...

Sher:  I knew he was from Harvard, and I also knew that he had left because he, too, had grown unhappy there. In fact, his wife Alice [Alice Hanson Neva] once took me aside and filled in the details for me. So we had that in common. But interestingly, the one NIAID person whom I did know while I was at Harvard was Ted Nash [Dr. Theodore E. Nash]. He had come to Harvard from NIH on a fellowship and was also interested in schistosomiasis. Ted was probably the person who first told Frank about me, although Frank may have heard from Lee also. I had also met Louis Miller [Dr. Louis H. Miller] at a meeting  and was excited about the strong malaria program he was building in Frank’s department. The LPD had an open position and were interviewing all sorts of people for this job trying to decide whether they wanted a biochemist or an immunologist. Eventually they settled on me and I was fortunate to become an NIH investigator!                   

When I took the NIAID job, people at Harvard came up to me and, said (once again as they had at Salk when I decided to go into parasitology), “You're committing professional suicide. You'll disappear down there. It's just such a pedestrian place, the NIH. Here you can work in the most famous medical school in the U.S. and become a Harvard professor.” Parenthetically, while I was at Harvard, the technicians went on strike for better wages and their motto was, “You can't eat prestige.” And that's the way I felt, too.  To me the prestige had become an intangible. I was looking for a place where I could pursue my work in a stable and collegial environment, so, I was absolutely delighted to join the NIAID Laboratory of Parasitic Diseases and to work under Frank Neva, who was truly one of the last of the gentleman scientists and was instrumental in building my career here. On one occasion during my recruitment, I flew down from Boston and Frank invited me to have dinner at his house to meet his family. This was the kind of warm-hearted open person he was.

Harden:  Tell Tell me about LPD, in general, when you first arrived. Who was here? What building did you work in? What sort of resources did you have? All of that.

Sher:                              When I arrived, my lab was in Building 5. (Actually, I can now walk across the NIH campus and see every building that I worked in—all four of them). They gave me one little module in Building 5, but I had been promised a lot more. This became a source of some tension because I had already started to recruit my group, and here I was, stuck in this one little room right across from the Scientific Director's office[*] At the time, the SD was a man named Ken Sell [Dr. Kenneth W. Sell], who was a kind of a controversial character. He had been hired by the NIAID director Dick Krause. Krause was the distinguished scientist and gentleman and Ken Sell was thought of as his tough guy administrator. I got along okay with them both—that that wasn't an issue—but I really didn't have the resources originally promised me. Stephanie came with me on her own WHO [World Health Organization] funding, and I was able to hire my first technician, Sara Hieny [Sara Hieny], someone that Stephanie had worked with when she was at Vanderbilt and who stayed with our lab for many years. I also hired another parasite immunologist, David Sacks [Dr. David L. Sacks]. David had been at Harvard when I was there. Then he went off to Mill Hill and did a postdoc, with basically the same group of immunologists with whom I had worked, so he and I had that connection. I had invited David to work with me when he came back from Mill Hill, but he thought that he was going to be at Harvard. He was disappointed that I had moved because he was a Bostonian, and his family was there. He loves New England and still has a place on Martha's Vineyard. Although I felt bad about dragging him down to Bethesda with me, it turned out to be a great opportunity for him too. (You'll be interviewing him, I'm sure, one of these days!) I also hired another postdoc from Mill Hill, Dr. Andrew (Andy) J. Simpson, who was Ron Smither’s golden boy at the time. Andy brought molecular biology expertise to the lab and later became a highly successful biopharma founder in Brazil. We were all stuffed into this little module in the corner of Building 5, where our desks nearly merged with the lab bench!

Lou Miller was across the parking lot in another building and had his own semi-independent group. Lou was the LPD’s ambitious super star at the time. He was not that involved with the rest of Frank’s program. But on the other hand, Lou was the guy who was delivering the major scientific goods, in malaria, and malaria was and still is the most important parasitic disease in terms of mortality. So Lou deserved his resources, and I was just the new kid on the block. But everyone said to me, “If Frank promised you these resources, you're going to get them.” And I did. Frank had to kick some people out to do it, which was, I'm sure, very painful for him. But there were a lot of old timers hanging around, and he managed to ease them out, in as gentle a way as he could, to create both the  resources promised to me as well as room to expand.

Harden:                         I think that's what he was hired to do.

Sher:                             Research on parasitic disease at the NIH goes way, way back, almost to the institution’s beginning. I always liked to stress this when I later addressed the Board of Scientific Counselors [BSC] as lab chief. The LPD is one of the oldest labs at the NIH, and it has a proud history. By the time I arrived, there was a lot of dead wood in the lab, and we younger scientists used to make fun of them for their waning contributions to the department and the field. This left a big impression on me and is actually one of my reasons for considering retirement. I don't want to end up in the same situation!

...

I have to tell you that, within a year of moving down to the NIH I was happy as a clam and really enjoyed being here. I particularly enjoyed working under Frank, who was low pressure. The scientific environment at NIAID was great, and the LPD offered many opportunities for collaboration in the field. Frank had built the department to broadly cover the field of human parasitic diseases, and there were investigators working on nearly all of them. Instead of only working on schistosomiasis, I picked up two or three other diseases that I was able to build my research program with. I did this first with David Sacks and soon after him, with another amazing postdoc, Phil Scott [Dr. Phillip Scott], who's now the Vice Dean of the University of Pennsylvania Veterinary School and a great colleague. With David and Phil, I built a really strong Leishmaniasis immunology research program. With help from Frank and another investigator, Jim Dvorak [Dr. James A. Dvorak], I was also able to resume and expand my work on Trypanosoma cruzi, contributing another publication to Nature. I was able to do this because there were experts all around me. Having been hired with tenure (there was no formal tenure track in those days) I was also grateful for the security of a civil service position and, of course, being freed from obligatory grant writing.

Harden:                         Did you have any collaborations with any of the clinical people who had patients with these diseases in the Clinical Center?

Sher:                             At that stage, no.  Collaborations were certainly offered to me because Frank was a clinician primarily, but he never pushed me in that direction. I've found over the years—and actually Lou Miller, I believe, had the same philosophy, which maybe Lou picked it up from Frank—that a good leader finds out what people are good at and lets them do that thing. You shouldn’t try to push them into things that they can't handle.

Harden:                         Before we get into your research, I want to ask you one more thing. The NIH Record article that reported your hiring said that you were to head the Cell Biology and Immunology Section. In 1995, the name of your section changed to the Immunobiology Section.  What prompted the change?

Sher:                              When I was hired, the section was called Cell Biology and Immunology because I was given an existing section. The section originally consisted of myself, Dennis Dwyer [Dr. Dennis M. Dwyer], who was a Leishmania cell biologist, and another, older investigator whom Frank coaxed into retirement. Frank created the section name so that the other people could be incorporated. Dennis Dwyer remained in the section with us for some time and retired about eight years ago. When Lou Miller took over as lab chief, Dennis Dwyer was separated off, and I asked that the section name be changed to “Immunobiology,” which more accurately reflected what we were doing.

...

So David was promoted, and he remained part of my section for a while. And then, in the late 90’s Frank stepped down as lab chief, and Lou Miller took over, abolishing all of the previous sections. This effectively was a demotion for me and for the first and only time I considered leaving the NIH and actually looked at another job back in La Jolla at the La Jolla Institute of Immunology. At that point I appealed to Tony Fauci, who by then was NIAID Director, and Tony supported me.  I was given more resources to compensate for the loss of my section and Lou Miller made me a kind of informal deputy for the non-malaria portion of LPD.

Harden:                         That's interesting.

Sher:                              Eventually Lou decided that he didn’t want the responsibility of being Chief for the non-malaria researchers in the LPD. He stepped down to  build a new department, the Malaria Vaccine Development Branch—but now I am getting way, way ahead of myself.

Harden:                         Yes, we've jumped ahead 20 years here. I want to drop back to the 1980s and talk about your research. The drug, praziquantel was found in the ’80s to be an effective therapy for schistosomiasis. It replaced the older therapy, antimony potassium tartrate. But because people treated with either drug regularly became reinfected, my understanding is that your goal, as an immunologist working on this, was developing a vaccine so people would not become infected in the first place. Am I correct here?

Sher:                             Absolutely correct. And that was the logic from the get-go. A vaccine would have been a great solution for preventing schistosomiasis. But when I arrived at LPD, I began to drift away from that goal. Stephanie and I worked on it for a time with some of our other postdocs, and her studies led to the identification of two vaccine candidates, paramyosin and calpain, the latter having been taken up by another group and currently in clinical trials.

            Its important to note here that around this time in the early eighties,  Stephanie and I married. Frank Neva and the NIAID leadership did not approve of our working as a husband-wife team.

Harden:                         There had been other husband-wife teams at NIH, of course. I’m thinking of Earl and Thressa Stadtman, Marshall and Perola Nirenberg.

Sher:                              Well, at the time, it was frowned upon. Frank didn't want to give Stephanie an independent scientific position. Though an inveterate gentleman, he didn’t consider the promotion of women in science a priority for the department. There was only one tenured woman in the LPD who had been hired by his predecessor, and she, I’m sorry to say, had ”checked out” by that time.   They had shoved her into one little lab module, and her work was of no interest to anyone else in the LPD. Frank struggled to get rid of her and eventually coaxed her into retirement. There were no other female investigators in the department and Frank didn’t want to consider Stephanie as a hire in part because of her marriage to me—one  of his other tenured scientists.  This was way before diversity and gender equity became recognized issues at NIH.

Harden:                         So what did your wife do?

Sher:                              Needless to say we were both deeply upset by this. Stephanie wound up moving to the Microbiology Department at George Washington University Medical School, where she ran her own lab for a number of years with her own funding and was able to continue to scientifically collaborate with our group. However, the research environment there was not particularly stimulating, and she had to commute downtown from our home in Potomac. The demands on her got worse when our first child, Lauren [Lauren Rebekah (Sher) McGuiness] was born in 1985 and for a while she would bring Lauren to work, camping her out in her office. Her technicians, Judy Glaven [Dr. Judith Glaven] and Lisa Desblois [Lisa Desblois], would look after Lauren while Stephanie was doing experiments in the animal room. Stephanie and I are proud to note that from this humble beginning, Judy has risen to be one of the seven senior scientific officers that direct the Howard Hughes Medical Institute.

Harden:                         You had two daughters, Lauren in 1985 and Alison [Alison Lea Sher] 1987, so you had a lot of childcare to deal with along with your work.  I wanted to ask you about how you dealt with what today is called work-life balance.

Sher:                              I’m afraid not well at all, and truly I regret than I didn’t help more withour with our childcare situation, particularly when they were babies. Eventually, we found a wonderful daytime Brazilian nanny who helped considerably. Nevertheless, Stephanie did not enjoy the scientific environment at GW at that period, and eventually the demands on her as junior faculty member in a soft money position (writing grants, teaching) as well as primary responsibility for care of our two young daughters led her to accept a position in the NIAID extramural Division of Microbiology and Infectious Diseases, where she could keep more regular hours. There she quickly climbed the ladder and was promoted to Chief of the Parasitology and International Programs Branch by Drs. Lamontagne [Dr. John R. Lamontagne] and Fauci. Her contributions to research in this area were well recognized by the constituent community, and during this period she was elected as President of the American Society of Tropical Medicine and Hygiene. Later in 2001, she moved to the Ellison Medical Foundation, where she served  as Foundation Deputy Director and Director of its new Global Infectious Disease Program.  There were hopes that Larry Ellison [Lawrence J. Ellison]  would establish an organization similar to The Bill and Melinda Gates Foundation [BMGF], but the Ellison Medical Foundation never achieved anywhere near the financial support that Gates put into his foundation. Stephanie ran her program successfully there for a number of years  before being recruited to the Foundation for the National Institutes of Health [FNIH] to help establish the Grand Challenges in Global Health initiative, a major Gates-funded program exploring how cutting edge science could be applied to health problems of the developing world. She became director of that initiative and several spin-offs at FNIH and held the title Senior Vice President for Science until about nine months ago, when she semi-retired. Stephanie remains there now in the position of Senior Scientific Advisor.  She's had a very successful career in research administration and has had the opportunity to contribute scientifically to several of the international global health programs she oversees as well as to develop her own projects.  A lot of her work (along with her salary) has been funded by the Gates Foundation, the FNIH being a major partner for the funding of NIH projects by Gates and other non-profits.

Harden:                         That’s interesting.  I have just learned something!

Sher:                              Let's wind it way back to your question about my schistosomiasis research. Despite the loss of Stephanie as a collaborator, by the late 1980s, I had mentored some very good postdocs who were producing important work and like her went on to be leaders in the schistosome immunology field. The first was Edward Pearce [Dr. Edward J. Pearce], a Welshman also trained at Mill Hill, who is currently Bloomberg Distinguished Professor at Johns Hopkins School of Public Health and now a world leader in the field of immunometabolism. Another was Tom Wynn [Dr. Thomas A. Wynn], who focused on pathogenic mechanisms in schistosomiasis and in particular those responsible for tissue fibrosis. While a postdoc in the lab, he produced an exciting study (again in Nature) on the use on Interleukin-12 to protect against this harmful response. More about Tom (now a vice president for research at Pfizer) later, but when he became an independent investigator and took his schistosomiasis projects with him, I was already heavily invested in work on other parasitic pathogens and the study of basic immune mechanisms they stimulate and protect against them. What had most excited me in the 1980s was the important work by Phil Scott, whom I mentioned above, on the role of T lymphocyte subsets in the outcome of Leishmania infection.

Prior to that time T cells were known to consist of two major types  CD4 and CD8. My colleague Bob Coffman [Dr. Robert L. Coffman], who had been a fellow grad student during my time in the Cohn lab, and Tim Mosmann [Dr. Tim R. Mosmann], working at DNAX in Palo Alto, showed that CD4+T cells actually could be further divided into two additional subsets Th1 and Th2 based on their cytokine secretion patterns.  They further showed that each had distinct functions in the immune response. Using a Leishmania infection model, Phil, Bob, and I showed in a paper published in the Journal of Experimental Medicine in 1989 that Th1 cells protect against the infection while Th2 responses actually make the infection worse. This was one of the first demonstrations that these two CD4 subsets can stimulate different disease outcomes and led our lab into a major pursuit of how the cytokines associated with these two subsets regulate host resistance and pathology in a variety of different infection models.

Harden:                         Wow.

Sher:                              Well, the irony of this was that having sworn off basic immunology at theconclusion the conclusion of my Ph.D work, I was now back in the thick of it, but this time utilizing important human disease models as the context for our work. So I got back into immunology, and of course, the NIH had a wonderful immunology environment to support and stimulate me. Here I am particularly grateful to the late Bill Paul [Dr. William E. Paul], the former chief of the NIAID Laboratory of Immunology, for his encouragement and intellectual support of these efforts.  

...

Let's do some campus geography. I started out in 1980 in Building 5, in that one little module I mentioned, and later (around 1987, I believe) moved to Building 4. Then, around 2000,  I decided that I wanted to work on tuberculosis [TB] which precipitated another work location change. 

Harden:                         Can you hold up for a while? I want to drop back to 1992. I do have TB down to get back to, so I won't forget.  But in 1992, the NIH Record published a major article on your group. Big photograph, everything. You were working on the understanding of cytokines as the trigger of nitric oxide produced by macrophages.  Would you tell me about this work?

Sher:                              Yes. I don't remember the article exactly, but thanks for flagging it, because a large part of our work in this period became focused on cytokines. They're chemicals produced by leukocytes that mediate all sorts processes both within and without the immune system.

Harden:                         Interleukin 12 [IL 12] in particular.

Sher:                              I became heavily involved in that particular cytokine. I even co-organized a meeting on it here the NIH.  I had a wonderful collaborator Giorgio Trinchieri [Dr. Giorgio Trinchieri] who now runs the cancer inflammation program at NCI [National Cancer Institute], who had discovered IL-12 while working at the Wistar Institute. We showed that resistance to Toxoplasma, and later other intracellular pathogens, was dependent on IL-12. If you didn't have IL-12, you couldn't develop immunity to those infectious agents. We further showed along with other groups that this happens, because IL-12 triggers another cytokine (interferon-g) that directly mediates macrophage control of these pathogens through the production of nitric oxide. We were pioneers in understanding the role of IL-12 in infection.

...

This and many other immunologic discoveries came out of studies on parasitic infection models. Nevertheless, none of our findings has so far lead to new treatments or vaccines for parasitic disease, and so in the end, maybe at heart I am a basic immunologist. When I became an immunoparasitologist, I thought I'd said goodbye to this field, but I really didn't at all. I was still a basic immunologist at heart.  That being said, in the early 2000’s I was left with a feeling that I was not really contributing anything to address human disease, and a lot of parasitic infections were becoming less important epidemiologically than when I started in the field in the 1970s.  Although we still don’t have any vaccines, except for the partially effective RTS,S recombinant protein-based vaccine for malaria,  the drugs and control strategies have substantially improved.

Harden:                         In 2001, you published a book chapter about coming to a consensus viewpoint on the immunology of schistosomiasis, and that scientists needed to identify an "as yet undiscovered Achilles' heel" of the parasite. Your hope was in genetic studies. Is it fair to say that you shifted gears after this article, and you left schistosomiasis research to move into toxoplasmosis and TB and some of the other parasitic diseases?

Sher:                              I’ve long felt that rather than mimicking the host response to chronic pathogens like schistosomes we need to find a target on the bug that is important for its survival/growth and direct our vaccines against that antigen.  This is what we have done with SARS-cov-2, and it works! We have to find out what that Achilles' heel is for schistosomes as well as other pathogens that lack effective vaccines.

            So, why did I go into TB? Remember I told you that toxo eventually soon ceased to be a problem in AIDS patients?

Harden:                         Yes.

Sher:                              Well, this inspired me to find other ways in which we could contribute to HIV research. So one day I walked over to the Clinical Center and talked to a friend and colleague of mine, Joe Kovacs [Dr. Joseph A. Kovacs], who's in Critical Care and who is our expert on opportunistic infection in the Clinical Center. I asked him, "Should I continue to study toxo? As you’ve told me, its really not a problem as an opportunistic pathogen in AIDS anymore." He said, "There's another opportunistic bug that you might study. It’s still a major problem and that's Mycobacterium avium.” It is an atypical mycobacterium and relative of M. tuberculosis. but in contrast to M. tuberculosis, M. avium usually only causes disease in immunocompromised individuals, where it can become deadly. It's one of the clinically important pathogens that Dr. Holland [Dr. Steven M. Holland] studies and is an intracellular pathogen like toxo.  Joe also said, "It’s  causing a lot of problems in our AIDS patients in part because we don’t have any highly effective drugs," so I said, "Okay. I study intracellular pathogens, so why don't I see if we can contribute on that front.”

...

Because human TB is so widespread globally, we also had the opportunity to participate in collaborative clinical research projects in India, South Africa, and Mali, I also became involved in clinical research really for the first time in any kind of depth. This came about in part because of a very talented Brazilian clinical fellow, Bruno Andrade [Dr. Bruno B. Andrade], who has become very successful in the global TB area. He heads several international programs and still helps us with our patient-related work from his lab in the Northeast of Brazil. We've learned a lot from these studies, which have been much more extensive than our few previous clinical research projects with parasitic diseases. The TB field has enormous depth and covers so many different disciplines.  It’s been fascinating to be involved with it, and there is no question about its continued vast importance to human health, especially now when TB research and control funding is being sucked into the war on COVID-19.  Nevertheless, the work is challenging and the need for a good vaccine or host-directed therapy is of even greater importance now.

Harden:                        Are they still using the BCG [Bacille Calmette-Guérin] vaccine?

Sher:                              Yes, but it only protects against certain forms of pediatric infection. We're actually studying BCG at the moment. In a recent publication we’ve shown in a mouse model system that BCG when given intravenously can non-specifically protect against lethal SARS-Cov-2.

Harden:                         That's very interesting.

Sher:                             It's an experimental model, but the fact that we're protecting against COVID-19 with something that's totally different is interesting. It's been proposed that BCG might have this effect, and while one cannot use intravenously administered BCG clinically, our findings could lead to the discovery of disease preventing mechanism(s) that could be stimulated by other means. Learning how to work with a new pathogen (SARS-Cov-2) has been a challenge but we were in a good position to do this research because we have the BSL-3 facilities and experience with containment procedures that is required.

Harden:                         What is your opinion about the mRNA vaccines? Do they hold any promise against TB or tropical diseases?

Sher:                             They've been suggested for TB. They're of course quite “in” now because of the COVID-19 vaccine successes. I'm not sure that mRNA is the answer for TB, but it's a technology that worked very well with COVID-19, because as soon as we discovered that a coronavirus was the cause of the disease, we knew that producing a neutralizing antibody response against the spike protein was likely to protect against SARS-cov-2 infection and the new mRNA technology was ideal for this purpose. In the case of TB we still don’t know what antigen to immunize against or exactly what type of humoral or cellular response we need to induce and certainly have not identified an appropriate “Achilles Heel”.

Harden:                         That's very interesting, because TB is such an old infection. It has been studied for so long, yet it's still a mystery.

Sher:                              TB is a much more complicated problem. It's had millenia to adapt to humans and Mycobacterium tuberculosis is a bacterium not a small genome virus. Understanding what immune responses can be used to control M. tuberculosis is the topic that I'm most interested in, and I do most of that work with murine experimental models. My colleague, Dr. Barber, whom I just mentioned, has set up a non-human primate infection model to more closely mirror the situation in humans.

Harden:                         You have mentioned a number of different animal models that you have used. Would you comment in general on the importance of these animal models?

Sher:                              Since I was a grad student I have worked primarily with mouse models, and in certain respects their  immune systems clearly differ from that of humans  That being said, I challenge anyone to find an animal model that has generated more information about human health. We use them for generating hypothesis that eventually need to be validated directly in humans or sometimes first in an intermediate model like non-human primates. So many basic discoveries have been made that way. Here's a recent example: checkpoint inhibitors in cancer. They came from basic discoveries originally made in mice. We use the mouse model to reveal immunologic mechanisms because we can easily manipulate these hosts genetically and perform experimentswe can't do with patients or other higher animal models.

Harden:                         In 2000, in addition to your responsibilities of being a Section Chief, you became Acting Chief of LPD. Then, in 2004, you became full Chief of LPD. You've told me some about Louis Miller, his role in stepping away, but I want to hear about the shift from your point of view. Why were you offered the position, why did you accept, and what new goals did you set for the lab when you became chief?

Sher:                             All good questions. In stepping down I’m guessing that Louis Miller suggested that the lab be split with Tom Wellems [Dr. Thomas Wellems] as the Chief of the Laboratory of Malaria and Vector Research  [LMVR] and myself as Chief of LPD. When the position was offered to me, I debated whether or not to take it. I wasn't the senior person in the Lab at that time, but I had one of the biggest research programs. I wasn't really sure I wanted to do it, but was encouraged by one of my respected mentors, the late Bill Paul. He said, "You don't let opportunities like that go by. They may never appear again!” And so, I took on the role, at first, as Acting, and later full Chief when the NIAID administration confirmed the appointment later on. I have to credit Kathy Zoon, my Scientific Director for most of that time, as being just a superb boss and leader. I still interact with her, because of her role in the NIH Oxford-Cambridge Program, which I will mention later on.

...

I had a sense—perhaps incorrectly—that  that our focus on parasitology did not have a high enough visibility in the infectious disease and immunology communities and that the Lab would be in a weaker position because of this. Also the malaria researchers had split off from LPD. They focused on the most important parasite affecting human mortality, and so I felt we needed to build other strengths. I encouraged the TB program, agreed to take on Dr. Leppla’s anthrax group, and heavily supported the elegant basic immunology that Yasmine Belkaid and Tom Wynn were engaged in. So the lab expanded, and some of the purists have accused me of selling out on parasitology. Well, the lab we built is strong, and although I am not the chief any more, we had a BSC [Board of Scientific Counselors] review in 2021, and LPD got a perfect evaluation. I mean, everybody got an “outstanding” rating. We lost both Belkaid and Wynn along the way, but they have moved into important leadership positions of their own.

Harden:                         Excellent.

Sher:                              So LPD maintained its strength despite the broadening that we did. I enjoyed being Lab Chief, but I have a philosophy that you should only do these type of demanding jobs for a certain amount of time. I think once you start to do them for too long, you lose your focus, you get bored, and you become fossilized in your attitudes, so it's time to pass it on to somebody else. I stepped down two or three years ago and my position was given to my deputy, Tom Nutman [Dr. Thomas Nutman], who has done an amazing job of running the lab and replacing the positions we lost because of departures. He's a parasitologist by training and keeps the parasitology side of the Lab going strong, but he's also a superb clinical investigator and heads the world class clinical parasitology program that  LPD has maintained for many years now. I have been serving as Tom’s deputy since then, helping him when needed, but he's very much in control and doing a great job.

Harden:                         If I may step sideways, one more time, you talked about hiring a mucosal immunologist, and you have also published on inflammatory bowel disease (IBD), which is mucosal. I interviewed Warren Strober [Dr. Warren Strober] a good while ago, and I’d like to know if there any overlap between what he did and what you did?

Sher:                              Yes, and Warren and I actually interacted for a while. I developed an interest in IBD because of our work on IL-10 and our concept that it protects us against “the friendly fire of the immune response.” Indeed, if you have an IL-10 knockout mouse, it develops IBD spontaneously, because the cytokine is not there to control inflammation. We developed a model that formally demonstrated (I believe for the first time) that specific gut bacteria can serve as the trigger of this inflammatory response. This model is still in use today by a number of groups in both the IBD and microbiome fields. Our contribution was a small forerunner to the beautiful work by Yasmine Belkaid on the role of the microbiota in immune homeostasis and disease.

...

Yasmine is now our microbiome immunology expert at the NIH. She is also an important role model for women scientists here and it is rewarding to me that she began her career as an independent investigator in LPD, a lab which historically—as I mentioned previously—had  neglected the cause of women in science. As I discussed earlier, my mother was a Ph.D microbiologist, my Aunt Marty was a famous vaccinologist and pediatric infectious disease expert, and my cousin Trudy was a Nobel laureate biochemist. Thus many of my own role models were women scientists! I was honored a number of years ago to receive an award from the Maryland chapter of AWIS, the Association for Women in Science, for encouraging the careers of women in biomedical research. It’s good to feel that I have made a contribution, if only modest, to this important cause.

Harden:                         I think Dr. Belkaid is one of the two new lab chiefs in NIAID, correct? 

Sher:                              That's correct and she’s off to a great start recruiting her own new investigators and programs. 

Harden:                         In 2008, you received an NIH Director's Mentoring Award, and you have mentioned throughout our discussion people whom you have mentored. You yourself had excellent mentors, so would you talk a little bit about your philosophy of mentoring and how this plays into people's careers?

Sher:                              My philosophy is pretty simple. I'm a cheerleader. I give my trainee’s a lot of freedom in the laboratory to find their own direction except in one area. And that's in writing. I really think that writing is an essential survival skill in science, and, sadly, I have to tell you that 90% of the  young people who join the lab don't know how to write well in English (or even in their own language if foreign.) Most importantly they don’t know how to put their ideas on paper. And I’m a tyrant about teaching them this.

I was talking to my wife Stephanie the other day—she was originally a postdoc in my lab, you recall—and she said she hated writing with me because I would stand over her and we'd struggle with every single word. But others have told me that learning how to write was the most important thing they learned in working with me. Because if you can't write, you're dead as an independent scientist.

Harden:                         I could also hold forth on this issue.

Sher:                              Okay good. So you know where I'm coming from.

Harden:                         I know exactly where you're coming from.

Sher:                              And I make sure that when they leave my lab they know how to write. We have this thing—it’s kind of a joke--that they call the “hot seat” because it's not comfortable. They come into my office and I put their manuscript up on my big screen.  I give them the keyboard. And I say, "What do you really mean? What are you're trying to say here?" We go through the manuscript, and it takes forever. My colleagues say, "Why are you spending so much time doing this? It must be awful." But I believe it's a major survival skill for going out into the scientific world, because they are going to have to write, write, write, write, write papers, grant proposals, letters all the time. There's no escape.

...

I also want to mention another mentoring related activity I’ve been involved in more recently, the NIH Oxford-Cambridge Scholars Program (referred to as OxCam). It has been going on for about twenty years. In fact, there's a banner on campus now commemorating its twentieth anniversary. It was founded by Mike Lenardo [Dr. Michael J. Lenardo]. It is an NIH based  graduate program in which American students get their doctoral degrees at either Oxford or Cambridge. But they also work at the NIH, so they're co-mentored by Oxford or Cambridge faculty and by NIH investigators. I'm the current Director of the NIH component of the program, and it takes about quarter of my time. I have a really talented staff that works with me along with an executive committee whose members share our passion for this program and our very bright students. The program has an amazing success record with many of our alumni in leadership positions in academia, medicine and industry.  

Harden:                         Are most of your students in this program English?

Sher:                              No they are American.

Harden:                         So they're Americans who go to England to study and then come back to do their research?

Sher:                              Not quite. The UK doctoral degrees do not require any course work. The students do half of their research there and the other half at NIH and are co-mentored. They get the advantage of both types of research institution and actually are allowed to design and form their own  collaborative research project between their 2 mentors.

Harden:                       Are    Are they graduate students or postdocs?

Sher:                            They   They're graduate students. There is also an MD-Ph.D component where they receive their MD from an American partnering med school and their Ph.D from our main program.

Harden:                         Where do they apply as undergraduates for their graduate program?

Sher:                              They apply to our program, and if they're accepted, they automatically get into Oxford or Cambridge.

Harden:                         That's very interesting. I didn't know about this program.

Sher:                              It's been going for about twenty years. I've been the Director for aboutthree about three years. It's really a pleasure to work with these very bright young scientists. We only accept about 10% of our applicants, and we're competing with all the major universities—Stanford, Harvard, etc. I think its fair to say that OxCam is the elite prestige graduate program at the NIH.  I took on the Director role as an older scientist, in part because I had more time to devote to it. The work involved is probably too time consuming for people who are in earlier stages of their careers. It's a trans-NIH program. It's not just for NIAID. There are people working everywhere, all over the campus. That's been another rewarding aspect, because I've been able to broaden my horizons at the NIH interacting with mentors and their students in many different institutes in addition to NIAID.

Harden:                        In addition to mentoring, you've served your professional societies and you've labored as an editor on the editorial boards of key journals. Would you comment on how you find the time to keep up with all this and what the benefits are?

Sher:                              Well, the main editorial job I've had over the years has been with the Journal of Experimental Medicine, which is an old and venerable journal run by the Rockefeller University Press. My uncle Lee, whom I told you about earlier, published his most important work in it, and I have published many of my own papers there. Serving as one of the senior editors for this journal took a lot of my time, and I lasted for about nine years. I'm still on the editorial boards of several other journals.  I was also greatly involved for many years with something called the Keystone Symposia [Keystone Symposia on Cellular and Molecular Biology] and served on their board of directors for three terms, which was also a very interesting and rewarding experience in terms of broadening my professional horizons. I’ve also organized (or co-organized) a lot of meetings over the years, and I'm the lead organizer for a Keystone Tuberculosis meeting in August 2022 that will likely be my last.

In assessing my own strengths I’d say that being interactive is near the top. What I enjoy most about research is its collaborative nature and putting people together to create novel discoveries.  Indeed, I like to think of science as the means that I, as a shy kid, found to socialize and build connections with people. It worked for me as my language, or to use a different, more colorful analogy, a musical instrument to play in the human orchestra. I’m so glad I found it.   

Harden:                        Reflecting then back to your desire in graduate school to use your expertise in immunology to do something relevant for humanity, how would you characterize your career to your younger self?

Sher:                              Directly, I clearly have fallen short of my idealistic, humanitarian goals. There are many disease interventions out there that I can’t claim to be part of. Yet indirectly, I would say that I succeeded because I've trained  a number of people who are making an impact. Indeed, as we discussed earlier, I see the mentoring and career building I have done as my main contribution and as something that I hope will be my legacy when I’ve left science.  As a young academic, I could have stayed with history or classics as my field. In fact, I still love history and devour books on it. But I seriously doubt that as a historian I could have had the same impact I’ve had as a biomedical researcher.

Harden:                         You have no doubt had numerous offers to leave the government and take a more remunerative position in academia or industry. But you have stayed at NIH. Would you comment on what keeps you here, despite all the rules and restrictions of a federal career? What has NIAID offered you that kept you here?

Sher:                            NIAID    NIAID has been terrific. Most of my time here, our institute director has been Tony Fauci. And I flatter myself by calling myself  “one of Tony's boys” (see photo of Tony giving me an award in the mid 80’s). I think he's an amazing leader and have enormous  respect for him. Although he's really much more clinically oriented than I am, he's still been good to me, forwarded my career and been there for me when I needed him. 

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While it is true that we have to deal with a lot of paperwork and administrative red tape, you quickly learn to put up with it, and it is certainly less burdensome than constantly writing grants. I say this knowing that preparing grant proposals does help you focus. And I have had a few small grants—those that I'm allowed to have while I’ve been here. But I doubt that I could survive now in the world of NIH extramural funding. As I mentioned earlier I only considered leaving NIH once (to return to La Jolla) but it was hard to give up all the advantages we have here.

Harden:                         What are your plans going forward?

Sher:                              I'm going to try to ease into retirement.  I have agreed to give up my research lab this summer and am considering becoming something called a re-employed annuitant. I will be able to work half-time with my current title and hopefully an office desk. I would be delighted if the lab resources I give up are used to support hiring of a new investigator for LPD. I have involved myself in a lot of mentoring activities and hope to expand this function in my new situation and be of help to NIAID in other areas where needed. In addition I still have a lot of papers to write with fellows who are finishing up, and perhaps I may even do a sabbatical—something I’ve never had time for previously.

Harden:                        These are all the questions I have. Is there anything else you want to get on the record before we stop?

Sher:                            No   No, except to re-emphasize that the greatest satisfaction I have as a senior NIH researcher is in my contribution to the careers of the wonderful people I have had the pleasure to work with in my lab. Its taken me a while to firmly grasp this, and it is nice to be winding down my career on such a gratifying note.

Harden:                         Thank you so much for this excellent oral history.

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