Albert Lasker
Clinical Medical Research Award

An Interview with Sir Ravinder Maini
Interview by Peter Lipsky

Dr. Peter Lipsky, of the National Institutes of Health, spoke with Ravinder N. Maini before the Awards Luncheon. Maini comments on winning the 2003 Albert Lasker Medical Research Award and his work with Marc Feldmann.

Date of interview: September 18, 2003

Lipsky: Tiny, first of all I want you to know that we're all delighted that you've been awarded the Lasker Prize. We think this is a wonderful recognition for the work that you've done in bringing the anti-TNF therapies and the anti-cytokines concept to useful application for people with inflammatory disease.

I wonder if you could take us back to the 1980s, when you began this work with Marc. What was motivating you? What were you thinking about? What were the challenges that you saw that led you to begin this line of investigation?

Maini: I think the die was cast already in 1970s when I was a research fellow and became interested in soluble mediators of delayed hypersensitivity. I worked for some time characterizing the biological properties of these factors and trying to make sense of them in a clinical context, but it was premature. However in 1975, Dr. Dumonde, with whom I worked with at that time, and I conducted a trial of extractable transfer factor. You probably remember transfer factor. Jerry Lawrence from NYU had the idea that you could confer delayed hypersensitivity by injecting extracts of lymphocytes from tuberculin-positive patients into tuberculin-negative patients. Because it was known that patients with rheumatoid arthritis had a suppressed delayed hypersensitivity response, the concept that had grabbed my attention was that there were regulatory defects in the immune response in rheumatoid arthritis and these could be put right by biological therapy.

So in 1975 I ventured into a clinical trial of transfer factor in rheumatoid arthritis. Of course we didn't know the molecular entities that we were working with at the time, and they turned out to be much more complex than we thought. Later in the 1980s, there was a revolution in molecular medicine following the cloning of cytokine genes. And suddenly this mish-mash of soluble factors that I had been working with began to assume real shape and form.

It was in the mid 1980s that Marc Feldmann's and my paths crossed with the intent of a collaboration. Since we could work with cytokines as molecular entities, we began to investigate the features of the immune response in rheumatoid synovitis. We were encouraged greatly by the fact that we could access tissues from rheumatoid patients relatively easily, as by then our unit was able to perform arthroscopic biopsies from patients quite early in disease. In addition, we had surgeons removing grams of synovium by surgical synovectomy and of course artificial joint replacement surgery had come into being. So there was plenty of tissue to study, which pragmatically speaking was a major reason why Marc and I, with our shared interest in pathogenesis and therapy, were brought together.

Lipsky: And tell me, what was it like for the patients in those days? What was the clinical spectrum when you started your work? What were the challenges that you saw in taking care of patients with rheumatoid arthritis in those days?

Maini: When I was a young clinician in the late 60s, seeing patients with rheumatoid arthritis in wheelchairs was quite a familiar sight. So, in a busy outpatient clinic maybe half the patient population attending were physically disabled to a greater or lesser degree. Well, now that's completely changed. Even before the impact of anti-TNF therapy, which is relatively recent, we had begun to witness a very significant improvement in the quality of life that rheumatoid patients had gained from what we now call standard conventional therapy. So that's the biggest change in the life of patients.

The other change is in the practice of rheumatology. Since the 1960s, there had been a move away from physical therapy to medical therapies based on understanding the scientific basis of rheumatology. Because immunological phenomena such as the presence of autoantibodies and the presence of lymphoid cells in inflammatory response in the joints are features of rheumatoid arthritis, there was an obvious opportunity to try and understand whether these processes could be put right. Thus immunosuppressive, disease-modifying and anti-inflammatory therapies came along. Later the hypothesis that cytokines are likely culprits in disease pathogenesis became established and led to the beginning of our work with TNF.

Lipsky: And back in those days, you did something a little unusual—you formed a partnership with Marc, a basic scientist. Maybe you can tell us how that developed and how you've managed to maintain a working relationship for nearly 20 years.

Maini: I met Marc in the 1970s at immunology meetings when there was a much smaller community of immunologists. For example, at the first immunology congress in 1970 in Washington DC, you practically knew everybody there. But to cut a long story short, I got to know Marc and his work well in the mid-80s and realized he was a very dynamic investigator with super ideas. More importantly, I thought he had a very perceptive, analytical mind, which somehow resonated with my own interest. We both realized then, that with Marc's foot more deeply in basic science than mine, and with my one foot in the lab and the other deeply in clinical medicine, we could achieve more than either one of us working alone. And this expectation was reinforced by our subsequent collaboration, which was basically very positive and productive. We enjoyed working together. We had fun designing experiments with our colleagues and writing papers. As this interaction and synergy developed, our respect for each other developed.

And I think our personalities are complementary. As our friendship grew we could sustain and support each other at what could have been otherwise troublesome times. Our work wasn't always looking as if it was getting somewhere, and at times we were being stopped at various roadblocks when people thought we had come up with some fairly unusual ideas.

Lipsky: What were some of those ideas? What were some of the challenges in those days?

Maini: Well, the challenge that really confronted us arose from our concept that in a disease characterized by the very complex molecular mayhem that we call the immune and inflammatory response, involving many mediators and many different types of cells, the process could be regulated by one molecule: TNF. That was the heterodoxy that emerged from in vitro work that Fionula Brennan in our lab had done with rheumatoid synovial tissue. The experimental approach had identified that TNF appeared to regulate interleukin-1 production, for example, and also GM-CSF and interleukin-8. So it looked to us as though there was a molecular hierarchy to the system. Interestingly, the existence of this hierarchy has been largely sustained by subsequent clinical experiments and clinical trials, but was not readily accepted as sound evidence then.

Lipsky: So these results that were originally published in the Lancet were not universally embraced originally? In fact, as things get controversial in rheumatology, one might say this was an extremely controversial idea that out of this soup of mediators and cytokines, one could pick out one and that would be the dominating cytokine that was driving the production of many others. How did you deal with that, let's say, lack or skepticism in the community that this was indeed a valid idea?

Maini: Well Peter, I think we obviously progressed from the in vitro models to the in vivo model system, which further validated this concept. So what we needed next was proving the concept in humans because in the end, as you know, there is no substitute to actually doing the experiment in humans and proving the point. Thus by 1992, we were very eager to try and block TNF in rheumatoid patients by administering a TNF blocker. Now at that time, TNF inhibitors had been developed by at least two or three companies. One of them was a murine anti-TNF antibody, but we realized that a murine antibody wasn't the way to go. For historical record, I should mention that we did talk to a company in the UK that had made a humanized antibody for use in sepsis, and were told that they did not wish to venture into this experiment.

So it was a bit of good fortune that Jim Woody, who was a physician in the US Navy and had previously worked for his PhD in London with Marc, happened to become the Chief Scientific Officer of Centocor. Centocor had developed a chimeric (human X mouse) monoclonal anti-TNF antibody. And to cut a very long story short, Centocor was persuaded to give us enough to experiment on ten rheumatoid patients initially. And that's the beginning of the saga of the anti-TNF trials. Of course, we then had to do some soul-searching ourselves and clear our own thinking about the ethics of obtaining informed consent for doing such an experiment in patients. The safety of giving a large slug of antibody, viz. 20 mg/kg based on the dose calculations from the animal work, was larger than used in any indication for a chronic disease at the time.

I have to admit that we had thought that only proof of principle of the role of TNF could be explored by this method rather than developing a viable new therapeutic. So anyway, we were concerned about adverse events and decided to admit the first five patients to the hospital for the intravenous infusions of antibody. But we were greatly encouraged that the patients tolerated the infusions without turning a hair. And the hemodynamics didn't change. Moreover, they didn't experience a cytokine release syndrome that had been described with some other antibodies that had been used in research.

On the contrary, the patients started to tell us by the next day that they were experiencing a huge relief of pain, and it was as though a cloud had been lifted from their minds or a long-standing flu-like illness had disappeared over night. This was all very impressive, but we were well aware that we might be witnessing a placebo effect. So we thought that we had better treat another few patients just to make sure that this wasn't just a flash in the pan. We were of course sampling objective biological responses of these patients as well as studying clinical responses very carefully.

What emerged when we had treated 20 patients altogether was that not only were patients reporting subjective improvements in their symptoms, but we were documenting very obvious reduction in the swelling of the joints and of the tenderness of the joints. There was also improvement in function and mobility of patients. In some cases extremely striking improvement in mobility was recorded on video by us. Much more strikingly, there was a reduction in C-reactive protein and ESR blood tests within days. This finding told us that something biological was happening, and we then reasoned that this might be the result of an effect on the cytokine network. Hence we measured interleukin-6, which regulated acute phase proteins, and this showed a very dramatic reduction following anti-TNF therapy. Thus the data was supporting our concept of TNF being an important regulator of other cytokines.

The story from there on is fairly well known and led to the first placebo-controlled trial on an anti-TNF agent in rheumatoid arthritis. And here, I have to acknowledge that this was only possible because we had very good relationships with many European investigators. Which by the way, has been a very gratifying feature of this emerging story, since it lit a flame of collaborative work in Europe, which eventually extended into our relationship with North America with you and others.

And you know how much you and I have enjoyed working together on the validation of this therapy, which took several more years, from 1992 to 1998, to actually reach a level that satisfied regulatory authorities that we have a safe and effective treatment. Well, the network of scientists and clinicians working together, and talking to each other, went well beyond what Marc and I had started in a microcosm of our environment. It brought in many more academic people to focus on anti-TNF therapy and oiling the wheels of the whole machine and stimulated the pharmaceutical industry to become very interested. Many companies took up this investigation and amplified the whole process. And I think the whole concept went from a very early stage of ideas to in vitro and in vivo animal work to patients with two drugs emerging extremely rapidly as these things go.

The conclusion has led to the revolutionary idea that biologicals actually can be real therapeutics, rather than just instruments for validating concepts.

Lipsky: But I want to get back to 1989. I want to get back to that three-year period between 1989 and 1992. You and Marc had some data from bits of synovium that you had confidence in, but was not generally accepted. The timing was such that most of the pharmaceutical industry believed it would be hopeless to give a monoclonal antibody repetitively in chronic disease. But somehow or another you had an insight and a motivation and a conviction that this would have a big impact on rheumatoid arthritis, and you persisted despite some adversity. Maybe you could think about that time. It's easy in retrospect to say, it all just happened. But it didn't happen. You made it happen. And the question is, what was going on in your mind? What were you thinking about? What were the issues that you had to overcome in order to make this experimental result from bits of synovial tissue into a commitment from a pharmaceutical company to do something, which in those days was considered to be quite unusual?

Maini: Well, I think one can rationalize as to what happened. There's no doubt that probably both Marc and I are very dogged in our personalities. So given a bone, we will chew it until we're satisfied that we've done a good job. We'd gotten to a certain point of obtaining clinical in vitro and in vivo data supporting the hypothesis that we had developed; the only way of proving it was to get into the clinic. We were determined to do the key experiment in humans, the final experiment, to get the triad of data to support the hypothesis. And I guess our kind of persistence and the wish to complete something that we started was a very big motivation for us.

So I don't know at what stage in my career I learned that in research it wasn't sufficient to have an idea, because everyone has ideas all the time. But what's important is to develop the idea, and once the idea has developed into what you might call a realizable entity, you have to complete that process. And this need to complete what we had started, I think, was the biggest motivation. By the way, in retrospect, I think it's a lesson that probably all good scientists that have achieved something know about. No one taught me that. I have learned that completion of something that you start off is a very important part of what I call commitment to science. So we could have pursued many other projects at the time, but there was this thing niggling at us saying we've got to complete this experiment.

We've got a hypothesis, and until we complete it we can't take our eye off the ball. So we did take a risk, but I think we felt that this risk was worth taking. And I now preach the lesson to my younger colleagues, and I tell them that if you develop something new, then completion is a very important part of that scientific experiment. A lot of people start off with things and never finish them. I don't know if I answered your question, but I think that there was a desire to complete the experiment and not let go until it was done. And of course, as I said earlier, because it led to a successful conclusion, it assumed a momentum of its own.

Lipsky: When the first patient finally got anti-TNF in the hospital, you were obviously worried. What were your feelings when that first patient reported benefit?

Maini: Elation, followed by depression. Elation, because the result was so good; depression, because it looked just too good to be true. Here we appeared to have a phenomenon that was very striking, remarkably so, because suddenly the patients were reporting that something was working for them, which they had not previously experienced. Well, that was obviously elating, but then there was the realization that okay, this has happened, but this could be a placebo effect. How are we going to actually consolidate this knowledge? And soon it became apparent that one infusion wasn't sufficient, since within 6 to 8 weeks of the first infusion, which worked so dramatically, these patients' signs and symptoms had reappeared.

Thus it was obvious that this was a temporary suppression of the process, and that knowledge was depressing since repeated therapy would be required and might not work. So, we proceeded with repeated infusions, up to four times over one year. And when this was done, we were encouraged. Each time we gave another infusion, we saw the same effect, although in some patients the effect seemed to not last so long, which in retrospect was because they were probably developing antibodies to infliximab with accelerated clearance. But clearly elation predominated and was the driving force for continuing our work and persuading us that what we had embarked on was really worthwhile.

Lipsky: And let me ask you another question. It's now ten years later, the drug has been approved. More than half a million people are taking it for one indication of another. When you're alone late at night, what impact does that have on you?

Maini: Well Peter, I am really pleased that it has helped so many patients. I'm aware that we have not yet defined the precise indications for anti-TNF in rheumatoid arthritis and other diseases, and that in the future there are probably going to be more answers. For example, even earlier intervention than is customary at the present time may help outcome in a more definitive way. One of the things that was not at all clear in the beginning was whether this treatment was simply going to be controlling signs and symptoms of the disease, much like corticosteroids, or whether it was going to have a more profound effect on the disease process. Well, in the animal model work, we had certainly found protection of both cartilage and bone in joints, and now joint protection is proven in patients. But even that possibility was viewed by skepticism by the scientific community because the feeling was TNF may not be such an important cytokine in mediating structural damage, and that interleukin-1 may be more important.

Now I'm delighted that there are trials being planned by an international group, including yourself, that will address the essential question of what happens when you start treating very early indeed—and whether this will have not only a better protective effect and therefore preserve and restore health of these patients, but may actually even switch off the disease process, in at least some patients, more effectively than any treatment appears to at the present time. Hence, when alone at night, I think of so many questions that have still to be answered to get the most from anti-TNF therapy.

Lipsky: And what do you think of the challenges for the future in terms of anti-cytokine therapy or other targeted therapies for diseases like rheumatoid arthritis? Clearly the anti-TNF is potent, very effective, but isn't a cure. What do you think of the challenges? What's the next step in this field?

Maini: I think the next step is to achieve total remission of the disease and preferably with an intervention which is given over a relatively short term and then has a long-term effect. So rather like treating an infection with antibiotics, I think what we're looking for now in the treatment of rheumatoid arthritis is an intervention that is given, say, over 2 or 3 weeks and leads to a remission lasting months or years. That would be the ideal. Intellectually speaking, this is not a hard thing to envision, because basically rheumatoid arthritis is a disease of loss of homeostasis. And although the loss of homeostasis is working at many different levels, I do believe that there may be many more upstream critical cells or molecules, which will be good therapeutic targets; much like TNF is. TNF turned out to be somewhat downstream in the whole disease process. But of course in the immediate future, the next step may not achieve this ultimate goal. We may only be able to get to a point where let's say 100 percent of patients respond to ongoing chronic treatment, as opposed to about 60 percent of patients responding to the currently available anti-TNF therapy.

And whereas nowadays remissions with anti-TNF therapy, even with methotrexate co-administration, only occur in about 20 percent of the patients, it's not unreasonable to expect that other targeted therapies may achieve much better responses in a greater proportion of patients, but still require continuing long term treatment—rather like treating an elevated blood pressure of a patient long-term. I think we are not far from that. But the ultimate goal of cure is further away and will be more difficult to achieve.

Lipsky: Certainly one aspect that has been achieved with the identification of anti-TNF is the idea that many things can be specifically targeted and that these might have a benefit. Which do you think of the ones that are the most likely to have a significant impact, or their combinations?

Maini: It seems to me that the link between the immune cell and the inflammatory cell is still an area that needs to be elaborated. Already there are hints that either blockading T cells or B cells, which in a sense are proximal to the cytokine inflammatory pathways, in combination with anti-TNF might be the way to go. We had done experiments between 1990 to 1993 in animal models, where we could show that combination of T-cell blockade and TNF blockade together was much more effective than TNF blockade alone. That hasn't yet been tested in man properly and should be done.

And although some anti T-cell therapies and anti B-cell therapies are in the pipeline, what hasn't been done yet is testing a combination of more than one defined target. Since rheumatoid is a complex disease, it is likely that more than one target needs to be addressed at any one time, and combinations are the way forward. I personally have reason to think from experimental data that the combination of T cell and anti-TNF is the way to go next. But exactly which combination provides the safest, as well as the most effective route is the dilemma—because of course if you disable not only an innate response molecule like TNF, but also an adaptive response mediated by a T or a B cell, infections could become more of a problem than they are with anti-TNF alone.

By the way, we have to start to dissect the non-adaptive functions of T and B cells, because although conventionally we have believed that these are the adaptive immune cells, it's very apparent that both T cells and B cells and for that matter NK cells act both in the adaptive and the innate immune response and that adaptive and innate responses interact with each other. So the original concepts of a dichotomy of innate and acquired immunity are way too simple. Thus it may be possible to dissect actions of the T or the B cell in such a way that you blockade the specific function that activates the cytokine cascade without compromising host defense. Feldmann and Brennan have such preliminary data.

Lipsky: Now one of the things that's happened as a result of developing the anti-TNF therapy is that socioeconomic status now has a major impact on treatment of a disabling disease. And certainly in many parts of the world the use of these drugs is highly limited or completely restricted based upon the ability to pay. Do you have thoughts about that?

Maini: Yes. It really came to my notice very forcefully when I was giving some lectures in India last year, where I understand that the total number of the Indian/indigenous population that has been treated with anti-TNF therapy doesn't exceed a few hundred patients. And the inequity of unequal access is of course reflected in the rest of the world, even in Europe. In certain European countries, the penetration of anti-TNF therapy despite its licensing is quite low for economic reasons. There is an urgent need for us to address how this can be put right. The problem is not peculiar to treatment of arthritis of course, and we've seen it with AIDS and with other infectious diseases. The developing world doesn't always get a look in with important advances that are occurring in medicine.

And I don't know how you solve it, but obviously one way is to have concessionary prices for the developing world. Clearly technology does not limit production of anti-TNF inhibitors. Basically it is a pricing issue, and at the Kennedy Institute we are quite interested in looking at the possibility of other options that might be exploited, such as producing an anti-TNF agent locally in these developing countries.

Lipsky: Let's go back for a minute 45 years or so. You're a young man. You're in the university. You're deciding on a career. What led you into medicine? What led you into academic medicine? What led you into arthritis research? What were the things that propelled you in this direction?

Maini: Well, there were a series of events in my life that determined the path that I followed. Already when I was a child I knew that I wanted to be a doctor. I grew up in East Africa and was quite a sickly child. My parents moved from Kenya to Uganda when Uganda was still a very unhealthy place to live in. So in the 1940s, I experienced malaria and typhoid, and many other illnesses that in those days were endemic. And the experience of being unwell as a child certainly made me determined to become a physician, in a family that had produced lawyers. Well, I wasn't discouraged, but I must say that my father was a bit surprised when he realized that I wasn't going to follow his footsteps in law. To cut a long story short, I was successful in gaining admission to study medicine in Cambridge.

Cambridge in the middle 1950s was witnessing a huge scientific explosion or molecular revolution. Some people think it began there. Crick and Watson had done their DNA work; insulin and hemoglobin structures were being worked out. So it was an exciting for an undergraduate to study natural sciences. And I think that the seed of an inquiring mind was sown there and stayed with me and germinated later.

I have to say that at that early stage, I never thought that I would embark upon a career based in experimental medicine. At the time I was only too anxious to become a caring physician and get on with doing my clinical attachments and learning how to be a practitioner. However, when I was at Guys Hospital in London, doing my graduate studies in clinical medicine, I was very fortunate to gain mentors who were deeply committed to experimental medicine.

So at Guys, I grew up with the idea that we are quite ignorant in understanding mechanisms of disease. Initially I became very interested in cardiology because that subject was taught well, and I thought I wanted to be a cardiologist. But after I had qualified and spent a couple of years working in a cardiology department, I realized that the discipline was very mechanical and unlikely to engage my interest for a lifetime. It dawned on me that I was much more interested in biology. And in those days, biology was really making an impact on immunology.

Medawar had published his very interesting experiments in transplantation and Gorer at Guys was working as a transplant immunologist. For a time I thought I might embark upon a fellowship in transplantation immunology. But, you know, one's influenced very much by one's mentors and where you happen to find yourself in a formative period. This directed me to clinical immunology and rheumatology.

Following an internship in internal medicine, I happened to gain a fellowship working with Dumonde at St Mary's and later at The Kennedy Institute in London. And that was the period when soluble mediators of delayed hypersensitivity had been identified by people like Barry Bloom and John David. I became fascinated by lymphocyte biology, and realized that rheumatology provided a unique opportunity to investigate immunological questions. So the paths of rheumatology and immunology then converged. And that's how it went on.

Lipsky: And during your development, have there been role models, mentors who particularly had an influence on the path that you took?

Maini: Yes. My first role model was John Butterfield, who was the professor of medicine at Guys Hospital. He was a diabetologist who combined a flare for excellent clinical medicine with investigating insulin resistance. I was a student on his firm, and was very deeply influenced by the way that he was able to combine the role of a caring physician, yet motivated to carry out research by remaining skeptical in terms of the knowledge that existed in understanding the pathogenesis of diabetes. Nobody wanted to work on diabetes because you could treat it with insulin. And there he was saying, "Actually, that's not enough. We need to understand what diabetes is, because there's more to diabetes than treating with insulin." Well, that stuck in my mind as an attitude to the understanding of rheumatic diseases that I became interested in later.

Others who were exciting my interest in the clinical description of rheumatological disorders included people like Eric Bywaters and Tom Scott in the UK. I worked with Tom as a young trainee when he himself was a young and dynamic rheumatologist at the Kennedy Institute. Your ex-mentor and chief in rheumatology, Morris Ziff, whom I met as a fellow, was influential, too. He lit my imagination and made me realize that immunology was an important scientific discipline which was the key to understanding rheumatoid arthritis. And it progressed from there.

Lipsky: And what are your views on the future of rheumatology research? Is it secure? Is there a pipeline of young Tiny Mainis who are going to pick up the mantle and continue to make progress? What are your thoughts about this?

Maini: I think it's in crisis, actually. This is a problem not only facing rheumatology but academic medicine as a whole. The demands that are put on our young physicians to be excellent bedside clinicians does not allow time or easy compatibility with also being a first-class investigator in the laboratory, which is the model that I grew up with. It seems that nowadays trainees who wish to achieve excellence in the clinic are unable to run a lab as well. And the combination appears to create real problems—for example, in getting grants. A clinician is basically jumping from a much higher point to achieve parity with a PhD who has no clinical responsibility. A PhD can devote his entire time and focus on gaining grants and recognition and publications, which of course require time and energy. The clinician is having to fit all this and more into his complex and busy clinical life.

So I think that there are a lot of impediments for a clinician to gain a credible laboratory presence. But I do think that the opportunities are there, because it is possible to apply basic scientific principles to physiology—and therefore to be able to develop not only a laboratory program, but a linked translational clinical research program. Once upon a time, there was a dichotomy between the laboratory program and the clinical program in immunology, but now it is possible to marry them. I do think that you have to work in a big enough team in an excellent environment.

Coming back to the partnership between Marc Feldmann and myself, I believe that our partnership has taught us some general points which are useful for investigators in the future in engaged in translational research. For a start, a clinical investigator has to have training in a basic scientific subject, to give him the knowledge, credibility and standing in the scientific world. But to succeed in translational research, there has to be a significant partnership with a scientist who is in the laboratory full time. This ensures that the clinical scientist standing on the bridge between the lab and the clinic is not worrying about the quality and integrity of the day-to-day work in the lab. By adopting this approach, it is possible to ensure that the bench in the back room and the clinic in the front room are secure and working in harmony. So teamwork is an essential component. More and more it has become necessary for people to work in groups and networks. Our anti-TNF experience has also illustrated very importantly that Marc and I weren't the only people that were responsible for bringing the work from the lab to the clinic, but many other people within our institution and externally were involved.

For example, other clinicians and other scientists on whom we depended either for the published work or concepts before our ideas and program of research developed. After all, we didn't clone TNF; someone else did. We didn't make the lab reagents or therapeutic antibody; someone else did. We didn't do the trials on our own; many other people were involved with the trials with us. So you do need an enhancing environment to succeed. I think the important development that has occurred in your and my time is that the macro-climate of collaboration across national borders has come along fantastically well. People now know each other very well across a big community. The European-American exchanges and working together are a reality and create an environment for people to work more effectively in a micro environment of their own.

The possibility of amplification and good ideas taking off is much better than before. I'd say to the young people that there's a terrific opportunity out there, but recognize that you alone can't achieve any big breakthroughs. Success has to depend on teamwork and collaboration. How you manage the team psychology as well as retaining leadership and creativity of the many people that get involved are issues that need to be understood. And I think a lot of give and take is needed here. You have to trust people. They have to trust you. You have to give generously to receive something back. These are realities that have certainly helped my career, and I think they are there for anybody else to take.

Lipsky: So now you've achieved this wonderful prize. You've had the opportunity to see a scientific idea develop into a clinical intervention that's remarkably successful. And now you've also stepped down as the head of the Kennedy Institute. What's next for Tiny Maini?

Maini: I think that my role now is to continue to catalyze the next generation's work, and I very much value the prospects that there are for the current and the next generation. I hope I can help both in the microenvironment that I still work in, at the Kennedy Institute, and with my external relationships. The Institute has been kind enough to give me an office and a secretary, and I attend lab meetings and contribute to discussions. Ask the right questions, I hope, and take some young people, especially clinicians, who are developing careers, under my wings. I hope to make them understand the long haul in front of them and what they have to do and how to do it. Perhaps I will be able to contribute more deeply to a research project that has not yet developed, but for which opportunities will arise.

I no longer have the responsibility of administration, so I can take on new things that I couldn't for the last few years. But one thing that I have realized is that I shouldn't run a lab anymore, because my technological expertise is no longer up to date. So I really have to rely on people who have the molecular tools available and skills to be able to use them. But I believe the questions they have to ask and how to apply them to clinical medicine is an area where I feel I can still continue to contribute. At our institute we are becoming interested in osteoarthritis, and we still have new thoughts on completion of rheumatoid arthritis projects. I'd like to be playing a small part in facilitating these projects and exploiting their potential rather than leading them at the bench. That's how I see my position now.

Lipsky: Well, we're certain that whichever direction your career develops, you'll be remarkably successful and remain a real role model for physician scientists. I've enjoyed the opportunity to have this conversation, and on behalf of all of your colleagues, dear friends, and on behalf of the many, many patients who have benefited from this therapy, our heartfelt congratulations on winning this award.

Maini: Thank you, Peter.