Abstract
Alan Sher, PhD, NIH
It was wonderful to see these people and hear about their successful careers. From the outset, I consider them to be my major accomplishment as a scientist, not my research itself. So, I am leaving my laboratory and research program with a very good feeling.
I worked on a pathogen called Schistosoma mansoni, which is a helminth parasite. It was a very good move for me because very few immunologists were involved in this kind of research. Moreover, the field suddenly exploded as people realized that parasitic diseases were still very important. At that time, there was a feeling that many other infectious diseases had been solved by antibiotics and vaccines, and we might actually see an end to all of them in the near future. But there were very few good interventions for parasitic diseases, particularly on the immunologic side. And so, I happened to be one of the few people in the field with solid training in basic immunology. That enabled me to get funding almost immediately when I set up my first independent research laboratory at Harvard.
I decided to go to the NIH in 1980 for a number of reasons that I will not go into. It was an excellent decision, because I really love this place. It is a very stimulating and collaborative environment. I was able to extend my research program, focusing on a range of different parasitic diseases. By then, I had worked on quite a number of them. In fact, over the years, I have worked on eight different pathogens, not just parasites, as I will go into in a minute. But the irony of my situation is that my work has not led to cures for these diseases, but if anything, I learned more about the immune system from studying them. So ironically, I wound up becoming a “basic” immunologist again. I realized immediately that studying infectious disease, particularly in animal models, could tell us some very important fundamental things about the immune system and how it works.
You asked me what particular discoveries stand out in my mind. The first would be work done with a postdoc, Phil Scott, now the vice dean of the University of Pennsylvania Veterinary School. Phil was studying Leishmaniasis and showed that the type of disease manifestation that Leishmania triggers in different mouse strains depends on the induction of different T cell subsets. This was when Th1 cells and Th2 cells were coming to the fore, and ours was one of the very first demonstrations that the induction of different CD4 T cell subsets could influence the outcome of a disease. It brought me back to basic immunology, especially T cell immunology. From there, I started to get involved in cytokine research, in particular, studying how T cell products of these different subsets could act to influence disease.
The next thing that became a major interest for me was interleukin (IL)-12, a new cytokine at the time. IL-12 was discovered by my colleague, Giorgio Trinchieri, who spent a year on a sabbatical with us. He helped Phil (now in his laboratory at Penn), and I demonstrated that the induction of Th1 responses in Leishmania, and later Toxoplasma, is highly dependent on this cytokine.
And then, perhaps even more important than that was work on another cytokine, IL-10. IL-10 at the time was thought to be produced only by Th2 cells, but that turned out to be wrong. It is produced by both Th1 and Th2 subsets. But the critical observation we made was that IL-10, by regulating the production of interferon-gamma by Th1 cells, plays a major role in dampening immunopathology and is thus host-protective. When people ask me about my “eureka” moments in science, this stands out as the major one. This “Eureka” occurred during the work of another very talented postdoc, Ricardo Gazzinelli, now the director of a new vaccine institute in Brazil, and an adjunct professor at the University of Massachusetts in Worcester.
We were studying Toxoplasma infection at the time, which induces a very strong Th1 response. We had speculated that a mouse unable to make IL-10 would cure the infection much quicker because you would be derepressing host-protective interferon-gamma production from Th1 cells. One day, when Ricardo came into the laboratory, I asked, “How's the experiment going?” He said, “Terrible, the mice are all dying.” But this unexpected outcome was, in fact, exciting as Ricardo followed up the observation to show that in the absence of IL-10, the T cells were overproducing interferon-gamma, resulting in immunopathology rather than more resistance against the disease.
This was my first exposure to the fact that cytokine regulation really can go in both directions—a delicate balance between mediating an effective immune response versus causing immunopathology. So, there is my eureka moment. We went on to do a lot of work with IL-10 in that setting. Another postdoc at the time, Dragana Jankovic, showed that Th1 cells can be induced to produce IL-10, and do so as an autoregulatory mechanism to regulate their own interferon-gamma production. In the case of Toxoplasma, this prevents immunopathology. In terms of work with parasites, I believe those have been my major accomplishments. Fortunately, Dragana stayed in the group and became a long-time colleague and collaborator.
Around the year 2000, I decided to switch to another field, mycobacterial research. The reason was 2-fold. One, I was very naive. I thought that in terms of their host interaction, mycobacteria would be like the intracellular protozoa I had studied, which they are certainly not. Although they both infect cells, they are very different pathogens with different rules. But two, in the back of my head, I wanted to work on a disease that had a much greater impact than any of the parasitic diseases I had been working on. And that disease was tuberculosis (TB). Among our contributions to that field, probably the most important has concerned the roles of interferon-gamma and type I interferon in regulating TB disease.
This was largely the work of 2 postdocs, Carl Feng, who is now a professor at the University of Sydney in Australia, and Katrin Mayer-Barber, who went on to get her own investigator position here at the NIH. In animal models, we demonstrated an association between type I interferon production and disease in Mycobacterium tuberculosis-infected mice. An association between the overproduction of type I interferon and TB clinical disease had also recently been observed in TB patients. Over the years, we have been working on this paradigm, trying to understand what triggers the decision between the production of these 2 cytokines and how type I interferon regulates this response.
When he was a postdoc in our group, Dan Barber (now a tenured NIAID investigator) worked on the role of PD-1 in TB disease. PD-1 plays an important role in dampening T cell function in a lot of situations, including tumors. But in TB, Dan showed the opposite function, in that PD-1 blockade in TB-infected mice makes the disease worse, not better. This is due to the T cells becoming more activated and more pathogenic. So, you can see that this flip-flop between protection and pathology has been a theme throughout our studies. To me, this is a core principle of the immune system. It is a balance, and you have to find that balance to maintain protection from both infection and disease during infection with these pathogens.
More recently, we have been getting involved in SARS-CoV-2 research using mouse models to study infection with this virus. We have been looking at whether or not BCG vaccination provides some protection against SARS-CoV-2 infection. We showed that this is not the case when the vaccine is given subcutaneously but elicits strong protection when given intravenously. The latter is not a route that is acceptable for human vaccination. Nevertheless, we have used this model to dissect mechanisms of protection against the virus that may have significance in designing other interventions.
When I was starting out, and Woody, you would remember this as well, there was something called fundamental immunology, which had been stripped away from disease immunology and evolved as a field of its own, with a lot of, how can I call it, intellectual elitism. Fundamental immunologists at the time would not work on immune responses to pathogens as they thought it was not in the realm of good basic science. So, they disconnected themselves from what is likely the primary function of the immune system, which was unfortunate. And I suffered from this when I started out at Harvard, because I was working on parasitic worms. People viewed our work as old-fashioned (I was in my 20s) since it did not address fundamental or molecular mechanisms. It did not have all the right buzzwords.
Later, I interacted with Bill Paul, one of my mentors here at the NIH. Bill was a great proponent of fundamental immunology, the title of his famous textbook, “Fundamental Immunology.” But Bill grew to appreciate the other side of this as well, using parasitic disease models in his work on the Th2 response. There is now a general realization that infectious disease immunology is very important, particularly lately, with all the work on COVID. Almost every fundamental immunologist I know is involved in some project with infection. So, I am glad to see that this transition has occurred, and I think it is good.
The good thing is that there is now a more global look at the immune system—not just focusing on one arm or another, but trying to tie it all together. And that is very complicated. I do not see myself as someone who really knows how to do that successfully. I am guessing that this approach has yet to produce anything that is remarkable in terms of an application. But this is the direction of the field right now. It is waiting to come up with something that will prove its worth.
In terms of what is new at the moment in the TB field, we are in an exciting period since, for the first time, we have vaccines that actually give complete protection. An important example comes from the work of my colleagues, Bob Seder and Trish Darrah at the NIH VRC, who have shown that intravenous BCG elicits essentially complete immunity in monkeys against TB challenge. So at least we know that there is such a thing as sterile protection, which, if we can duplicate in humans using other vaccine formulations, would result in the global control of this deadly disease.
So that is very encouraging. In contrast, understanding such mechanisms has turned out to be very difficult. Again, it may involve the interaction of multiple pathways and may give heterogeneous outcomes in different individuals if this vaccine is tested in humans. This variation in the host, and all the different manifestations of TB disease, makes the problem very complex.
Also central to our thinking now is the distinction between disease and infection. Is getting rid of infection the only means of preventing disease? The answer is almost certainly not. It is much more complicated than that. You can have disease with very little infection, and vice versa. So, understanding the connection of infection with immunopathology is another area I see as becoming very important. I also see the interface between the pathogen and the immune system as another critical focus, particularly in the field of immunometabolism, where you can have an element such as iron utilized by both the host immune system and the pathogen. How it is regulated can have a major effect on both the bug and the immune response to it. All of these are exciting new directions in the field. The challenge is there waiting for us.
I know you know this story, Woody, and I referred to this earlier. In the 1970s, the surgeon general was quoted as saying (although he did not say it quite like this) that “the world of infectious disease was over. Infectious disease, as a problem, was going to be a thing of the past for the human race.” He said this because of the advent of effective antibiotics and vaccines. Then, HIV came along and blew that idea out of the water. So, there is a big challenge to studying infectious diseases. They are not going to go away, and I see getting more young people interested in the field as an important goal.
I find this humanitarian crusader attitude somewhat lacking in young scientists these days. I do not know the explanation for this. Maybe we are not presenting the problems to them the right way. I was in a discussion yesterday with a group of young TB investigators who were starting their own laboratories, and I said, “What if we could send your postdocs to an endemic TB area in South Africa? We could take them through the TB wards in Cape Town and India and let them see the human impact of the disease they are working on.” I am guessing that would change the mind of many of them about the value of their research because what they are seeing now is just laboratory work. When they become postdocs and get offered jobs, many choose to go out and do something where it will be easier to produce high-profile articles, or go into industry to get paid better with shorter hours.
Indeed, there is now an exodus of young scientists leaving academia and going into industry. It is quite frightening. One of my former postdocs, now a Rutgers professor, told me that many of the graduate students in his department have already been recruited to jobs in industry before they have submitted their PhD theses. They are not even considering doing a postdoc. They are young, have families to feed, and see colleagues making much more money. Why would you want to go and be a postdoc working 10 h a day on a complex problem, and then fight your way through the system to get tenure at an academic institution? So, we need to inspire them about the humanitarian goals of basic research, in addition to its intellectual fascination and challenge.
So, we have a problem here. The drug companies feed on the basic science that is done in academia without working on some of the most pressing humanitarian problems. This is a bad situation. The answer is that we need to put more money into academic science, particularly in the area of infectious disease. Fortunately, the COVID pandemic has awakened a lot of people, and the successful development of vaccines has been a very positive thing. But unfortunately, the science is fading back now. Why work on new vaccines or new approaches when you have interventions that already work?
And so, in the Bill & Melinda Gates Foundation, they were concerned that vaccines that worked in mice would not necessarily work in humans, or that there was quite a different response. So, they said, “Well, we're just going to work on monkeys from now on. They're the only decent model.” And a lot of people, including my close colleague here, Dan Barber, subsequently set up monkey models. But they are still animal models. Obviously, they are an important intermediate between the mouse and the human. But I am reading an article of Dan's right now, in which he takes observations in monkeys and goes back into mice to examine the mechanism, because you cannot validate a mechanism in humans or monkeys.
So, the mice will always be there to provide the basic information we need about mechanisms. In the end, although the Gates Foundation was ready to throw the mouse out the window, they subsequently decided not to. And, of course, if they had refused to support work in mouse models, they would have done away with many young investigators, because none of them could afford to work on monkeys when setting up a new laboratory. Also, the mouse models themselves have become much more sophisticated. We now have humanized mice as well as outbred mice to study the issue of genetic diversity. At one time, inbred strains of mice were really important, because we could do adoptive transfers and get very reproducible results. Now this genetic uniformity is considered a bit of a handicap because humans are not inbred. So, incorporating that genetic diversity into our research studies is important.
Many of our colleagues now work with genetically diverse mice and are also looking at different ways to study the murine infection. For example, 1 colleague, Kevin Urdahl, whom I think you know, has decided to study mice given ultralow-dose infections, which better replicate the infection exposure of humans. He is getting some quite exciting results that look very optimistic in terms of the ability to define mechanisms. So, mouse research is alive and well. I would hate to see it disappear. And to be honest with you, I do not think it will. I think the criticisms of it are getting a little bit boring. We have heard the message before, and I believe immunology without mouse models would be quite handicapped as a science. It would be almost entirely descriptive. So, I certainly feel very strongly about this issue, and I know you do too.
I have other articles similar to it, which were very nifty little things at the time but never went anywhere. They got into good journals because they were then very original and “sexy.” So, to judge science, and what is important, by the journal name associated with the discovery is, I think, really bastardizing the field. It is made worse by the fact that the editors themselves are the ones who are picking out these topics. They are saying things like, “Ah, single cell analysis, that's got to be the way you do it immunology now. And if you don't do it, you're doing out-of-date science, or you're in some backwater.”
But single-cell and other “omics” research is very expensive. One young investigator from Ed Pearce's laboratory told me that she decided to take all of her startup money and just put it into RNA-seq analyses because she knew that she would be more likely to garner more high-profile publications from doing that than buying a centrifuge. She figured the centrifuge could wait, or she could use somebody else's centrifuge in the meantime!
The whole thing is being driven by the faddish mentality that is maintained by the editors. I am not saying all editors are misguided. I am just saying that it is often not just the scientists themselves determining the direction of the field. I mean, they are, in the sense of reviewing articles, but the fact that a high-profile journal such as Cell will probably reject 90% of the articles submitted to it without even seriously considering them is very scary. It means that 10% are probably being chosen by either the topic and approach or the authors' prestige in the field. So many other submissions are being overlooked because they do not have the right theme, or the authors do not have the right political connections.
It is very frightening to me, and yet we all do it. If we are looking at a job application, we go through the CV and say, “Oh, this person didn't have anything in any high-profile journals. So how can I support this applicant over another person with four Cell papers?” By definition, the person with the 4 Cell articles is better, and the work is better. So you either play this game or do not. One of my former colleagues says he refuses to play the game. He has got tenure now and only publishes his work in lower-profile journals (yet he is known for publishing excellent work). Of course, he is not considered a glamorous scientist because of that, but people respect what he does. So, I do not know what the answer to this is.
I also feel, and I have some evidence for this, that there are cliques of people who just review each other's articles with this “You accept my paper, I'll accept yours,” mentality. I am not saying it is all that way, but I think that this is very demoralizing for young scientists and others struggling to survive in the field.
Yet young scientists are told that they must have a high-profile article to get tenure. I see their work suffering from this. They will not write up their findings because they are waiting for that big result to give them that Nature article. Sometimes the big finding never materializes, yet the work they have done is very good. So, your future as a researcher is built on the backs of Cell, Nature, and Science, publications, and little else. It does not matter whether the work is good or bad; it is where it is published. I wonder what science would be like if we got rid of this attitude. I suspect it would be better.
When discussing an idea proposed by a young scientist, I will often say, “Well, I don't think this is going to work, but go ahead and try it, convince yourself.” They have got to be able to use their own creative minds, and you have to encourage that. And if you are a hands-on supervisor who controls every little experiment someone does, that person will not develop well. I think they need to get that sense of freedom. And I think that in the case of the people who say that their experience in my laboratory was important to them, each of their discoveries were not mine, they were theirs. I just steered them toward a problem, and they took over. So I am a hands-off kind of mentor and supervisor.
So, it should be evident from the previous discussion that writing is a critical skill in science. This reminds me of a colleague. C.C. Wong, a parasitologist at UCSF, who once told me, “For every brilliant Chinese scientist that you see publishing groundbreaking findings, there's just as many who are just as brilliant, if not more so, who failed because they couldn't write or speak English.”
So, I devoted a lot of time teaching my fellows and students how to write. And the joke about this, that many at the symposium recalled, is something called the “hot seat.” The hot seat was my trainee and I sitting in front of the computer screen (or later giant monitor) banging out their article, sentence by sentence. I seldomly just take somebody's draft and rewrite it for them. Instead, I help them to grasp concepts, put their ideas into clear English, and teach them all the mechanics necessary for creating a well-organized, readable, and interesting article.
My major goal is to get each trainee to think clearly, and state clearly what they want to say. So I will spend hours, even an entire day, working on someone's article with them. They are in agony. We have to eat a lot of junk food (chocolate, nuts, and pretzels) because we are nervous, struggling, and exhausted. We keep on snacking down; we get fat, and the hot seat gets hotter.
One of my ex-postdocs has a picture on the wall in her office in Brazil of the 2 of us in the hot seat, working on an article. It is a critical skill they have all had to learn. And those who did not learn it—I do not know how they survived unless someone else wrote up their work. Because if you cannot write good English, and particularly if you cannot put your ideas into clear sentences, you are doomed. If you submit an article with bad English to a decent journal these days, they will not even look at it.
The other thing that I do is to encourage people. You need to work on people's egos. I have grown to believe that research caters to manic depressives. Because the lows are so low, the highs are truly mind-blowing, and you feel so good when things work out after struggling so hard with them. Getting trainees to experience these highs is important in building their passion for research.
Sending young scientists to meetings is very important. I served for many years on the Board of Directors of the Keystone Symposia. One of the things that Keystone is good at is giving trainees from all over the world the opportunity to meet people, interact with them, build collaborations, and discover long-standing colleagues.
Another important challenge for young scientists is staffing their new laboratories. Learning how to select the right people, motivating them, and dealing with troublesome personalities can be one of the most difficult aspects of launching one's independent research career. They need guidance and support during their first few years doing this.
The final thing I will say about mentoring is that we all need mentors. My former institute director confessed to me that she had a mentor and would not tell me who it was, but she said, “I talk to my mentor about some of the same issues that you're talking about with me right now.” And she said, “You should have a mentor too. We all need at least one.”
I have been downsizing my office because I have to move into a smaller one. And I am looking at reprints of the >500 articles I have published. Will anyone ever look at these again, even the very significant ones? The answer is probably not, and that highlights another problem, by the way: ignoring history. Young people do not read historical literature, so they constantly rediscover and rehash things that are already known. My dad, who was a physical chemist, used to say, “What they should do, is just burn the literature every ten years, and it won't make any difference at all but will keep a lot of researchers in business.” We seem to be “burning the literature” heavily now, and I think it's a wasteful practice that ultimately hurts science.
In the end, the symposium that my colleagues ran in honor of the history of our laboratory reinforced for me that the most wonderful thing about my career has been simply the people I helped train and the fact that most of them appreciated the experience and remain excited about their work to this day. I am very proud to have this as a legacy!