reason was that the pool should yield the most viable virus, by a process akin to natural selection.
6 Even the media shied away from covering the AIDS epidemic during its early years. When news stories about AIDS did appear in newspapers, they tended to be buried in the back pages, and AIDS stories were seldom reported on television. This was largely because it was difficult for the media of the day to talk openly and honestly about sex; particularly gay sex. The watershed event that changed this state of affairs was actually the July 1985 disclosure by movie star Rock Hudson that he was suffering from AIDS. Hudson was the first major public figure to reveal that he had AIDS, and his celebrity status put AIDS on the front page. The press now covered AIDS with gusto, and they had photos of Hudson to add pizzazz to their stories.
Younger readers may get an accurate glimpse of the homophobia and public attitudes towards AIDS during the early years of the AIDS epidemic from the 1993 movie Philadelphia, which often appears on TV. The main character, played by Tom Hanks, is a brilliant lawyer who is set up to be fired from his prestigious Philadelphia law firm when it discovers that he has AIDS. He then sues the firm, basing his case on the Americans with Disabilities Act of 1990, which prohibits discrimination against any individual with a disability, including those living with HIV/AIDS.
7 Slow-growing HIV isolates like Bru tend to be present at early stages of HIV infection, whereas rapidly growing viruses like Lai are seen in late stage infection. Also, the slow-growing isolates like Bru are not readily transmissible to permanent T cell lines, whereas fast-growing isolates like Lai are. This was important in the current context, since only some viral isolates from patients with fully developed AIDS could be grown in permanent T cell lines, as soon would be learned. The fast-growing strains also induce the formation of large syncytia. For details on the relevance of these points to infection in vivo, see Virology: Molecular Biology and Pathogenesis.
Leonard Norkin Virology Site 