The Nixon administration was essentially building a scientific structure guaranteed to become corrupt because it concentrated absolute power in the hands of relatively few senior scientists/administrators. These scientists would often remain in their positions for decades. For example, Dr. Anthony Fauci has now served as head of the National Institute of Allergy and Infectious Diseases (NIAID) since 1984, a timespan longer than the corrupt J. Edgar Hoover spent heading the Federal Bureau of Investigation (FBI).
The Special Viral Cancer Program funds were used to support industrial laboratories, which were then used by NCI scientists for their own research. In addition, the scientists were often allowed to hire “outside contractors,” essentially scientists for hire at private companies, to perform the work. My wife Sandy was technically employed by one of these private companies (Meloy Labs), while my work for Gallo was as an employee of Litton Bionetics. In addition to allowing principal investigators to hire many more people (because they wouldn’t show up on the budget of the federal government), they were also able to pay the employees of these off-site contractors less money, give them fewer benefits, and make it easier to fire them. In essence, the legislation allowed people like Gallo to become the unquestioned ruler of a scientific empire, while at the same time transforming an entire class of researchers into the equivalent of medieval serfs.
Gallo would often command his contract employees to attend dinners where extramural scientists from around the world were wined and dined. The contract employees would pay the dinner expenses and get the company contractor to reimburse them because sending the bill to the federal government would have been an ethics violation. But Gallo, unlike most other NCI investigators, who did not engage in such activities, was somehow able to get away with it.
During the early 1970s, the Special Viral Cancer Program’s single-minded approach to discover a human cancer virus led to several possible candidates obtained from continuously growing human cell lines. These cell lines were usually developed from cancer tumors, and it was believed that a viral infection is what had caused the cells to become cancerous, or essentially “immortal,” and continue to grow, rather than be replaced, die, and be degraded, as happens with normal cells. These “discoveries” were usually announced in the media before peer review, and often turned out to be a mouse, cat, or monkey retrovirus which had somehow found its way into the culture, most likely from the addition of some product made from these animals included in the mixture.
When Gallo had wooed me at the American Society of Hematology meeting in December 1974, it was with the promise I’d come and work on a recently identified viral candidate, HL-23.2 Scientists from around the world like Robin Weiss came to work on this human rumor virus.3 However, it was discovered that HL-23 contained not one, not two, but three monkey retroviruses. At the time, Gallo was luring me with the promise of HL-23; he already knew it contained three primate retroviruses, meaning it was essentially up to me to start over.
As an explanation, Gallo first said that the patient’s cells were contaminated, which we showed to be false. His next theory was that it was a plot against him by somebody in the National Institutes of Health (NIH) to discredit him. In private discussions with me it was clear Gallo was paranoid about enemies in the NIH being out to get him, and he fervently believed somebody in his lab had slipped these viruses into his cell cultures. The lab workers he suspected were never fired for fear of revealing the truth. To this day, I have no explanation why the HL-23 paper from Gallo’s lab has never been retracted.
However, I was starting to learn some valuable lessons about my new boss. First, I learned to never show him data that I was unsure of because he would rush it into publication. The lead author on the HL-23 paper told me he was stunned to see the first public mention of his work in the pages of the Washington Post prior to being able to confirm his work, the information no doubt leaked by Gallo himself. The whole human embryo cells used to obtain the growth factor for the cell-line that produced the HL-23 virus had been lost in a freezer accident the previous November, which Gallo neglected to mention to me in December, making it difficult, if not impossible, to reproduce the work.
Later in the 1970s, viral candidates from the labs of two well-respected scientists (Henry Kaplan and Werner Kristen) turned out to be primate viral dead ends, too. As a sign of Gallo’s tyrannical personality, although HL-23 had turned out to be a bust as a human virus, several researchers were interested in studying the HL-23 virus and requested samples, a common scientific practice. Gallo told his workers to irradiate the cell cultures before sending them to these researchers, which would kill any viruses in the sample. I cannot vouch that this was done, but I know that Gallo made the request.
I started to wonder what the hell I’d gotten myself into. Gallo told me I should attempt to reisolate the whole embryo growth factor lost in a freezer accident. This was needed to grow HL-23 myeloid leukemic cells and to isolate the virus he knew was causing acute myeloid leukemia (AML). That’s all the direction I ever received, and one could still hunt for AML-causing viruses in 2021 because one has still not been found. Not much of a mentor. Simply a boss.
As one can imagine, these repeated public failures by Gallo and others were usually announced in the pages of the Washington Post rather than in peer-reviewed journals. This made the leaders in science proclaim loudly and to whoever would listen that human retroviruses did not exist.
As one of the human virus hunters in the Gallo lab, I started to attend the RNA Tumor Virus meetings held every year at the Cold Springs Harbor Laboratories. For many this was almost a mecca, a holy place of science, but I couldn’t help but note that in the 1920s it had been the center of the American eugenics movement. The eugenics movement was based on the idea of white racial superiority. Italians and Southern Europeans were on the fringe of acceptable races, and this movement justified restrictive immigration laws, forced sterilization edicts, and gave Hitler a lot of the ideas for his “Final Solution.”
As I attended these meetings, I was besieged by scientists, including five former Nobel Prize winners, who all vied to tell me how useless it was to search for human retroviruses. Many of them told me I should have made a better career choice and gotten a job with a real scientist, not one who was chasing phantoms.
The RNA Tumor Virus meetings started on Thursday afternoon. Following Saturday’s presentations, there was a banquet on Saturday night. The human retrovirus research talks were always scheduled on Sunday morning, when most of the researchers were nursing hangovers and the leaders in the field did not attend the Sunday sessions. I was shocked by the misogynistic language used by many of these powerful male scientists, as well as their belittlement of women in science and their sexual crudeness.
The men I’d worked with on the road crew in Massachusetts when I was seventeen, who’d visit a house of ill repute on their lunch hour while I waited outside, were absolute princes compared to these scientists. My father had told me I had a choice of working with my back or my brain.
But these learned men of science seemed to be thinking from a completely different part of their anatomy.
***
When I started working at Litton’s two-story facility in downtown Bethesda, Maryland, I met in Bob Bassin’s lab a French post-doctoral fellow, Françoise Barré-Sinoussi, who would later win a Nobel Prize with Luc Montagnier for the isolation of the HIV retrovirus, establishing for all time how devastating retroviruses can be to human health.
It’s amazing to realize how so many of us who interacted together at the NCI in those early years would have our lives so dramatically intersect.
Under Gallo’s directive I searched for a growth factor in thirty-six different whole human embryo cultures, but had no luck. When I arrived at the NCI, the enormous Gallo lab operation was divided between several major scientists, including Alan Wu, Bob Gallagher, and Dave Gillespie. It was Gallo’s habit to give the same project to multiple individuals in different sections and wait
to see what developed. Unbeknownst to me, the project of using whole human embryos as a source for growing myeloid leukemia cells had previously been given to Doris Morgan and Zaki Salahuddin. They also had failed in the project, and I was assigned to replace Salahuddin and get it done with no other direction.
One of the many sources chosen to look for such a cell growth factor was mitogen (antigen) activated human peripheral blood mononuclear cells (PBMCs), even though the cells gave no indication of having such a growth factor. Human bone marrow cells, used as a source of myeloid progenitors, were cultured under many variations, with repeated additions of supernatants from stimulated PBMCs needed to prevent cell death. Despite many attempts, both Doris and I found independently that the immature and mature myeloid elements rapidly died, leaving only lymphoid cells.
At the time, it was thought only virally transformed B lymphocytes and leukemic cells proliferated in suspension culture. People in the lab were disappointed, thinking we only had B-cells. But B-cells did not require additional factors to grow in suspension culture. I thought the lymphoid cultures had to be something else, maybe T-lymphocytes, which had never been grown in culture before. I demonstrated that the continuously growing cells were almost pure cultures of human T-lymphocytes and could be kept alive for a long period of time by repeated additions of the T-cell growth factor I’d helped discover, which was later called interleukin-2 or IL-2.
For the rest of my research career, this discovery would be both a source of intra and extra scientific politics. When I first presented the work in abstract form, Alan Wu, Doris Morgan’s supervisor] Bob Gallagher, my supervisor; and Ray Kiefer were coauthors. When it came time to submit the manuscript, those three names disappeared, which in my opinion could only have been through the intervention of Robert Gallo. Why didn’t it dawn on me that such theft of credit could also happen to me at the hands of my paranoid boss, Gallo, who believed agent provocateurs from the NIH were secretly slipping monkey viruses into his cultures to contaminate them? The faith that good science and rational thought would save me was so mistaken! The lunatics were running the asylum!
Doris Morgan was also always claiming that these cells would only grow in small test tubes, but I was having success in the larger culture flasks as well.
Today, we would have published the first papers on the discovery as equal contributors; that is, as co-first authors.4 The first author is the author who conceives of the idea, designs, and carries out the majority of the experiments and drafts the manuscript. Under pressure, I acquiesced and Morgan was the first author on the first paper of the discovery, T-Cell Growth Factor, and I was first author on the second paper. Morgan’s version is that she always deserved to be first author, when in fact like the rest she thought that the lymphoid cells were B-cells and would never have hypothesized and proved as I did that they were T-cells. In retrospect, I believe we should have been equal authors on both papers. Her next project was to purify IL-2, which she failed to do, and soon afterwards, Gallo let her go.
Much later, Gallo started a whispering campaign through surrogates that I was the one responsible for Morgan leaving the lab. Nothing could be further from the truth. There was only one boss in that lab, and it was Gallo.
Gallo was initially disappointed that my approach seemed to generate the wrong type of non-myeloid cells for cultivating human retroviruses. He told me not to work on T-cells, but since production of retroviruses needs growing cells in order to replicate, we continued to look at the T-cells.
Gallo’s lack of appreciation for the serendipitous nature of science was unfortunate. Until 1960, most scientists considered the lymphocytes to be an unimportant end stage of cell development. In fact, they should be considered some of the most critical guardians of the immune system, and their proper functioning is essential to the health of an organism. Peter Nowell, using phytohemagglutinin (PHA) to cause red blood cells to stick together, reported that this approach stimulated cell division in some white blood cells. Several investigators reported limited growth and survival of these cultures using PHA.
After our publication demonstrated we had discovered IL-2 and its properties, others claimed the credit. However, we had reported TCGF/IL-2 (T-Cell Growth Factor, or IL-2), as a factor capable of generating normal T-cells in large quantities and predicted that these factor-dependent normal T-cells would provide an excellent tool for molecular and immunological studies of the growth and differentiation of T-cells. In addition, the classification of T-cell subtypes made possible by this discovery could also be utilized in the treatment of cancer patients. Our predictions were quite conservative, as IL-2 has made possible an entirely new area of scientific research.
From the years 1976 to 1982, well over fifty investigators told me they could not reproduce my findings with IL-2 and growing T-cells in large quantities, as we had reported. It’s important to realize that the failure of the scientific community to reproduce the data of a particular scientist does not mean that first scientist was wrong.
More often than not, I’ve found the trouble lies in the inability or unwillingness of the second researcher to follow the procedures provided by the first researcher. I know this will sound shocking to the average member of the public, but it has been my common experience.
Let me state this as clearly as I can.
Scientists often do not follow the precise materials and methods from the published study and then disparage you when they fail because of their own biases and dogma. Inviting such scientists to the lab to observe the results first hand, or sending them reagents, often solved the problem.
At first, Gallo’s disinterest in my findings allowed me to collaborate with others, which was a good thing. Dick Metzgar from Duke University and I demonstrated that the cell surface of growing T-cells was far different than that of non-growing T-cells.5 This dispelled the notion widely held at the time, that T-cells did not have cell surface antigens to kill foreign cells and pathogens. You might even say the T-cells were figuratively bristling with armor and sharp spikes to destroy invaders. Immunological studies were initiated by Kendall Smith and Steve Gillis, in collaboration with me. We showed the availability of IL-2 made it possible to study cloned T-cells with a single antigenic specificity6, giving unparalleled data as to their inner workings. Smith’s lab made seminal observations into the biochemical mechanisms of IL-2 regulated growth.7
In the concluding line of the abstract, we wrote, “The ability to sustain differentiated antigen-specific T-effector cell in long-term culture may provide a means for the study of both the mechanism and regulation of T-cell mediated immunity.”8 In my opinion, that was a dramatic understatement. It’s interesting to note that the material I supplied to their lab was originally referred to as “Frankie’s factor.”
The discovery of IL-2 stimulated the development of the new discipline of cellular immunology. The studies of many investigators over four decades have led to an understanding of how to therapeutically use T-cells’ recognition of antigens, as well as the identification and use of receptors for IL-2 and its antigens. As Steve Rosenberg and colleagues wonderfully demonstrated, IL-2 alone could result in “durable, complete, and apparently curative regressions in patients with metastatic melanoma and renal cancer.”9
The concept that manipulation of the immune system could be effective has revolutionized cancer therapy. The discovery that IL-2 is necessary for the development, survival, and expansion of T regulatory cells that repress immune responses against our own tissues (auto-immunity) led to the concept that IL-2 is nothing less than the Yin and Yang of positive and negative immune responses. These discoveries have led to the tremendous increase in attempts to use immunotherapy for treatment of chronic diseases.
It was particularly gratifying that at the hundredth anniversary meeting of the American Association of Immunology in Honolulu, Hawaii in 2013, our report of the discovery of IL-2 was selected as the second most important paper their journal had published in the last century.10
Things were less successful back at my Gallo-mandated project of trying to grow more than fifty human leukemia biopsies, with me eventually stopping at HL-58. You can’t say I didn’t give it a good shot. One of the pleasures of working at the NCI during that time was meeting the brilliant, young clinical fellows (men and women), who often reminded me of the famous quote by Will Rogers that “It’s great to be great, but it’s greater to be human.”
One of my favorite people from that time was Steve Collins, who wanted to continue trying to culture human leukemia biopsies. I’ll be damned if in his second attempt, with HL-60, from a patient with acute promyelocytic leukemia (APL), he was successful. Nobody was happier for him than me and that single discovery launched him into an outstanding scientific career. Steve and I would often laugh at the twists of fate in life as we had lunch at the Pines of Rome restaurant, just off the NCI campus. One person stops pursuing an idea, the next person walks in without the weight of that failure, and voila! the world changes. In a series of manuscripts, we demonstrated that these immature and nonfunctional cells could be made mature and functional.11
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