Ending Plague

by Francis W. Ruscetti

  Latent cells could be activated a year later to produce virus by demethylating agents. Increasing NF-kappa-B activity increased expression from the cells that has restricted its production.

  We naturally asked if normal monocytes from AIDS patients had the same ability.

  The answer was an overwhelming yes.

  Monocytes from AIDS patients harbored latent HIV virus, which was inducible to produce infectious virus during an immune response, leading to T-cell infection and death.

  One of the arrogant reviewers for her first manuscript wrote, “Not only do I not believe this paper, but also, I did not believe their last one.” This was my first experience, but certainly not my last, that while peer review might be good for technicians or mediocrities that make minimal contributions to the field, it was brutal on innovators.

  Well, thirty years later it’s clear that monocyte macrophages are a major reservoir for HIV persistence during highly active anti-retroviral therapy and are the major source of virus and viral pathology in the brain.

  Allen Goldstein, then the head of the Department of Biochemistry and Molecular Biology, was always very supportive of Judy and her groundbreaking work. (Except when at a department party, she sank a hook shot over him to win a basketball game!) At the private session of Judy’s thesis defense, Dr. Goldstein said he wanted to give her a special award, but was told there was no provision which would allow such an award.

  ***

  After the discovery of HIV, the dogma surrounding it quickly prevailed over the science of AIDS. All other research projects were dismissed, ostracized, and/or not funded.

  AIDS was defined by an antibody positive blood test and any one of several opportunistic infections. However, having one of these opportunistic infections and a negative antibody test meant you were AIDS-free! Anybody who published different data that challenged this dogma was a pariah, who often faced career-altering repercussions.

  When there began to be a large number of patients with AIDS-like diseases, but without an HIV antibody positive blood test, the CDC immediately pronounced it was not AIDS, because the patients were HIV-negative.

  What a ridiculous circular argument!

  You define something that causes a disease but when you find that disease without the cause you defined or that the victims do not meet the demographics, the CDC simply pronounces it is not that disease and makes up a new syndrome for this new idiopathic (unknown cause) disease. Judy likes to say that the idiots don’t understand the pathogenesis.

  In other words, you had AIDS, but not HIV, and you were not a gay man but a woman. Therefore, you did not have AIDS

  Shyh-Ching Lo, who we would meet again decades later, published a series of articles showing the isolation of a microorganism called mycoplasma from AIDS patients.17 Instead of a scientific discussion on the implications of a mycoplasma infection in people with AIDS, he received essentially nothing but personal attacks.

  In 1990, at an AIDS conference, Luc Montagnier, always one to show all the data, stated that he found mycoplasma in about 40 percent of AIDS patients. Dr. Montagnier said, “we thought this one virus was doing all the destruction. Now, we have to understand all the other factors in this.”18 Many scientists castigated Montagnier for squandering his credibility and risking his professional standing, including perhaps a future Nobel Prize. It’s incredible to realize a scientist can risk his professional credibility by simply presenting data.

  What?

  They want a scientist to present only the politically and socially acceptable data. Several scientists have told me that data they do not present is as important as the data they show! Heaven forbid the day that the dogma becomes so important that even its discoverer cannot add or detract from it.

  When Dr. Paul Hoffman, working in my lab, made the observation that HTLV-1 could productively infect human macrophages and brain microglial cells, we decided that Judy should do a postdoctoral fellowship in the molecular/virology of HTLV-1, rather than continue in the savage rat race HIV research had become.

  At the NCI-Frederick, Maryland, her first choice for a postdoctoral mentor was Dave Derse. For non-scientific reasons, it turned out to be a very poor choice. Better choices might have been non-retroviral molecular biologists. That said, the project of making the first infectious molecular clone of HTLV-1 and the molecular virology she learned has served us both very well, as two decades later, we appreciated the difference between the Silverman infectious molecular clone of XMRV (VP-62) and the natural isolates and defective viruses of the murine leukemia virus family

  ***

  As the 1980s were coming to a close, it was a bittersweet time for me. Both of my parents had died without my being able to tell them how much I appreciated them.

  In 1981, my father’s Hodgkin’s lymphoma recurred. I have always wondered that if maybe I’d paid closer attention, then perhaps the outcome might have been different. On his death bed, my old-fashioned father said the family needed a male heir. I’m sure he would have been delighted with our son, born a few years later, and now nearing thirty-five years old. He is and always was a joy.

  In 1987, while Sandy and I were at a meeting in London, my mother passed away. I lament that we would never have the opportunity to understand each other.

  Sandy and I had been talking about moving to a more family friendly environment like Frederick, Maryland, rather than the rich and posh neighborhood of Bethesda where we were living at the time.

  In 1989, Sandy had the chance to join the laboratory of molecular oncology, headed up by Dr. Takis Pappas, at NCI-Frederick. We looked around for a property and found one we really liked in a planned community. We bought the largest unzoned lot with direct views of the lake. I had to petition the Frederick zoning commission to get the property zoned for residential use. Sandy and I had plans drawn up for a contemporary home and found an architect. Friends like Judy made useful suggestions.

  Our place in Bethesda sold quickly, even though we listed it for more than our realtor suggested. We stayed in Judy’s apartment in Frederick until our home was ready. Judy had been spending most of her time with her mom after Ken’s death, and her commute to complete her research thesis was much shorter from northern Virginia.

  We loved the bright and airy place we designed, and it was a short fifteen- to twenty-minute drive to work. It was a great place to raise children, providing easy access to events in either Washington, DC or Baltimore. We lived there from 1990 to 2014, until we moved to Carlsbad, California, located on the Pacific Ocean.

  CHAPTER EIGHT

  Be Careful What You Wish For

  The section chief at NCI is the best job in science;

  Laboratory chief has all the “crapola.”

  —Mike Potter

  Science does not have a moral dimension. It is like a knife.

  Give it to a surgeon or murderer. Each will use it differently.

  —Wernher Von Braun1

  By the time we moved into our new lakeside home in Lake Linganore, we felt we could have a normal family and professional life.

  In 1992, as a result of Judy’s thesis and my discovery of TGF-beta as a master regulatory switch of blood stem cells2, my laboratory focused on the innate immune system, retroviral surface proteins, viral pathogenesis, and normal cytokine regulation of inflammation, immunity, and hematological stem cell growth. Throughout the 1990s, my lab varied from eight to twelve people.

  As chief of the Lymphokine (proteins released by lymphocytes) section of Joost Oppenheim’s Laboratory of Molecular Immunoregulation, I was only responsible for the research of those eight to twelve people. I was responsible for integrating the data/knowledge generated by those scientists and technicians in my section. It was a challenging and exciting position.

  Joost and I would occasionally argue about many topics. Once, he stopped me in the middle of an argument to ask if I was Jewish.

  I said, “No, why?”

  He replied, “You argue like one!”

&n
bsp; I took it as a compliment.

  In 1992, I was awarded the Distinguished Service Award, the highest honor the US Department of Health and Human Services can award. The award read as follows: In recognition of the fundamental co-discoveries; Interleukin-2, the first human leukemia virus, and for discovery of hematopoietic regulatory activities of transforming growth factor beta.

  In addition, I had the honor of organizing a human retroviral symposium in Genoa, Italy. That honor did not come without a price, as scientists can be just as demanding as any bad tourist. Some wanted free airplane tickets for their spouses, first class tickets, or to change their speaking order or time. For me, it was only about communicating the knowledge.

  Of course, it did not hurt to be in a beautiful castle in Genoa, Italy and eating fine food. But some scientists seem to believe it’s not about the knowledge, the beautiful surroundings, or good food, but about what science can do for them. The meeting went off smoothly and I was able to get the job done. It turned out to be a great experience, and I learned valuable lessons about the politics behind the organization of scientific meetings.

  In 1992, I was made chief of a new laboratory, the Laboratory of Leukocyte Biology. I’d like to believe the laboratory was created because our team had made so many paradigm shifting discoveries. However, it was quickly apparent that there were other agendas.

  It probably would have been better if I’d taken over an existing lab with some established administrative and obvious research goals. I should have heeded fellow scientist Michael Potter’s warning that “the section chief at the National Cancer Institute is the best job in science. Laboratory chief has all the crapola.”

  I had no choice in the decision of which independent investigators would be in my lab, regardless of whether their research was relevant to the mission of the Laboratory of Leukocyte Biology. My current boss wanted me to hire two young investigators; one scientist was a natural choice, while the other, a former technician, was a poor fit. George Vande Woude, who would become my boss, wanted me to take another scientist because there “weren’t many Dutch Jews in science.” This was a terrible choice, as this scientist would go over my head and report directly any complaints to George. Finally, Dave Derse begged to let him join my lab because he despised his current boss. I also felt I owed him because he’d agreed to be Judy’s post-doctoral mentor, so I agreed. These additions greatly added to my administrative burden and associated stress.

  Ironically, at the same time in 1993, Sandy’s lab chief, Takis Papas, departed for a cancer center in South Carolina and she was appointed acting lab chief. Dr. Pappas left without performing any of the administrative tasks necessary for closing a laboratory. Of course, they chose a woman to clean up the mess a man left behind. But at least her dissatisfaction was shorter-lived than mine.

  There were some nice opportunities that came with supervising a laboratory. I had a chance to invite seminar speakers whose work I really admired. I was able to invite established investigators like Steve Bartelmez from Seattle and Shin Kang from South Korea to spend time in the lab. Steve and I have now collaborated for almost four decades, making seminal discoveries regarding TGF-beta regulation of stem cells, just as Judy and I have worked for nearly the same amount of time, making seminal discoveries in human retrovirology. It seems that never a day has gone by without Steve or Judy challenging me to consider their perspective.

  And neither of them ever challenge me quietly.

  ***

  Sports was always a fun way to relax from the pressure of the lab.

  The Baltimore Orioles opened Camden Yards in 1992, and Judy and I bought two seats in the twenty-nine-game season ticket plan. The plan was set up so we got to see one game of every visiting team that came to town. Either Judy and I would take in a game, or I’d take my son, or Judy would take one of her two nephews. The best evening of all was the September 6, 1995 game where Cal Ripken broke Lou Gehrig’s record for the most consecutive games played. The next week we saw Eddie Murray hit his five-hundredth home run.

  As I mentioned before, Fort Detrick had an intramural slow pitch softball league and Judy would recruit and manage the team. We were always in the playoffs and often won the title.

  Judy had a little sister in the Big Brothers, Big Sisters program, Karen, who eventually married a local disc jockey, Dan Stevens. Like us, Dan started his disc jockey job before 5 a.m. and would occasionally dedicate his opening song to us, saying we were already at work trying to cure cancer. It was such a pick me up and it made us want to keep working hard.

  Around this time, Sandy and I began a habit of taking our son to international meetings to which we were invited.

  We eventually took him to meetings in Brazil, Jamaica, Canada, Germany, Sweden, Morocco, Japan, and South Africa. In South Africa, we saw one of my personal heroes, Nelson Mandela, and took a safari in Kruger National Park.

  If possible, I think everyone should travel outside the country, as it is a great education.

  Sandy and I received many invitations to speak at international meetings. Among my favorites was a presentation at a symposium in the reopening of the Curie institute in Paris in 1995. The speaker podium in the conference room had been made from Marie Curie’s laboratory bench. Being told that it was actually her bench, I slowly backed away from the podium (radioactive, maybe) while speaking. Another was being made a fellow of the University of Bergen during Sten-Eirik Jacobsen’s doctorate celebration.

  ***

  Things were changing at the NIH after the 1987 announcement by Harold Varmus that the French scientists would get more of the HIV test kit royalties.

  This put subtle pressure on Gallo to leave the NIH.

  I shall quote from the book, Science Fictions: A Scientific Mystery, A Massive Coverup, and the Dark Legacy of Robert Gallo, written by Pulitzer Prize-winning Chicago Tribune writer, John Crewdson. After a three-year investigation of Gallo’s actions by the Office of Research Integrity at the NCI, he resigned in 1994, and after a search, started the institute of Human Virology at the University of Maryland. In the closing paragraphs of Crewdson’s book, he tried to capture the character of my former boss. Crewdson wrote:

  Robert Gallo played the game of Big Science better than it had ever been played before. He had published, by his own count, over a thousand scientific papers, including the ones he had actually written. His curriculum vitae listed eight single-spaced pages of prizes, honors, and awards. He had become the most famous AIDS researcher in the world, treated like scientific royalty on three continents.

  But for the tens of millions of dollars that flowed into Gallo’s lab the taxpayers had gotten precious little beyond HTLV-1 and T-Cell Growth Factor …

  Being wrong in science is hardly a sin. Scientists are wrong every day, and in a curious way mistakes are what pushes science forward. What set Robert Gallo apart was his profound disinclination to acknowledge his mistakes, preferring to ignore them, insist they hadn’t occurred, blame someone else, or propagate outlandish fictions that only confused science further and slowed its forward march.3

  I thought Crewdson did an accurate job of capturing the duplicity of my former boss. But is it enough to point out the flaws of the man, as well as his good friend, Anthony Fauci, who has messed up the coronavirus crisis every bit as badly as Gallo and Fauci did the HIV-AIDS epidemic?

  People like Gallo and Fauci thrive because of a system put in place by President Richard Nixon, in which a few leading government scientists were given unprecedented control over funding decisions, while at the same time creating a subservient class of researchers who must vie for their approval.

  During the same time period that Gallo was being driven out of government service, three of his associates were getting into trouble over the misappropriation of government funds.

  Prem Sarin, Gallo’s second in command who I claimed took a cell line I developed and published it as his own, was convicted of monetary abuses:

  A prominent AIDS research
er was sentenced today to two months in a work release facility for embezzling $25,000 earmarked for AIDS research at the National Institutes of Health.

  Prem Sarin, 57, of Gaithersberg, who faced up to 20 years in federal prison, pleaded for leniency, citing a need to continue his research.

  Sarin contended in court papers that he is a victim of a vendetta by a House subcommittee investigating scientific claims of Sarin’s former boss at NIH, AIDS researcher, Robert C. Gallo.4

  Get the argument? I’m arguing that my research is too important for you to put me in jail, and I’m also saying this is all because of an evil “vendetta” by a House subcommittee.

  Zaki Salahuddin, who Gallo thought put the viruses in HL-23, resigned over financial abuses:

  A biologist working for the National Cancer Institute in the U.S. has been suspended following claims that he has been steering government funds toward a firm partly owned by him and his wife. The firm has provided equipment and materials to the laboratory in which he works.

  The case has attracted widespread attention because the biologist, Syed Zaki Salahuddin, works in the NCI’s laboratory of tumor cell biology, which is headed by Robert Gallo, co-discoverer of the AIDS virus.5

  Importantly from my perspective, the research by my laboratory on the developmental regulation of blood cells was proceeding excellently. Our team, consisting of Keller, Jacobsen, Dubois, and others, was pioneering the role of cross-talk between cytokines in regulating the surface expression of cytokine receptors. This was important in producing the additive effects of positive-acting cytokines on cell function.

  Also, this mechanism was important in controlling the interactions between opposing factors that inhibited or stimulated cell functions, depending on the context. These results and Sandy’s work on the interactions between viral surface proteins and cell surface receptors in viral pathogenesis greatly informed our viral work. Sandy’s work showing that changing just two amino acids in a viral envelope protein could change the pathogenesis from a leukemia to a neurological disease was a real breakthrough in our understanding of how subtle sequence changes in retroviruses can affect disease phenotype.