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Science and Sensibility: An Interview With Professor Rolf M. Zinkernagel

Science and Sensibility: An Interview With Professor Rolf M. Zinkernagel, Nobel Prize Winner for Medicine 1996

Interviewers: Hrishikesh Satish Kulkarni; Ajit H. Goenka, MBBS
Interviewee: Rolf M. Zinkernagel, MD, PhD

Science is perceived to be the panacea to many of the world's problems. No wonder then that scores of brilliant minds are busy applying time-tested scientific tools to find a sustainable solution to problems, such as HIV and tuberculosis — problems that may challenge the very existence of humankind unless they are reined in within time. In this context, when Rolf M. Zinkernagel, MD, PhD, the pioneering immunologist, suggests that the ultimate solution may not be through scientific research, it makes you sit up and listen.

Prof. Rolf M. Zinkernagel was awarded the Nobel Prize in Medicine/Physiology in 1996, along with Prof. Peter C. Doherty, for discovering the specificity of cell-mediated immunity. They conclusively demonstrated that recognition of microbial antigens by our immune system is possible only in association with self-molecules, known as the major histocompatibility complex (MHC). Unless the foreign antigen is coupled to an appropriate MHC molecule, the immune system will simply not recognize it. By a complex process of immune regulation (which works right from birth), the MHC helps our body to differentiate between self-antigens and non-self-antigens. This work profoundly influenced contemporary understanding of the mechanisms through which our body deals with microbes, cancer, autoimmune diseases, and other immune phenomena. In addition, it opened up exciting frontiers in vaccine development.

Prof. Zinkernagel completed his basic medical education in 1968 from the University of Basel, Basel, Switzerland. After initially taking up surgery as a specialization, he decided to change fields within a year and found his calling in basic and applied immunology. Although he initiated his research in Basel, he soon went to Australia in 1973 where he worked with Prof. Doherty on the mystery behind the recognition of virus-infected host cells by cytotoxic T cells. Within a year, the combined efforts of these brilliant young workers (Prof. Zinkernagel was only 30 when the first results were published) led to the fundamental discovery of MHC restriction in T-cell responses with the lymphocytic choriomeningitis virus. After a stint at the Scripps Clinic in California (1975), he returned to Switzerland in 1980. He is currently Professor of Experimental Immunology at the University of Zurich, Zurich, Switzerland, where he is working on the immune protection and immunopathology of viruses.

Hrishikesh Kulkarni and Ajit Goenka, MBBS, spoke to him on his work, life, and beliefs after his lecture on "Why Do We Not Have a Vaccine Against TB or HIV (Yet)?" at the 57th Meeting for Nobel Laureates and Students in Lindau, Germany, in July 2007.

Why Don't We Have a Vaccine Yet?

Dr. Zinkernagel, which arm of the human immune response has the potential to protect against diseases, such as HIV?

Antibodies. They are the key. The course of any infection depends on the host's response, and I believe that this has to be through antibodies.

Only antibodies? What about cellular immunity?

As long as a host adequately responds to viral infection (even if it is unprimed initially), it will survive. However, if the host responds inadequately, then the virus will kill it. Simply put, it is the response at that particular time that determines the course of the infection, and this is basically in the form of antibodies. Moreover, the antigenic shifts and drifts of influenza viruses have shown that induction of a T-cell response by one serotype doesn't protect the host from another, even if it is cross-reactive. Thus, it has to be the maintenance of neutralizing antibody titers that is essential for protection against such an infection. This is purely antigen-driven.

May we infer that the antigen is the sole regulator of the immune response?

Absolutely. However, a single dose of antigen isn't enough. Only the repetitive activation of the immune system by an antigen or its fragments can stimulate protective immunity.

Could something like this work for a chronic disease, such as tuberculosis?

Possibly. To combat an infection, one first needs to understand the host immune system. Our immune system is mainly geared to eliminate acute infections, such as poliomyelitis. It hasn't been tuned to eliminate chronic infections, such as tuberculosis and HIV — or malignancy, for that matter. That is why diseases, such as tuberculosis and herpes, resurface, especially in old age, when the immune system wanes. The solution lies in providing some form of continuous antigenic stimulation, by which we may be able to control these infections, if not eliminate them.

What about the role of regulatory T cells then?

In my opinion, there is no such thing as a regulatory T cell.

But people have spent their lives working on regulatory T-cell mechanisms! How do you justify such an argument?

I question the very role of T regulatory cells because the experiments performed to demonstrate them are so complex! Moreover, they depend on highly specific individual experimental conditions. Obviously, no second laboratory can repeat these experiments. In addition, we are barely able to analyze 2 modulating factors in their complex interactions. How can we possibly accept the myriad postulated pathways in these regulatory circuits?

HIV, SARS, multiple Drug-resistant tuberculosis, Ebola — the list is endless. We never had them until a few years ago. Why do we continue to grapple with all of these diseases despite our scientific prowess?

This is simply because the life span of human beings has far exceeded what it was intended for. The main function of human beings in evolution is procreation, which is usually completed by the 25th year of age. With our scientific prowess, we have prolonged our age, thus inviting a host of new diseases. I would add autoimmune diseases to the ones that you have mentioned. However, from an evolutionary point of view, this is perfectly fine. Most of the diseases affect man after the age of 25, by which he has procreated in any case. So it doesn't really matter if you die after then; your contribution to evolution is complete! The irrational behavior of human beings has also significantly contributed to the above-mentioned predicaments.

So, in a way, nature is trying to shift the mean age group back by a couple of decades through these diseases?

Yes. Biology has always been and still remains the driving and limiting force for human survival. In vitro fertilization may postpone the age limit for procreation, but this is not for general application. Therefore, I argue that the biological function of humans is basically over with at 20-25 years, and that is what nature is used to as well. Through the various balancing forces, it will always try to maintain the mean age around this.

But there has to be some lasting solution against the menace of HIV?

A virus such as HIV is too smart for us. It keeps mutating so that it can accustom itself to the human body, thus fooling our immune response. For any solution, we would have to fight this variability, this mutability of the virus, which I do not think is possible. In fact, I wonder whether it is even necessary.

Are you suggesting that we should resign ourselves to the onslaught of HIV?

Well, it's an onslaught only as of now. Look at HIV-2. In many parts of the world, the HIV-2 virus has found a way to live symbiotically in the bodies of human beings. This is the way that it was intended to be in the first place! It continues to be transmitted but rarely causes disease. It isn't eradicated, but it's harmless. Thus, it has become an ideal vaccine in itself — preventing reinfection by inducing a protective immune response. A few hundred years down the line, I see the HIV-1 virus adapting to the human body in a similar fashion. So we don't really need to eradicate it. By trying to eliminate it, we are actually compounding the problem!

You mean that we should just wait passively until HIV-1 decides to become symbiotic?

No. We can keep looking for better approaches. We tackled small pox and polio successfully because we were able to stop them at the first line of defense. For example, you know that HIV enters the blood through sexual contact and intravenous products. We have already succeeded in controlling a large amount of HIV transmission through screening during blood transfusions. The best way would be to stop the virus from entering the body itself by stopping unprotected sex or intravenous drug abuse. It's really quite simple.

Life in Basic Research

You did your pioneering work around 1973-1975 and received the Nobel Prize in 1996. What are the characteristics of a scientist that help him stay in the same line of research for his entire life?

In my case, the intrinsic need to know how things work has kept me going. The most important thing is to be a good, honest person. You must have a keen sense of self-belief and trust your results. In the end, the desire to solve a problem overcomes everything else. You just have to do it, no matter what or where.

We are given to understand that you had difficulty in getting a postdoctoral position despite applying to as many as 50 institutions. A disappointment of this magnitude could possibly annihilate even the most spirited aspirants.

That's just normal! You must realize that nobody is waiting for you. Why do we go to an institution? We do that to learn, to gain more experience and knowledge. Sure it was busy with all of the rejections because I had to keep applying without a stable position, but it was normal. Just set your goals; keep a straight mind; and address the principal question that you are trying to answer.

How about disagreements from the scientific community about your work?

Disagreement is normal. It takes some time for hypotheses and even results to be accepted. However, getting published in journals, such as Nature, does provide reassurance. There is an entire article on comments counterarguing the opinions that I had published in an issue of the Scandinavian Journal of Immunology. However, I am never worried about the hypotheses that I publish because many of these are testable.

Do you believe that being in big institutions ( such as the Ivy League institutes) enhances the prospects of one winning the Nobel Prize as against, say, being the head of a smaller laboratory early in your life?

There is no such standard rule, provided that you have the facilities needed to carry out your research. At the end of the day, you simply need to be lucky. You can get lucky in a small institution or a big one. When Peter and I were working on solving the problems of MHC-restricted immune T-cell recognition, the Eureka moment came in Canberra, Australia. It was so unexpected, so serendipitous, that the most important thing we did was not to miss it! Had we not discovered it, somebody else would have surely done so sooner or later. Discoveries can occur anywhere.

Does medical education equip one better to deal with the challenges of research?

You need both. Laboratory work teaches you to be more analytic in your approach. By studying medicine, you realize the importance of quality control, and can better apply it. If I were to advise a student, it would be better to get a basic medical background and then acquire molecular skills, for that's much easier. Also when you start off with medicine, the road ahead is wide open: There is a variety of paths that you can pursue.

Is it necessary to strive for international scientific exposure during one's formative years?

Definitely. Being in one's own geographic niche is not enough. For example, I went all the way from Switzerland to Canberra because I wanted to compare cell-mediated immunity vs antibody-effector mechanisms in infectious disease models, such as Salmonella and Listeria. These weren't available in our laboratory back then. Dr. Robert Blanden was already working on this in the Department of Microbiology in Canberra, so I joined him. After that, I met Pete, who was working on immune responses to the lymphocytic choriomeningitis virus. While he did the immunopathologic analyses with the brain and the cerebrospinal fluid, I could do the cytotoxicity assays with the prior experience I had from Lausanne, Switzerland. Through our work, we discovered MHC restriction. Moreover, I met some of the people who influenced my life the most during my stint in the Scripps Clinic, La Jolla, California. Science is one of the most international activities there is. It can never be restricted to a single laboratory or even a nation, if progress is to occur.

What advice would you give to students who are at the start of their scientific careers?

You have to make a choice to take big risks, or to safeguard yourself by earning good money. However, you can only make a significant discovery by taking risks, because you will have to go somewhere where no one has gone before. Everybody will give you advice, but I personally believe that once you reach the age of 16, you don't change. You just pick the suggestions that fit your character. You learn from experience. Pick out the advice that has worked for you early on, and leave out what hasn't.

Life After the Nobel

How does your life after the Nobel Prize compare with the earlier routine?

It really hasn't changed anything for me, but that is because I haven't let it. I admit that there is pressure to come out with better results. We have done more research on immunologic memory, the role of the immune response in autoimmunity, and the development of better vaccines for hepatitis B and C and HIV, but none of them are as fundamental as the discovery [of MHC restriction] in itself. Our work with MHC restriction gave a biological role to this system, which till then was only associated with transplantation. Even Nobel Prize winners do not get better with age!

What do you do to maintain your sanity amidst the stress of balancing fame, fortune, science, and family life?

I could have spent 350 days a year traveling and lecturing, but I choose not to. If this would change me fundamentally, it would have done so a long time back. You learn to deal with it.

What do you believe about Nobel Prize winners being invited to comment on or influence the political scenario?

Scientists have a social responsibility. However, one must understand the difference between politics and science. In politics, the reasons for implementing something are solely correctional, but science does not remain science when you want to correct science in itself. So you ultimately may end up where you didn't want to be originally. Moreover, a Nobel Prize does not make you an expert on every issue. For example, regardless of getting many propaganda letters, I only support those in which I have sufficient expertise.

On the Future of Human Health and Disease

Just where are we messing up in our approach to infectious diseases?

As I have earlier mentioned, most of the chronic diseases have resulted from the prolongation of man's own life and his irrational behavior. We must understand that it is not in the nature of microorganisms to kill human beings (take HIV, for instance), because, as viruses, they wouldn't be able to survive if they killed the host. This pursuit of trying to eradicate an infection may principally be wrong. Our objective to dominate nature has led to most of the problems like, say, antibiotic resistance.

Dr. Zinkernagel, not many of us will be comfortable with the idea of dying at around 25-30 years of age or, for that matter, not taking antibiotics for bacterial meningitis.

Well, that's what is in nature's best interests. Regardless, the fact remains that, with medical advancement, something like that isn't really going to happen and hence, we will keep suffering from such disease.

The answers to everything do not necessarily lie in science. We should concentrate more on improving the socioeconomic status of the population and the education of women. Second, we need to keep finding innovative approaches to the same problems. To research the hidden intricacies of nature, which has been working perfectly since ages, is something which I find most fascinating.

Which areas in immunology need more attention?

Basic research is not yet applied research. We need to start translating the laboratory work into clinical science as soon as possible. Nobody has really seriously considered the induction of an immune response with peptides. This may change with tumor therapy. Polysaccharide antigens are decisive in the pathogenesis of diseases, such as malaria and tuberculosis. These could be an area for designing vaccines. There are plenty of things in nature to explore, yet we know so little.

Which problems should be accorded a priority status?

The biggest problem is human behavior itself. No other problem comes as close. If we wouldn't smoke, overeat, or have as much alcohol, we wouldn't have most of our problems in the first instance. We are all too stupid for our own good. The sooner we understand that, the earlier we will be able to save ourselves.

Thank you, Professor Zinkernagel, for speaking with us.

It was a pleasure.

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