Tag Archives: Harold Varmus

John Enders: “The Father of Modern Vaccines”

John Enders (1897- 1985) was one of the subjects of a recent posting, Vaccine Research Using Children (1). In the 1950s, Enders used severely handicapped children at the Walter E. Fernald State School in Massachusetts to test his measles vaccine—a vaccine that may have saved well over 100 million lives. Irrespective of the ethical issues raised by the incident at the Fernald School, Nobel laureate John Enders was one of the most highly renowned of virologists, and there is much more to his story, some of which is told here.

John F. Enders, November 17, 1961
John F. Enders, November 17, 1961

Enders grew up in West Hartford, Connecticut. His father, who was CEO of the Hartford National Bank, left the Enders family a fortune of $19 million when he passed away. Thus, John Enders became financially independent, which may help to account for his rather atypical path to a career in biomedical research.

Enders was under no pressure to decide on a vocation, and had no particular objective in mind when he enrolled at Yale University in 1915. In 1917 (during the First World War) he interrupted his Yale studies to enlist in the Naval Reserve. He became a Navy pilot and then a flight instructor. After three years of naval service, Enders returned to Yale to complete his undergraduate studies.

After Enders graduated from Yale he tried his hand at selling real estate in Hartford. However, selling real estate troubled him, in part because he believed that people ought to know whether or not they wanted to buy a house, rather than needing to be sold (2, 3). Thus, Enders considered other callings, finally deciding to prepare for a career teaching English literature.

What might have motivated that particular choice? Here is one possibility. During the years when Enders was growing up in West Hartford, his father handled the financial affairs of several celebrated New England writers, including Mark Twain. [The young Enders always admired Twain’s immaculate white suits whenever he visited the Enders home (3).] So, perhaps Enders’ early exposure to eminent writers among his father’s clients planted the seed for his interest in literature. In any case, Enders enrolled at Harvard to pursue graduate studies in preparation for his new calling.

Enders received his M.A. degree in English Literature from Harvard in 1922. Moreover, he was making substantial progress towards his Ph.D., when his career took yet another rather dramatic turn; one reminiscent of that taken later by Harold Varmus, who likewise did graduate studies in English literature at Harvard, with the intent of becoming an English teacher (4).

The changes in the career plans of both Enders and Varmus—from teaching English literature to biomedical research—were prompted by the friends each had who were at Harvard Medical School. Varmus’ friends were his former classmates from Amherst College. Enders first met his friends from among his fellow boarders at his Brookline rooming house.

Dr. Hugh Ward, an instructor in Harvard’s Department of Bacteriology and Immunology, was one of the friends Enders met at his rooming house. Enders wrote, “We soon became friends, and thus I fell into the habit of going to the laboratory with him in the evening and watching him work (5).” Enders was singularly impressed by Ward’s enthusiasm for his research (5).

During one of the trips that Ward and Enders made to the laboratory, Ward introduced Enders to Hans Zinsser, Head of Harvard’s Department of Bacteriology and Immunology. Zinsser was an eminent microbiologist, best known for isolating the typhus bacterium and for developing a vaccine against it.

Enders soon became fascinated by the research in Zinsser’s lab. So, at 30-years-of-age, and on the verge of completing his Ph.D. in English Literature, Enders changed career plans once again; this time to begin studies toward a doctorate in bacteriology and immunology, under Zinsser’s mentorship.

Zinsser, a distinguished microbiologist, was also a sufficiently accomplished poet to have some of his verses published in The Atlantic Monthly. That aspect of Zinsser likely impressed the literate Enders, who described his mentor as: “A man of superlative energy. Literature, politics, history, and science-all he discussed with spontaneity and without self-consciousness. Everything was illuminated by an apt allusion drawn from the most diverse sources, or by a witty tale. Voltaire seemed just around the corner, and Laurence Sterne upon the stair. . . . Under such influences, the laboratory became much more than a place just to work and teach; it became a way of life (3).”

Enders was awarded his Ph.D. in Bacteriology and Immunology in 1930. Afterwards, he remained at Harvard, as a member of the teaching staff, until 1946, when he established his own laboratory at the Children’s Medical Center in Boston.

Why might Enders have been satisfied staying so long at Harvard, for the most part as Zinsser’s underling? Perhaps that too might be explained by his financial independence. In any case, in 1939, while Enders was still at Harvard, he initiated the singularly significant course of research for which he is best remembered.

In 1939, in collaboration with Dr. Alto Feller and Thomas Weller (then a senior medical student), Enders began to develop procedures to propagate vaccinia virus in cell culture. After achieving that goal, the Enders team applied their cell culture procedures to propagate other viruses, including influenza and mumps viruses.

Enders and his coworkers were not the first researchers to grow viruses in cell culture. However, they were the first to do so consistently and routinely. Thus, the Enders lab launched the “modern” era of virus research in vitro. Virology could now advance much more quickly than before, since most virologists would no longer need to grow, or study their viruses only in live animals.

A recurrent theme on the blog is that key scientific discoveries may well be serendipitous. The case in point here was the unforeseen 1949 discovery by Enders and his young collaborators, Tom Weller and Frederick Robbins, that poliovirus could be grown in cultured cells. That crucial discovery made it possible for Jonas Salk and Albert Sabin to generate a virtually unlimited amount of poliovirus and, thus, to create their polio vaccines. Importantly, the discovery happened at a time when polio researchers believed that poliovirus could grow only in nerve cells. Their dilemma was that nerve cells could not be cultured in the laboratory.

Enders, Weller, and Robbins were not working on polio, nor did they have any immediate intention of working on polio when they made their finding. In fact, when the thirty-year-old Robbins (see Aside 1) came to work with Enders, he proclaimed that he wanted to work on any virus, except polio (6).

[Aside 1: Weller was one year older than Robbins. Both had been Army bacteriologists during the Second World War, and they were classmates and roommates at Harvard Medical School when they came to Enders for research experience. Robbins’ father-in-law, John Northrop, shared the 1946 Nobel Prize in chemistry with James Sumner and Wendell Stanley (7). In 1954, Robbins joined his father-in-law as a Nobel laureate (see below).]

The Enders team was trying to grow varicella (the chicken pox virus) when, on a whim; they made their critical discovery. It happened as follows. While attempting to propagate varicella virus in a mixed culture of human embryonic skin and muscle cells, they happened to have some extra flasks of the cell cultures at hand. And, since they also had a sample of poliovirus nearby in their lab storage cabinet; they just happened to inoculate the extra cell cultures with polio virus.

The poliovirus-infected cultures were incubated for twenty days, with three changes of media. Then, Enders, Weller, and Robbins asked whether highly diluted extracts of the cultures might induce paralysis in their test mice. When those highly diluted extracts indeed caused paralysis in the mice, they knew that poliovirus had grown in the cultures. See Aside 2.

[Aside 2: Whereas Enders, Weller, and Robbins did not have pressing plans to test whether poliovirus might grow in non-neuronal cells, they probably were aware of already available evidence that poliovirus might not be strictly neurotropic. For instance, large amounts of poliovirus had been found in the gastrointestinal tract.]

Despite the exceptional significance of their discovery, Robbins said, “It was all very simple (6).” Weller referred to the discovery as a “fortuitous circumstance (6).” Enders said, “I guess we were foolish (6)”—rather modest words from a scholar of language and literature. See Aside 3.

[Aside 3: Current researchers and students might note that Enders’ entire research budget amounted to a grand total of two hundred dollars per year! The lab did not have a technician, and Weller and Robbins spent much of their time preparing cells, media, and reagents, as well as washing, plugging, and sterilizing their glassware.]

In 1954, Enders, Weller, and Robbins were awarded the Nobel Prize for Physiology or Medicine for their polio discovery. Interestingly, they were the only polio researchers to receive the Nobel award. The more famous Salk and Sabin never received that honor (8).

If Enders were so inclined, might he have produced a polio vaccine before Salk and Sabin? Weller and Robbins wanted to pursue the vaccine project, and Enders agreed that they had the means to do so. In fact, Weller actually had generated attenuated poliovirus strains by long-term propagation of the virus in culture; a first step in the development of a vaccine (3). Yet for reasons that are not clear, Enders counseled his enthusiastic young colleagues to resist the temptation (6). See Aside 4.

[Aside 4: Enders may have spared Weller and Robbins the sort of anguish that Salk experienced when some of his killed vaccine lots, which contained incompletely inactivated poliovirus, caused paralytic poliomyelitis in some 260 children (8).]

The Enders poliovirus group began to disperse, beginning in 1952 when Robbins became a professor of pediatrics at Western Reserve. Weller left in 1954 to become chairman of the Department of Tropical Public Health at Harvard.

Regardless of whether Enders might have regretted not pursuing the polio vaccine, he soon would play a hands-on role in the development of the measles vaccine. The first critical step in that project occurred in1954, at the time when the Salk polio vaccine was undergoing field trials. It was then that Enders and a new young coworker, pediatric resident Thomas Peebles (Aside 5), succeeded in cultivating measles virus in cell culture for the first time.

[Aside 5: Enders was known for nurturing bright young investigators. His latest protégé, Tom Peebles, spent four years in the Navy, as a pilot, before enrolling at Harvard Medical School. Peebles graduated from medical school in 1951, and then did an internship at Mass General, before coming to the Enders lab to do research on infectious diseases in children. When Enders suggested to Peebles that he might try working on measles, Peebles eagerly accepted.]

Here is a piece of the measles vaccine story that happened before Peebles’ success growing the virus in cell culture. At the very start of the vaccine project, Enders and Peebles were stymied in their attempts to get hold of a sample of measles virus to work with. Their quest for the virus began with Peebles searching the Enders laboratory freezers for a sample. Finding none there, Peebles next inquired at Boston area health centers; still without success. After several more months of fruitless searching, Peebles received an unexpected phone call from the school physician at the Fay School (a private boarding school for Boys in a Boston suburb), telling him about a measles outbreak at the school. Peebles immediately rushed to the school, where he took throat swabs, as well as blood and stool samples from several of the school’s young patients. He then rushed back to the Enders laboratory, where he immediately inoculated human infant kidney cells with his samples. [Enders obtained the cells from a pediatric neurosurgeon colleague, who treated hydrocephalus in infants by excising a kidney, and shunting cerebrospinal fluid directly to the urethra.]

Peebles monitored the inoculated kidney cell cultures for the next several weeks, hoping for a sign of a virus replicating in them. Seeing no such indication of a virus in the cultures, Peebles made a second trip to the Fay School, which, like the first trip, was unproductive.

On a third trip to the school, Peebles obtained a sample from an 11-year-old boy, David Edmonston. The sample from young Edmonston indeed seemed to affect the kidney cell cultures. Still, Peebles needed to carry out several additional experiments before he could convince a skeptical Enders and Weller—first, that a virus had replicated in the cultures and, second, that it was measles. Peebles convinced the two doubters by demonstrating that serum from each of twelve convalescing measles patients prevented the virus from causing cytopathic effects in the inoculated cell cultures. That is, the convalescent serum neutralized the virus. The measles virus growing in those cultures was named for its source. It is the now famous Edmonston strain.

Enders, in collaboration with Drs.Milan Milovanovic and Anna Mitus, next showed that the Edmonston strain could be propagated in chick embryos (3). Then, working with Dr. Samuel Katz (1), Enders showed that the egg-adapted virus could be propagated in chicken cell cultures.

By 1958, Enders, Katz, and Dr. Donald Medearis showed that the Edmonston measles virus could be attenuated by propagating it in chicken cells. Moreover, the attenuated virus produced immunity in monkeys, while not causing disease (3). Thus, the attenuated Edmonston strain became the first measles vaccine. [Tests of the vaccine in humans led to the episode at the Fernald School (1).]

The Enders measles vaccine was attenuated further by Maurice Hilleman at Merck (9). In 1971 it was incorporated into the Merck MMR combination vaccine against measles, mumps, and rubella (9, 10).

The MMR vaccine has had a remarkable safety record, and it was widely accepted until 1997; the time when the now discredited claim that the vaccine is linked to autism first emerged (10). However, even prior to the MMR/autism controversy, vaccine non-compliance was already a problem. But, in that earlier time, parents were declining to have their children vaccinated, not because of safety issues, but rather because they questioned the severity of measles. Ironically, that was why David Edmonston refused to have his own son receive the vaccine.

Despite receiving the Nobel Prize for his polio work, Enders maintained that developing the measles vaccine was more personally satisfying to him and more socially significant (3).

References:

  1. Vaccine Research Using Children, Posted on the blog July 7, 2016.
  2. John F. Enders-Biographical, The Nobel Prize in Physiology or Medicine 1954. From Nobel Lectures, Physiology or Medicine 1942-1962, Elsevier Publishing Company, Amsterdam, 1964.
  3. Weller TH, Robbins FC, John Franklin Enders 1897-1995, A Biographical Memoir www.nasonline.org/publications/…/endersjohn.pdf [An excellent review of Enders’ life and career.]
  4. Harold Varmus: From English Literature Major to Nobel Prize-Winning Cancer Researcher, Posted on the blog January 5, 2016.
  5. John F. Enders, “Personal recollections of Dr. Hugh Ward,” Australian Journal of Experimental Biology 41:(1963):381-84. [This is the source of the quotation in the text. I found it in reference 3.]
  6. Greer Williams, Virus Hunters, Alfred A. Knopf, 1960.
  7. Wendell Stanley: First to Crystallize a Virus, Posted on the blog April 23, 2015.
  8. .Jonas Salk and Albert Sabin: One of the Great Rivalries of Medical Science, Posed on the blog March 27, 2014.
  9.  Maurice Hilleman: Unsung Giant of Vaccinology, Posted on the blog April 24, 2014.
  10.  Andrew Wakefield and the Measles Vaccine Controversy, Posted on the blog February 9, 2015.

 

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Tony Hunter and the Serendipitous Discovery of the First Known Tyrosine Kinase: the Rous Sarcoma Virus Src Protein

In 1911 Peyton Rous, at the Rockefeller Institute, discovered the Rous sarcoma virus; the first virus known to cause solid tumors (1). Although Rous’ eponymous virus also would be known as the prototype retrovirus, his discovery generated only scant interest at the time, and would not be recognized by the Nobel Committed until 65 years later! [Nobel prizes are not awarded posthumously. Fortunately, Rous had longevity on his side. He died 4 years after receiving the prize, at age 87.]

In 1976 Harold Varmus and J. Michael Bishop, then at the University of California San Francisco, discovered that the Rous sarcoma virus oncogene, v-src, as well as the oncogenes of several other tumorgenic retroviruses, actually were derived from cellular genes that normally play an important role in controlling cell division and differentiation (2). Moreover, Varmus and Bishop showed that these cellular “proto-oncogenes” can be altered by mutation, to become “oncogenes” that contribute to cancer. [Varmus and Bishop received the 1989 Nobel Prize in Physiology or Medicine for their discovery of proto-oncogenes.]

But what is the actual activity of the protein coded for by the normal cellular c-src, and by v-src as well? The story of that discovery is rather delightful and begins as follows.

In 1978, Raymond Erikson and coworker Marc Collette, then at the University of Colorado Medical Center, were the first researchers to isolate the Src protein. They accomplished this by first preparing lysates from avian and mammalian cells, which had been transformed in culture into tumor cells by Rous sarcoma virus. Next, they precipitated those lysates with antisera from rabbits that bore Rous sarcoma virus-induced tumors. The premise of their strategy was that antibodies from the tumor-bearing rabbits would recognize and precipitate proteins that were specific to cells transformed by the virus .

With the Src protein now in hand, Ericson and Collette next sought its function. They initially asked whether Src might have protein kinase activity (i.e., an activity that adds a phosphate group to a protein.). This was a reasonable possibility because protein phosphorylation was already known to play a role in regulating various cellular processes, including cell growth and differentiation.

Ericson and Collette tested their premise by incubating their Src immunoprecipitates with [γ-32P] ATP (i.e. 32P-labelled adenosine triphosphate). In agreement with their proposal, they found that the antibody molecules in the Src immunoprecipitates had been phosphorylated. [Note that Src’s protein kinase activity was simultaneously and independently discovered by Varmus and Bishop.]

Ericson and Collette also carried out control experiments that were particularly revealing. When the same rabbit antisera was used to immunoprecipitate extracts from normal cells, or extracts from cells infected with a transformation-defective mutant of Rous sarcoma virus, no signs of protein kinase activity were seen in those immunoprecipitates. What’s more, the protein kinase activity was found to be temperature sensitive in immunoprecipitates from cells infected with a mutant Rous sarcoma virus that was temperature-sensitive for transformation.

These control experiments confirmed that the protein kinase activity in the immunoprecipitates was coded for by the virus. What’s more, they confirmed that the kinase activity of the retroviral Src protein plays an essential role in transformation. Furthermore, when taken with the earlier findings of Varmus and Bishop, they implied that the kinase activity of the cellular Src protein plays a key role in the control of normal cell proliferation.

While Erickson and coworkers were carrying out the above experiments in Denver, Walter Eckhart and Tony Hunter, at the Salk Institute, were looking into the basis for the transforming activity of the mouse polyomavirus middle T (MT) protein. [Unlike Rous sarcoma virus, which is a retrovirus, the mouse polyomavirus is a member of the Polyomavirus family of small DNA tumor viruses. SV40 is the prototype Polyomavirus.]

Tony Hunter
Tony Hunter

Since Erickson’s group was finding that Src expresses protein kinase activity, Eckhart and Hunter asked whether the polyomavirus MT protein might likewise be a protein kinase. Thus, as Erickson and Collette had done in the case of Src, Eckhart and Hunter examined immunoprecipitates of MT to see if they too might express a protein kinase activity, and found that indeed they did.

Interestingly, it was not known at the time of these experiments that MT actually does not express any intrinsic enzymatic activity of its own. Instead, MT interacts with the cellular Src protein to activate its protein kinase activity. See Aside 1.

[Aside 1: For aficionados, MT is a membrane-associated protein that interacts with several cellular proteins. Importantly, the phosphorylation events carried out by MT-activated Src cause a variety of signal adaptor molecules [e.g., Shc, Grb2, and Sos] and other signal mediators [e.g., PI3K and PLCγ] to bind to the complex, thereby triggering a variety of mitogenic signaling pathways. These facts were not yet known when Eckhart and Hunter were doing their experiments.]

At the time of these experiments, serine and threonine were the only amino acids known to be phosphorylated by protein kinases. In fact, Erikson and Collette, as well as Varmus and Bishop, believed that threonine was the amino acid phosphorylated by the Src kinase (see below). Consequently, Hunter asked whether the polyomavirus MT protein likewise would phosphorylate threonine. [Recall that MT actually does not express any intrinsic enzymatic activity of its own.]

Hunter’s experimental procedure was relatively straightforward and reminiscent of Erikson’s and Collette’s. It involved incubating immunoprecipitates of MT with [γ-32P]ATP, hydrolyzing the immunoglobulin, and then separating the amino acids in the hydrolysate by electrophoresis. But, to Hunter’s surprise, the position of the labeled amino acid in his electropherogram did not correspond to that of either threonine or serine.

Hunter was well aware that tyrosine is the only other amino acid with a free hydroxyl group that might be a target for the MT kinase activity. And, while there was no precedent for a tyrosine-specific protein kinase, Hunter proceeded to ask whether the polyomavirus MT protein indeed might phosphorylate tyrosine.

Hunter began by synthesizing a phosphotyrosine molecule that could be used as a standard marker against which to compare the labeled amino acid in a repeat of his earlier experiment. And, to his pleasure, Hunter found that the amino acid that was phosphorylated by the MT kinase activity ran precisely with the phosphotyrosine standard marker in his new electropherograms.

But why had other researchers not detected tyrosine phosphorylation earlier? It was partly because phosphotyrosine accounts for only about 0.03% of phosphorylated amino acids in normal cells. The remaining 99.97% are phosphoserine and phosphothreonine. But, again, that is not the entire explanation. The rest is truly precious.

In Hunter’s own words, he was “too lazy to make up fresh buffer” before doing his experiments. Had the buffer been fresh, its pH would have been the usual 1.9; a pH that, unbeknownst to all at the time, does not separate phosphotyrosine from phosphothreonine during the electrophoresis procedure. The pH of the old buffer that Hunter used in his experiment had inadvertently dropped to 1.7; a pH at which phosphotyrosine is resolved from phosphothreonine. That fact enabled Hunter to discriminate phosphotyrosine from phosphothreonine for the first time. Thus, Hunter attributes his hugely important discovery to his laziness.

The finding that tyrosine is the amino acid phosophorylated  by the polyomavirus MT protein kinase activity led Hunter and his Salk Institute-colleague Bart Sefton to ask whether Src too might phosphorylate tyrosine, rather than serine or threonine (4). Indeed, they found that the retroviral Src protein, as well the normal cellular Src protein, function as tyrosine-specific protein kinases. [Recall that it became clear only later that MT actually has no intrinsic enzyme activity of its own and that it acts through Src.] Moreover, the levels of phosphotyrosine were 10-fold higher in cells infected with wild-type Rous sarcoma virus than in control cells, consistent with the premise that Src’s protein tyrosine kinase activity accounts for the altered growth potential of those cells.

Subsequently, Stanley Cohen, at Vanderbilt University, discovered that the epidermal growth factor (EGF) receptor contains an intrinsic protein-tyrosine kinase activity, further underscoring the importance of protein-tyrosine kinases in the normal control of cell proliferation. [Cohen shared the 1986 Nobel Prize in Physiology or Medicine with Rita Levi-Montalcini for their discoveries of growth factors, including EGF.] Subsequent studies identified additional receptor protein-tyrosine kinases, such as the fetal growth factor (FGF) receptor, and non-receptor protein-tyrosine kinases, such as Abl, each of which activates a mitogenic intracellular signaling pathway.

Tony Hunter and coworkers went on to demonstrate that protein-tyrosine kinases play key roles in additional crucial cellular processes, including cellular adhesion, vesicle trafficking, cell communication, the control of gene expression, protein degradation, and immune responses. Moreover, discoveries regarding the role of protein-tyrosine kinases in cell transformation and cancer gave rise to a promising new rational approach to cancer therapy; i.e., the targeting of protein-tyrosine kinases. For example, the drug Gleevec, which inhibits activation of the Abl and platelet-derived growth factor (PDGF) tyrosine kinases, was approved by the U.S. Food and Drug Administration for the treatment of chronic myelogenous leukemia and several types of gastrointestinal tumors.

References:

  1. Howard Temin: “In from the Cold,” Posted on the blog December 14, 2013.
  2. Harold Varmus: From English Literature Major to Nobel Prize-Winning Cancer Researcher, Posted on the blog January 5, 2016.
  3. Collett, M. S. and R. L. Erikson, 1978. Protein kinase activity associated with the avian sarcoma virus src gene product. Proc. Natl. Acad. Sci. USA 75: 2021-2024.
  4. Hunter, T., and B. M. Sefton. 1980. Transforming gene product of Rous sarcoma virus phosphorylates tyrosine. Proc. Natl. Acad. Sci. USA 77:1311–1315.

Harold Varmus: From English Literature Major to Nobel Prize-Winning Cancer Researcher

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
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.

The Politics of Science: Vignettes Featuring Nobel Laureate Harold Varmus during his Tenure as Director of the NIH

During his extraordinary career, Nobel laureate Harold Varmus practiced science and served science with distinction. The vignettes that follow are, for the most part, about Varmus’ service to science during his tenure (1993-1999) as director of the U.S. National Institutes of Health. But first, we begin with a brief account of Varmus’ most significant scientific accomplishment.

In 1976, Varmus and collaborator Michael Bishop reported that retrovirus oncogenes (cancer-causing genes) are versions of genes that actually are present in the genomes of normal cells (1). Indeed, retroviruses acquired their oncogenes by “capturing” them from the genomes of their host cells. Perhaps the most singularly important conclusion to be drawn from Varmus’ and Bishop’s finding is that since retroviral oncogenes are versions of genes that are actually part of a normal cell’s genetic makeup, mutations in those particular cellular genes, or the inappropriate expression of those genes, might lead to cancer.

Varmus’ and Bishop’s findings led to a mushrooming of discoveries in cell signaling, cell growth, and cell differentiation (see Aside 1). Moreover, their discoveries are increasingly relevant clinically, as recounted below in the main text.

[Aside 1: The v-src gene of Rous sarcoma virus was the first retroviral oncogene that Varmus and Bishop showed is a version of a cellular gene. Next, in 1978, Raymond Erikson and coworkers isolated the Src protein. Then, Erikson’s research group and that of Bishop and Varmus independently discovered that Src has protein kinase activity. Protein kinases add phosphate groups to a specific target protein, generally triggering its activity. (Actually, Src phosphorylates itself, thus regulating its own activity.)

At the time that Erikson isolated Src, all protein kinases were believed to add phosphate to serine and threonine residues on their target proteins. Then, in 1980, Tony Hunter and Bart Sefton discovered that Src adds phosphotes to tyrosine residues. Thus, Src was the first known protein tyrosine kinase.

Stanley Cohen then discovered that the epidermal growth factor (EGF) receptor too is a protein tyrosine kinase, underscoring the role of tyrosine kinases in the control of normal cell proliferation, while also affirming the notion that inappropriate phosphorylation of a cellular protein can lead to cancer.

These discoveries led to a burst of research activity in cell signaling, and to the discovery of additional tyrosine and serine/threonine protein kinases, many of which act in mitogenic signaling pathways. What’ more many of the cellular genes encoding these proteins were initially discovered as retroviral oncogenes. For details on these points, see Virology: Molecular Biology and Pathogenesis.]

[Aside 2: An earlier posting on the blog, Renato Dulbecco and the Beginnings of Quantitative Animal Virology, noted that Renato Dulbecco shared the 1975 Nobel Prize for Physiology or Medicine, in recognition of his opening up the study of transformation by the DNA tumor viruses (i.e., the polyomaviruses, papillomaviruses, and adenoviruses). How then did analysis of transformation by the oncogenic retroviruses (i.e., the RNA tumor viruses) complement analysis of the DNA tumor viruses?

As suggested above; studies of the oncogenic retroviruses led to the identification of cellular signaling pathways that positively govern cell replication (i.e., that trigger cell growth). In contrast, studies of the DNA tumor viruses led to insights into cellular processes that negatively regulate cellular replication; in particular, processes affected by the key cellular tumor suppressor protein, p53, which activates apoptosis in cells that attempt to divide without having appropriately passed cell cycle checkpoints. The DNA tumor viruses affect transformation by inactivating tumor suppressor proteins. See Virology: Molecular Biology and Pathogenesis for details.]

[Aside 3: Varmus tells us that early in his career, in the late 1960s, he looked for places and people that might offer research training in the tumor viruses. “However, when I wrote to the already famous virologist Renato Dulbecco, at the Salk Institute in La Jolla, just North of San Diego, for a postdoctoral position, I was rebuffed by not one but two letters from his secretary (2).” See Aside 2.]

In the days before Varmus and Bishop published their findings, many cancer researchers actually were reluctant to believe that cancer has an underlying genetic basis. This was partly because it was not yet possible to clone and sequence genes, and there were no other apparent methods by which to identify putative cancer-related genes. [The means by which Varmus and Bishop made their breakthrough discovery are recounted in the Appendix, below.] In recognition of their discovery, Varmus and Bishop were awarded the 1989 Nobel Prize for Physiology or Medicine.

Varmus looked back on all aspects of his career in his 2009 autobiography, The Art and Politics of Science (2). [Unless otherwise noted, all of the quotations that follow are from Varmus’ 2009 memoir.] Here, are his remarks on the clinical significance of his and Bishop’s Nobel Prize-winning findings:

“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.”

In 1993, Varmus was named by President Bill Clinton to serve as Director of the U.S. National Institutes of Health; a position he held through 1999. As such, he was the only Nobel laureate to ever serve as the NIH director and he was also the first NIH director to also run an active laboratory. What’s more, during his tenure as director, he managed to nearly double the NIH’s research budget.

nih clinical center NIH Clinical Center

One of Varmus’ major responsibilities as the NIH director, and also one of his most contentious ones, was to apportion research dollars among the individual NIH institutes and programs. Why was there contention? As might be expected, the directors of the individual institutes actively advocate for their shares of the NIH budget. But, a further source of contention was Congress, in which the most ardent NIH supporters were generally motivated by their interest in a particular disease or program. What’s more, public advocacy groups likewise championed their own favored disease. Consequently, as Varmus explains:

“Apart from the difficulties of predicting where and how discoveries will arise, the priority-setting process can be ugly—for instance, when advocates refuse to recognize, or to care, that funds for their disease must come from funds being spent elsewhere, including funds used for a disease important to another group of advocates.”

Here is one such instance that Varmus notes:

“One of my first exposures to this problem occurred soon after I arrived at the NIH, when I received a call from my own former congresswoman, Nancy Pelosi, asking me to add $50 million to the budget for AIDS research. As the representative from one of the districts most heavily affected by the epidemic, her wishes were understandable. Since she was a member of the House Appropriations Committee for the NIH, she was in a position to try to increase funds for AIDS research when the subcommittee was debating the size of the NIH budget, without taking the money from some other research program. But, in the period of spending caps, she had presumably been unsuccessful in negotiations with her fellow committee members and was now trying to fulfill a promise to her constituents by asking me to shift funds from some other budget categories into the OAR (Office of AIDS Research) account. I declined as politely as I could.”

Varmus notes that it can difficult to refuse such requests (demands?) when they come from powerful people; especially so when the come from the President. For instance, President Bill Clinton “requested” that $10 million more be spent on spinal cord research; this coming after he spent an afternoon with recently paralyzed actor, Christopher Reeve.

“But the President’s wishes are always obeyed. When the next accounting was made of disease-specific spending at the neurology institute (formerly known as the National Institute of Neurological Diseases and Stroke, or NINDS), the funds for spinal cord research were accordingly higher, and funds for other purposes were lower.”

Here is an additional example, this time involving the vice-president:

“But Vice-President Al Gore posed a potentially serious dilemma for the NIH late in 1997 when he proposed that the National Cancer Institute (NCI) should receive a much larger share than the other institutes in the record-breaking $1 billion budget increase that the president was going to request for the NIH for fiscal year 1999. Possibly as a result of promises made to cancer research advocates, possibly because of personal concerns about cancer (his sister died of lung cancer at an early age), possibly because cancer research was popular politically, Gore asked that the cancer institute’s budget grow at twice the rate accorded the others.”

Varmus continues:

“I was very unhappy about this. The differential rates of growth were not in accord with clearly defined medical needs or with carefully considered scientific opportunities. No major changes in disease rates or outcomes and no sudden developments in cancer research made the needs for the NCI any greater than those for brain disorders, metabolic diseases, or infections. By any measure, the NCI was already the largest institute by a considerable margin, and Gore’s plan would further accentuate the differences. And, of course, there would be strong negative reaction from the supporters of the other institutes when the plan was announced. But, he was the vice-president, and conceivably the next president, so the idea of arguing with him on this issue was not appealing.”

However, Varmus had an ally in Donna Shalala, the Secretary of Health and Human Services (HHS), who supported his position. And, with her help, Varmus was able to take the issue directly to Gore:

“… we were able to reach a rapprochement when I pointed out that many institutes did cancer research, not simply the NCI, and he was very pleased to learn this. That gave us an opening for a compromise: we would ensure a relatively large increase for cancer research, but it would be spread among all the institutes that could be said to do cancer research.”

[Aside 4: Varmus was featured in an earlier posting on the blog that recounted how, in 1986; he resolved the dispute between Luc Montagnier and Robert Gallo over the right to name the AIDS virus (3). It’s been said that Varmus developed diplomatic skills while resolving the naming dispute that served him well as Director of the NIH. The following comment from Varmus shows his subtle diplomacy when interacting with the directors of other government agencies that he competed against:

“Often the best way to support the NIH and science in general was to make a magnanimous gesture toward the other agencies, emphasizing their importance in an increasingly interdisciplinary world of science and hoping the gesture would be reciprocated. This strategy was appreciated by my colleagues in other disciplines, helped to dispel jealousies about our fiscal success, and is remembered as a hallmark of my time at the NIH.”]

Irrespective of any political considerations, the setting of research priorities is an inherently difficult process. The following quotation points up the often conflicting scientific and public health considerations that Varmus took under consideration when determining research priorities. And, bearing in mind his recounting of Nancy Pelosi’s request for additional funding for AIDS, these remarks also demonstrate that he was hardly insensitive to the AIDS issue:

“For much of my time at the NIH, I was castigated by advocates for research on heart disease because the NIH was spending about as much on AIDS research as on studies of heart disease, even though there were about twenty times more deaths from heart disease than from AIDS in the United States each year. The arguments tended to ignore other important facts: that AIDS was a new and expanding disease, that it is infectious, that it is devastating large parts of the world, or that age-adjusted death rates from heart disease have fallen by two-thirds in the past 50 years.”

Elsewhere Varmus notes: “Of course, very different impressions can be produced by the use of different criteria—the number of people living with a condition, the number who die from it each year, the age adjusted death rate, the number of healthy individuals at risk, the number diagnosed each year, the annual medical expenditures, the annual cost to society, or the degree of pain and suffering. These are legitimate aspects of the nation’s burden of disease, but they are crude tools for deciding how to spend research dollars appropriately.”

Another difficulty that Varmus had to contend with was that laypeople, both in Congress and in public advocacy groups, often did not appreciate that science usually works best when scientists are free to investigate the particular issues that most intrigue them. And, when biomedical scientists follow their own inclinations, they often focus on basic or fundamental questions that may seem to have no apparent clinical relevance. Yet, and importantly, the knowledge gained from untargeted basic research may have a more positive affect on the understanding and treatment of a particular disease than all of the clinical research specifically targeted at that disease. [Indeed, the Nobel Prize-winning research of Varmus and Bishop is a good example of that very point.]

Speaking to that notion, Varmus said the following in a June 2009 interview with Catherine Clabby in American Scientist:

“Look at what pride people take now in advances made in diabetes and cancer research and infectious disease research. Almost all of it is based on recombinant DNA technology, genomics and protein chemistry. These are methods that grew out of basic science that was funded for years and years in a non-categorical way.”

Still and all, while basic research often may lead to significant clinical advances, Varmus acknowledges that the NIH still must have programs that are targeted at public health concerns:

“One of the potential strengths of the NIH is its ability to encourage scientists throughout the country to pay greater attention to underserved and deserving problems, even when the opportunities may not be obvious. Simply by encouraging attention to such problems—autism, rare neurological diseases, imaging methods, emerging infections, or bioengineering, to mention a few areas promoted during my tenure—new ideas may emerge to create those opportunities.”

But, Varmus adds:

“In this regard, the NIH must walk a narrow line: to respond responsibly to public health needs and yet to provide the freedom for investigators to exercise their imaginations as freely as possible.”

[Aside 5: An earlier posting on the blog, Jonas Salk and Albert Sabin: One of the Great Rivalries of Medical Science, described how the National Foundation for Infantile Paralysis financed the crusade against polio in the pre-NIH days of the 1950s. But, the Foundation’s efforts went beyond merely raising money for research. It also attempted to provide direction to the research, which often placed it at odds with its grantees. That was so because the principal goal of Harry Weaver, the Foundation’s director of research, was to bring a vaccine to the public. In contrast, most of the Foundation’s grantees were more interested in investigating basic virological issues, such as poliovirus transmission, replication, and dissemination.]

Research involving human embryonic stem cells was a particularly contentious issue that Varmus dealt with as NIH director. Stem cell research “attracted controversy mainly because the cells are obtained from human embryos, linking stem cell research to historical battles over abortion and over the legal and moral status of the human embryo and fetus.”

Yet Varmus took up the cause for stem cell research because “embryonic stem cells were likely to have the potential to develop into many specific tissue types…if so they could be used to repair damaged tissues or to treat chronic degenerative diseases of the brain or spinal cord, endocrine organs (such as pancreatic islets), muscles, joints, or other tissues.”

In 1993 Varmus assembled the Human Embryo Research Panel, tasked to advise him on what types of stem cell research might be suitable for federal funding. Not surprisingly, an immediate hullabaloo followed the panel’s recommendation that in vitro fertilization might be used to create embryos, from which stem cells could then be derived. Varmus remarked on the reaction to the panel’s recommendation as follows:

“Although well received by scientists who were watching its work, the panel’s report ignited a storm of government opposition; even within the liberal Clinton administration…the White House was in shock from the Democratic Party’s loss of control of both congressional chambers in the midterm elections held a month earlier. Democrats across the nation, especially those at the highest ranks of the Clinton administration, were concerned about a shift in the electorate toward the conservative policies of Newt Gingrich and his Republican revolutionaries, and already anxious about the presidential election of 1996…I remember getting a call from Leon Panetta, then the White House chief of staff, telling me that I was supposed to repudiate some of the panel’s recommendations, in particular any that might permit the use of federal funds to create embryos for research purposes. I refused to reject the recommendations of my panel summarily. I was not fired, as the tone of Panetta’s call had threatened.”

Although Varmus wasn’t fired for his independence, the Clinton White House quickly issued an executive order forbidding the use of federal funds to create human embryos for research. Varmus attributed the political pushback to the undue influence (“on the conduct of science in a diverse society”) of a few conservative religious groups. Varmus went on to say:

“Few arguments can seem as insulting to medical scientists as the claim that we are ethically irresponsible when we toil to extract stem cells from donated early human embryos, which would otherwise be destroyed, and use them for beneficial, potentially lifesaving purposes.”

Varmus lamented the fact that President George W. Bush limited federal funding for stem cell research during his administration. Nevertheless, stem cell research was being done even during the Bush presidency, although it was supported by the private sector and by several states (California, New York, Massachusetts, Wisconsin and others). Yet because potential stem cell investigators would need to obtain funding from less well-endowed non-federal sources to do this research, it is likely that many were discouraged from entering the field.

Varmus also fought a difficult and frustrating battle to secure federal funding for needle-exchange programs. By way of background, intravenous drug abusers were accounting for one-quarter of all new HIV infections in the United States. And, while other industrialized nations had needle-exchange programs that were successful at reducing the number of new HIV infections, many powerful individuals in the United States, including General Barry McCaffrey, head of the Clinton White House Office on Drug Control, regarded efforts to make drug use safer to be the equivalent of condoning drug use.

In 1998, HHS Secretary Donna Shalala, using evidence compiled by Varmus, advised President Bill Clinton that needle exchange programs were proven to be effective at preventing HIV transmission and, moreover, they did not increase drug use. Nevertheless, the President did not lift the ban on federal support for needle exchange programs.

By coincidence, the day that Clinton announced his decision not to lift the ban, Varmus and his wife were having dinner with Rahm Emanuel, who, at that time, was a domestic policy advisor in the Clinton White House. Interestingly, the liberal Emanuel was not sympathetic to lifting the ban. Instead, he believed that doing so would open the Democratic Party to charges that it was soft on drugs. At any rate, not lifting the ban did not enable the Democrats to regain either house of Congress. Varmus adds:

“The only satisfaction we received was the later admission by Bill Clinton, speaking at an international AIDS conference in Spain, less than two years after he left the White House, that his failure to lift the ban on funding needle exchange was wrong and one of the worst decisions he made during his presidency.”

Another of the good fights that Varmus fought on behalf of science was to establish new approaches to publishing scientific papers. His purpose was to enhance access to the scientific literature by taking advantage of new opportunities being offered by the internet and by new computational tools. His efforts resulted in two important new ways in which scientific research is published, stored, and retrieved; specifically, public digital libraries and “open access” publishing.

Varmus credits Stanford biologist Pat Brown with pushing him, in 1998, to think about improving access to the scientific literature by making the most of the internet. Brown had earlier worked with Varmus and Bishop on retroviral integration in the 1980s.

Varmus was still the NIH director when he helped to launch PubMed Central; the NIH’s full-text public digital library for the biomedical sciences, and the first of its kind. [In contrast to PubMed Central, PubMed is the NIH’s on-line archive of titles, authors, and abstracts. Access to full text articles was possible via PubMed, but only if one had a personal subscription to the particular journal, or had access via their institution.] But, many scientists and journal publishers were initially opposed to PubMed Central. Consequently, in 2000, after Varmus had left the NIH, he and Brown, together with Mike Eisen, a computational biologist at Berkeley (who had worked as a post-doc with Brown), took more vigorous steps to promote it:

“Pat, Mike, and I wrote a short declaration of purpose—we called it a pledge, publishers called it a boycott—in which we said that one year hence, the signatories would no longer submit articles, provide reviewing or editing services, or purchase individual subscriptions to journals that had not agreed to deposit their articles with PubMed Central.”

Thirty thousand scientists worldwide signed the pledge, but most didn’t. One reason for the lack of wider support was that leading scientists typically strove to have their papers published in the most prestigious journals, and most of those journals had not bought in to the open access idea. Journal publishers were opposed because their revenues from subscriptions would be undermined by the open access model.

Since most journal publishers were not willing to participate in PubMed Central, Varmus, Brown, and Eisen decided to found open access journals themselves. They began by creating two outstanding journals, PLoS (for Public Library of Science) Biology and PLoS Medicine. Their business model was to use author’s fees to cover publication costs, usually paid from research grants. [Incidentally, no favorably reviewed paper would be turned away for inability to pay the fee. All of the PLoS journals can be seen by anyone, anytime, at http://www.plos.org.]

The public access situation began to change dramatically in 2007 when a coalition of leading scientists, open access publishers (including PLoS), and concerned members of Congress advocated for a policy that would require all scientific papers reporting NIH-funded research to be deposited in PubMed Central. This cause came to fruition when President George W. Bush signed the 2008 appropriations bill, which included a clause making the NIH public access policy the law of the land.

So, wrapping things up, considering that the NIH director’s job can grind one down with its “incessant and inevitable conflicts,” why did Varmus put up with it? His answer is he enjoyed it:

“Above all, there was the pride, excitement, and (at times) historical significance of being the leader of the largest funding agency for medical research in the world. The position represents medical science and the good things it does for the country, if not the world. I felt this when working within the administration, when speaking to members of Congress, when talking to reporters, and when addressing the public at commencement exercises, and elsewhere.”

Varmus left the NIH to become President of the Memorial Sloan-Kettering Cancer Center in New York City; a position he held from 2000 until 2010. He then returned to the NIH, where he serves as director of the National Cancer Institute.

In the Epilogue to his memoir (2), Varmus refers to the work of scientists, and its potential benefit to society, as follows:

“Scientists may work and compete as individuals, but the competitive efforts are ultimately directed to the construction of a common edifice, knowledge of the natural world. There are few other fields in which such fierce independence serves the public good in such a transparently shared fashion”

But he adds: “…our knowledge does not improve the societies in which we live unless other kinds of actions, both political and pragmatic, are taken.”

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. Varmus, H. 2009. The Art and Politics of Science, (W. W. Norton & Company)

3. How the Human Immunodeficiency Deficiency Virus (HIV) Got Its Name, on the blog

Appendix:

Varmus and Bishop turned to nucleic acid hybridization to test their hypothesis that v-src might be a version of a cellular gene. They could not use the complete Rous sarcoma virus genome as a probe for the putative cellular src gene, because the complete virus genome might have detected endogenous retrovirus sequences within the cellular genome, rather than a cellular src gene per se. So, they needed to generate a more specific probe.

In the days before recombinant DNA procedures, Varmus and Bishop cleverly generated their specific src probe by making use of a transformation-defective mutant of Rous sarcoma virus, isolated earlier by Peter Vogt. The important feature of this mutant virus was that its src gene was deleted.

Varmus and Bishop generated their src-specific probe by first using reverse transcriptase to make a radioactively labeled, single-stranded DNA copy of the entire standard Rous sarcoma virus genome, which contains the src gene. This cDNA was then fragmented and annealed to an excess of RNA genomes of the src deletion mutant. The only DNA fragments that did not anneal were those containing only src sequences. These single-stranded DNA fragments could be separated from the annealed product and used as the src nucleic acid hybridization probe.

Using their cDNA probe, Varmus and Bishop were able to demonstrate the presence of src not only in the genomes of normal chicken cells, but also in the genomes of many other vertebrates as well, including humans (reference 1). These experimental findings led to the remarkable conclusions that the cellular src gene was present early in vertebrate evolution and that it has remained conserved to this day.

More experiments of this kind demonstrated that other highly oncogenic retroviruses contain other oncogenes of their own, which likewise have their counterparts in normal cell genomes. Indeed, each of the known retroviral oncogenes corresponds to a gene present in a normal cellular genome, and each of these retroviral oncogenes appears to be derived from a cellular genome.

But, why did Varmus and Bishop suspect that v-src might have originated as a cellular gene? In part it was because Steve Martin had earlier isolated a mutant of Rous sarcoma virus that was temperature-sensitive for transformation, but not for replication. Why would a virus carry a gene that it did need for it to replicate?

 

 

 

How the Human Immunodeficiency Deficiency Virus (HIV) Got Its Name

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.

varmusHarold 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, which proposed 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.

 

Who Discovered HIV?

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, Charles Mérieux.
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.

8 Barré-Sinoussi, F., J.C. Chermann, F. Rey, M.T., Nugeyre, S., Chamaret, J., Gruest, C Dauguet, C. Axler-Blin, F. Vézinet-Brun, C. Rouzioux, W. Rozenbaum, and L. Montagnier, (1983) Isolation of a T-Lymphotropic Retrovirus from a Patient at Risk for Acquired Immune Deficiency Syndrome (AIDS), Science 220: 868-871.

9 Chang, S-Y. P., B. H. Bowman, J. B. Weiss, R. E. Garcia, andT. J. White, (1993) The origin of HIV-1 isolate HTLV-IIIB, Nature 363: 466–469.