Maybe there’s a lesson in that for all of us.
With another researcher, Ted Breitman, Steve showed that retinoic acid, a metabolite of vitamin A, at low amounts, could also stimulate this maturation (a process called differentiation).12 That set the stage for a curative treatment for APL from a biologic! The idea that one could cure a leukemia with differentiation to a stage where the cells no longer grew, rather than killing the cells, was highly controversial. In essence, we were turning these dangerous, life-threatening cancer cells back into normal cells, thus restoring balance to the body.
Successful clinical trials in China and France were needed before Steve’s treatment plan became standard in the United States. Years later, Judy and I had a student in our lab who was diagnosed with APL. We watched in delight at her recovery when her doctor used the treatment my friend Steve Collins developed. It was gratifying to have played a small role in the development of the therapy. But far more important was that working together we could accomplish what neither of us might have accomplished alone. That is how I’d been trained by Lew and Dane. Much more can be accomplished with a collaborative approach, rather than the cutthroat, competitive approach of Gallo. I am humbled by the scope of many of these problems. People’s lives are at stake in the success or failure of research. We must bring our very best selves and bring back selflessness to science.
In 2016, the journal Blood honored our work in an article about the research that Steve Collins, Bob Gallagher, and I had done as one of the highlights of their seventy years of publication.13 It was ironic in retrospect to be honored in this fashion, as none of us wanted to write what we thought was a review article because we were all so busy at the time. Another oddity I must note is how many times over the years I’ve been told by notable investigators that it’s risky to be the first to publish groundbreaking research. Instead, they claimed, it’s better for one’s career to be second or third to confirm a discovery, and write the first review article which puts the research findings into their lab’s credit. This has always struck me as a stunningly selfish way of thinking. To me it’s like saying, “Don’t be like the Wright Brothers and build the first airplane.” Instead, be the idiot standing on the sidelines saying, “Hey, I think that thing just flew; I think I should write about flying one.” Taking credit for the hard work and risks of others to enrich one’s self should have nothing to do with the discipline of science.
Yes, it can be more dangerous to be first, but it’s only on the frontiers of knowledge that you have the chance to change people’s lives.
***
As I think you can understand by now, it wasn’t just science, but the camaraderie I felt with other researchers that made this such an emotionally satisfying time in my life.
After work, Steve Collins and I would often play tennis. In the beginning, I would usually win. Steve was a hard worker and perfected his game, such that later on, I struggled mightily to win a match. I’d give him pointers on how to improve his game and he’d do the same for me. Afterwards we’d often get a meal or just sit around and talk about things.
In comparison, once when I played tennis with my boss, Robert Gallo, I beat him 6-0, 6-0, 6-0, eighteen straight games in a row. Gallo insisted on continuing, though. Gallo won the last two games. The final total was eighteen games for me and two for Gallo.
But that didn’t stop Gallo from claiming afterward, “You see, I am a better player than you, Frank. I just needed longer to warm up.”
I must note, purely for historic reasons, of course, that during the match, Gallo appointed himself referee, calling balls in or outside of the lines on both his side of the court and mine.
We never played again.
Another charming aspect of Gallo’s personality was his treatment of his employees when they interviewed for another job. At one point, Steve applied for a position at the medical department of the Veterans Administration in Seattle, Washington. Gallo wrote a glowing letter of recommendation for Steve and then followed up with a phone call to the chief of staff of the department, denigrating Steve’s abilities. For good measure, he added that all of Steve’s good ideas had come from Gallo. In complete confusion, the chief of staff called me to get a better fix on what was really going on. I explained Gallo’s behavior to him as best I could.
I guess I was successful.
Steve got the job.
I always enjoyed our two-way discussion about hematopoiesis and was honored when I had the opportunity to be one of his reviewers every five years when there was an assessment of his lab.
One of the last communications I had with Steve was several years ago, after he’d been diagnosed with a pancreatic neuroendocrine tumor. Steve had decided on a therapy protocol from the Zentral Clinic in Bad Berka, Germany. The treatment utilized radiolabeled peptides to bind and kill tumor cells, a procedure that was not available in the United States until recently. I remember thinking that if a brilliant physician like Steve couldn’t find the best treatment in the United States, what chance did the rest of us have?
I dearly miss my conversations with Steve but am grateful for the years of friendship we shared.
***
Through the last half of the 1970s, nearly all virologists quit trying to isolate a disease-causing human retrovirus. The few stalwart souls who continued to make this effort were belittled by the leaders in the field who believed if they couldn’t find such a virus, it didn’t exist.
Fortunately, some good luck intervened. I’ve always loved the stoic concept of amor fati, which translates roughly as having the mindset to love fate, and make the best of what happens. The second of the three wonderful scientists I want to discuss in this chapter is Bernie Poiesz, a city boy like me, but from Philadelphia. Bernie had studied in the lab of Larry Loeb, where he learned how to test for reverse transcriptase, the enzyme used by retroviruses to convert their viral RNA into DNA, so that they could integrate their genes into the host cell genome. Bernie had just completed a year of clinical work and we were keenly interested in studying T-cell lymphomas (tumors).
Despite Gallo’s instructions not to study lymphoid cancers, we knew that most retroviruses reproduced to detectable levels only in growing cells, which had been found in animals. That meant T-cell tumors, which grew quickly, would be an ideal candidate to find such retroviruses if they existed in humans.
While Bernie was demonstrating that IL-2 stimulated growth of these tumor cells, I reviewed a paper by Adi Gazdar, which reported that IL-2 had been successful in establishing several human tumor T-cell lines.14 Bernie knew Adi and his boss from clinical ward rounds and had been given several of these T-cell tumor lines in a collaboration. In a marvelous irony, the most interesting cell line, Hut-102, was developed from a patient Bernie had admitted for a lymph node biopsy. Bernie found small, but measureable levels of reverse transcriptase in the sample.
We were encouraged, but also disappointed because we wanted to find extraordinary amounts of reverse transcriptase, hoping to show a great amount of viral replication as well as a virus to convince the skeptics.
Bernie was wonderfully precise in developing an experimental plan, and we developed an “A-team” of all the researchers in my lab to accomplish the Herculean task of producing thirty-two gallons (120 liters) of cell culture for viral analysis. Bernie was then able to identify a retrovirus.
We knew we had something, but what was it?
We were concerned about a rerun of the HL-23 fiasco, where the three viruses isolated were later found to have come from a monkey. Bernie knew that Adi Gazdar often passaged his human cells through mouse tissue and worried the virus we had might be a mouse virus. Bernie informed Adi of our results and our concerns about the meaning of the data, and Adi generously provided another sample of which there could be no question of mouse contamination. In a painfully slow process, we checked all the available retroviruses and confirmed no animal retroviruses were in the sample.
The data suggested we had isolated the fi
rst known disease-causing human retrovirus. We had reverse transcriptase, we had the virus, and we’d compared it to known animal retroviruses and had come up empty.
At this point, we had not told Gallo of our findings because we wanted to check our work before we found it splashed on the pages of the Washington Post. However, Adi Gazdar’s boss, John Minna, apparently loved to one-up Gallo, and told him of our discovery when the two of them were at a Saturday night cocktail party at Gallo’s home.
Both Bernie and I were awakened late that night by Gallo screaming at us over the phone about why we’d kept this information from him.
At the tense Monday morning staff meeting that followed, Gallo was still angry at us and felt the need to reassert his authority. He asked us to provide him a readout of the reverse transcriptase counts (which we had ready), and after reviewing them declared in an imperial voice, “I know viruses and you don’t have a virus. Go back and prove it.”
Gallo then insisted on being in charge of the project, with regular meetings with the three of us. However, not only were the findings about Hut-102 reproducible, but we were able to establish the presence of the retrovirus in uncultured cells of T-cell tumors. We were also able to establish the virus was only present in T-cells and not B-cells of a second patient.
Bernie and I had bagged the first identified disease-causing human retrovirus.
But of course, it was Gallo who wanted to claim all the credit.
***
While the science was going well, the politics were not.
In keeping with tradition, Gallo was given the right to name the retrovirus. When he brought it up to us, we encouraged him not to be like Rous, Maloney, Friend, and Epstein-Barr, and give the virus the name of a person. Gallo finally agreed and named it the Human T-Cell Lymphoma Virus (HTLV-1). Bernie properly wanted to be cautious as we did not know for sure if it was of human origin and whether it caused disease. The evidence certainly suggested these two ideas, but there had not been rigorous investigation.
In publishing the first paper on a new infectious entity, disease causality is almost never proven. Gallo put us in a difficult position because those critics who said that human retroviruses did not exist were now claiming we were asserting this was a disease-causing virus. However, Gallo was adamant about the title. He was going to plant his flag on this virus. We were going to have enough baggage associated with our discovery without the continued sniping by our critics. Even in our lab, other scientists who had not studied HTLV-1 because they did not believe us were now resentful for being left out. However, some researchers did come to our side, and we welcomed their assistance because it was clear that many important questions needed to be answered.
There were a number of odd events that took place as we continued our investigation. One day, Bernie’s lab book mysteriously disappeared. Bernie eventually found it on the desk of Mika Popovic, a new virologist from behind the Iron Curtain who was working at the NCI. Remember, our lab at Litton Bionetics was miles away. Gallo defended Popovic against Bernie’s concerns, but Bernie thought the defense insincere. He believed Gallo had, in fact, set up Popovic to take the blame for Gallo’s removal of Bernie’s lab notebook from our lab.
While preparing the manuscript, Gallo asked the editor-in-chief of the Journal of Virology to review the paper. Gallo reported to us that the editor replied, “No. And you should stop working on these viruses. We know they do not exist.”
In the process of submitting the paper to the Proceedings of the National Academy of Sciences (PNAS), where it was eventually published in December 1980, Gallo told me he wanted to be first author on the paper.15
I replied that Bernie had done most of the intellectual and technical work and deserved to be first author.
Gallo looked out the window, and after a moment said, “Frank, with an attitude like that you’re never going to get ahead in science.”
As I walked out of that office, I knew my future working for Gallo was bleak.
***
The Proceedings of the National Academy of Sciences paper was not well-received, especially since HTLV-1 had not yet been definitively associated with human disease.
The next May, in 1981, Bernie and I were each given short five-minute talks to discuss our research at the Cold Springs Harbor RNA Tumor Virus meeting—of course, on a Sunday afternoon. From the start of the meeting on a Thursday, until Saturday, Gallo had us call him every day and deliver our presentation to him. He’d suggest minor changes and then ended each conversation promising he’d be there for our Sunday afternoon talk. Needless to say, he didn’t have the courage to show. After our talk to a half-empty room, everybody filed out without talking to us, with the exception of future Nobel Prize winner Harold Varmus. He came up to us and said, “I think you have something there. Keep working on it.”
In the spring of 1981, Gallo flew to Japan to meet with scientists studying acute T-cell leukemia. Drs. Hinuma, Miyoshi, and Ito did excellent work identifying retroviral particles in cells with the disease. This was critical in establishing the virus caused the disease, but Gallo was always dismissive of their contribution.
Our work and that of many others clearly demonstrated HTLV-1 was the first identified human infectious cancer-causing retrovirus, which in addition to lymphoma, also caused an accompanying neurological disease, called Tropical Spastic Paraparesis/HTLV-1 associated myelopathy, TSP/HAM. At the time, we knew this was revolutionary, but did not realize the major impact this discovery would have on methods used for viral investigation and the resulting therapies.
For its one hundredth anniversary, the Proceedings of the National Academy of Sciences (PNAS) selected our paper as one of its thirty most important papers. John Coffin, never a particular friend to me or Judy, and the most vociferous critic of our future XMRV work, wrote of our HTLV-1 paper:
There is little doubt that, without the trail blazed by the highlighted PNAS papers and its predecessors, the discovery of HIV which led to screening technologies to prevent transmission and eventually to effective antiviral therapy now prolonging the life of millions of infected individuals worldwide would have been greatly delayed. Contributions to delays were the pre-1980 mindset among virologists of the unlikelihood of human retroviruses. Thus, both the technology of growing T-cells in culture and isolating viruses from them and the paradigm represented the discovery of a pathogenic human retrovirus, laid the critical foundation for some of the most important medical advances of the late 20th century, without which many more millions would have died of AIDS.16
It’s a remarkable statement because it shows how negative dogma proposed by arrogant and powerful leaders can hurt public health, and how many of the current critics of our work have no problem admitting the importance of our work in the past.
In retrospect, the potential of long-term growth of T-cells, and subsequently other cell types, including immature myeloid cells, the original cellular target, was as important as the discovery of a single growth factor or virus. For example, we showed that stem cells from human cord blood cells could support cell growth and differentiation in long term cell cultures, which suggested the stem cells from cord blood could be used medically.17
This was another paradigm shifting discovery, years before its acceptance by the gatekeepers of medical dogma.
***
The last of my clever and humane clinical fellows I wanted to talk about is Joe Gootenberg, a progressive thinker who first made me aware of the deplorable medical care on Native American reservations.
Joe and I first worked together demonstrating these T-cell tumor cells had growth advantages because they produce their own growth factors.18 Using our old friend, the Hut-102 cells, Joe found a biochemical variant T-Cell Growth Factor, and we presented evidence that they were different molecules and could be expressed by separate genes.19
In 1984, Joe set up his own lab at Georgetown University and submitted several grants to isolate the gene for this new variant T-Cell Growth Factor. Hi
s research was not funded because he was not a member of the club and did not have experience with the new techniques. How does one get experience without getting a chance? Ironically, the gene for the new T-Cell Growth Factor which we had discovered in 1984 was cloned, sequenced, and named IL-15, by the NCI in 1994 and a company named Immunex, where investigators did not have to apply for grant money. They were not allowed to patent their discovery because of our prior knowledge.
Ten years into my career, it had been my good fortune to have contributed the knowledge of several critical discoveries to medical science, which had been decorated by highly honored publications. The discoveries fostered therapies which have prolonged lives and improved quality of life for many individuals. In addition, there were also anti-IL-5 therapies for severe asthma and other diseases with eosinophil pathology. IL-15 has already shown some promise in expanding the range of cancers treatable by immunotherapy.
But why didn’t I have a sense of great satisfaction to be present at these moments of discovery? I should have been happy knowing what I had achieved, and indifferent to the fact I was unlikely to get much external acknowledgment.
The problem was that I was working for a narcissist peacock, who had an exaggerated sense of entitlement and required constant complete admiration. He was reckless, doing things like prematurely announcing the discovery of HL-23 in the pages of the Washington Post.
It was like watching a madman play with a pistol.
You never knew who was going to get shot.
He kept us waiting every Monday morning staff meeting beyond the time the meeting was supposed to start because as the boss he believed he was the most important person in any room he might occupy. I was told I should not ask challenging questions of other scientists who visited our lab for fear it might make Gallo look bad politically. I was told not to discuss my work with my wife for fear she’d tell her bosses, who would then steal Gallo’s work.
Science was supposed to be about collaboration, especially since as government scientists we worked for the public, but not with egomaniacs like Gallo and Fauci. It was all about their own personal glory.
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