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诺贝尔奖获得者Bruce Beutler和Kurt Wüthrich访谈

已有 4128 次阅读 2013-12-10 22:32 |个人分类:读-思-拾|系统分类:人物纪事| 诺贝尔奖

每年的12月10日,诺贝尔奖颁奖典礼在斯德哥尔摩举行。2013年的颁奖典礼将在瑞典时间今天举行。值此之际,PeerJ对两位诺贝尔奖获得者(2011生理学或医学奖获得者Bruce Beutler,2002年化学奖获得者Kurt Wüthrich)进行了采访,请他们谈谈自己的研究历程、对相关学科领域发展的看法、对年轻科学工作者的建议等。建议大家一读。

Professor Bruce Beutler was one of the three recipients of the 2011 Nobel Prize in Physiology or Medicine for his discovery of the first mammalian receptor protein of the innate immune system. The receptor, called Toll-like-receptor 4 (TLR-4), activates the innate immune response—the body primary line of defense against pathogens—upon detecting a bacterial product, called lipopolysaccharide (LPS).

PJ: What drew you into immunology and genetics?

BB: I began to get familiar with genetics during the early 1970s, in the lab of Susumo Ohno at the City of Hope Medical Center, and in the lab of Daniel Lindsley at UCSD. Ohno was also strongly interested in immunology, and I first learned to use immunological tools and methods with his group. All MDs learn (or should learn) quite a lot about both genetics and the immune system in the course of their training, and I certainly did. I also remember wondering about the nature of self/non-self discrimination long before college, and discussed it quite frequently with my father (Ernest Beutler, also a biomedical scientist). But it was quite by chance that I became a practicing immunologist. I was drawn into immunology by isolating tumor necrosis factor, and by my realization that TNF was a key executor of innate immunity. This occurred during the early 1980s. My use of genetics as a tool to understand immunity began in the 1990s. I felt there was no other way to identify the Lps locus in mice, and I viewed this locus as the key to understanding how endotoxin was sensed by the immune system; possibly the key to understanding all microbe sensing.

PJ: Could you tell us a bit about your current work? What is the goal of the Center for the Genetics of Host Defense?

BB: We are engaged in the systematic destruction of the mouse genome by random germline mutagenesis. Every protein-encoding gene is being altered by a series of point mutations induced using the alkylating agent ENU, and those mutations are being brought to homozygosity. At present, we have banked nearly 80,000 ENU-induced mutations that alter coding sense, and we hope to produce more than one million in all. Concurrently, we monitor the effect of each mutation on multiple aspects of the host immune response. In that way, we plan to identify all genes essential for antibody response, an innate immune response, antiviral defense, tissue repair, and other phenomena that contribute to our survival in a world filled with microbes. We are also able to exclude most genes from consideration. Having a “list of parts” of the immune system is a necessary step toward mechanistic understanding. The Center for Genetics of Host Defense will build upon the classical genetic approach just described to achieve mechanistic understanding, by incorporating strength in cell biology, structural biology, and biochemistry.

PJ: In your opinion, what are the biggest unanswered questions in your field?

BB: There are many. Less is known about the immune response than we would like to admit. Why are we tolerant to self when many self-reactive lymphocytes escape central tolerance mechanisms? Conversely, why do some individuals develop autoimmune diseases, and how can we best intervene? Why is there such a vigorous reaction to allografts in the complete absence of microbial stimuli? What does it really take to activate an adaptive immune response (most innate sensing pathways, at least individually, seem to be quite dispensable)? Are there innate immune sensing mechanisms and signaling pathways that have yet to be discovered? In almost every area of immunology, much remains to be clarified.

PJ: What influences have shaped your research?

BB: The unbiased quality of genetic research, and firsthand recognition of its power to enlighten where hypotheses had failed to do so, had a strong influence on me. Adopting genetics was a major turning point in my career.

PJ: What do you see as the major changes in the field since you started your career?

BB: When I began my career, much had been inferred about the transmission of genes, and remarkably, the genetic code had been solved. Nonetheless, there were huge technological barriers to progress. We couldn’t sequence DNA except by way of an RNA intermediate. We didn’t know how many genes there were in mammals or in any other species. DNA had not yet been cloned.  In immunology, we didn’t know the function of MHC proteins (Ohno speculated that they served as anchorage sites for organogenesis-directing proteins). We didn’t know the nature of the T cell receptor, nor anything about how diversity was generated in the adaptive immune system.  So in many ways, it was a very different world.

However, there was a tendency to look at what we did know (antibody structure, for example) and pride ourselves on those accomplishments. In point of fact, westill know rather little about the immune system. And we still tend to be smug about what we do know, though all the while, there are tough challenges to be addressed.

It must be said that there have been unimaginable technological advances since I first began working in the lab. I would never have dreamed that we’d be sequencing DNA at the present rate, nor identifying mutations almost in real time, nor cloning mice, nor making conditional knockouts. These changes have opened doors that were formerly locked. So many, in fact, that there are opportunities in abundance.

PJ: Were there any challenges or difficult times that you had to overcome before being awarded the Nobel Prize?

BB: There most certainly were. The work that won the Nobel Prize was the toughest I ever undertook. We needed to find the cause of a phenotype that could only be loosely confined by genetic mapping, to a critical region several millions of base pairs in length. And in those days, we might sequence only a few thousand base pairs of DNA each day, working by hand. Few of my colleagues felt that we were on the right track, and even today, scientists who never attempted positional cloning can’t begin to understand what a commitment it entailed. Howard Hugues Medical Institute, which provided the bulk of my funding, grew impatient and decided to de-fund my lab just as we were on the cusp of a great discovery. The pressure was intense. At the same time, perhaps partly because of its difficulty, the search for the Lps mutation was addictive and thrilling.

PJ: What impact does the Nobel Prize have on your day-to-day life?

BB: There is broad admiration for our work, both on the part of scientists and the public. And at last, we can perform long-term research, which as I described, is aimed at the discovery of new molecules needed for the immune response. This has been the most important change. Beyond that, the accolades have not ended, and there is certainly a warm feeling left by the Prize.

PJ: Is there a downside to being awarded the Nobel Prize?

BB: There are some new obligations. There are an enormous number of invitations one cannot accept, and opportunities one cannot pursue. But the downside is quite trivial, and far outweighed by benefits.

PJ: What keeps you motivated in your work?

BB: The lure of discovery is paramount. The feeling of satisfaction at seeing a new phenotype, and finding the causative molecule, has never left me. This tends to happen more and more frequently, and motivates everyone in the lab.

PJ: Do you always think and behave scientifically?

BB: Like all normal people, I have an active emotional life. Maybe unlike most people, I tend to be a rationalist even when it comes to my own emotions. Why do they occur? What is the basis of semantics as opposed to symbolism? To be sure, science pervades all aspects of my life.

PJ: What did you learn from your mentors?

BB: I have had many mentors over the years. It might surprise you to know that I don’t hold all of them in high esteem. In fact, some served me best by providing models of what not to do, or how not to behave. Of those mentors who were the best, I would summarize that they taught me a great deal, and I am grateful to them. But it never suffices merely to learn from a mentor, or to imitate one’s mentor. One must try to surpass one’s mentor. And the best mentors are always deeply pleased when this happens.

PJ: Conversely, how do you try to mentor your students?

BB: I try to lead students by example. I take a deep interest in what they are doing. And I encourage them to work quite relentlessly to solve problems. I find that one learns most from actually doing work in a field; far more than by reading about that field, or discussing it.

PJ: In your opinion, which of your qualities helped you in your career?

BB: Tenacity was one important quality. I did not give up when things were tough, even though there were voices that told me to do just that. And “scientific taste” was another. I believe that on several occasions, I recognized which questions were critically important long before others did.

PJ: Do you have any advice for researchers who are just starting in the field?

BB: Pursue a career in science for the right reason: because you have a true fascination with the natural world and wish to answer difficult questions. Moreover, be sure you get a sense of satisfaction from doing so. Once this decision has been made, be prepared to work very hard! Relying on your scientific taste, pick a question you deem important. In approaching it, be honest with yourself and your colleagues. Never try to “prove” a hypothesis, which amounts to trying to make the shoe fit. It’s best if you can avoid hypotheses altogether, using an unbiased method to tackle the question you’re asking. Don’t try to attack too many questions at once. A single question would be best if you want to make deep inroads. Be an effective writer and speaker; nobody gets far without a strong ability to communicate. And finally, be brave. Don’t agonize about the possibility of failure. Very likely you will fail. If so, dust yourself off and try again.

Professor Kurt Wüthrich was one of the three recipients of the 2002 Nobel Prize in Chemistry “for his development of nuclear magnetic resonance (NMR) spectroscopy for determining the three-dimensional structure of biological macromolecules in solution”. Biological macromolecules—the DNA, proteins, sugars, and lipids—make up all the important structures of the cell, but they are much too small to study under a microscope. Determining the structure of these macromolecules through NMR was pioneered by Wüthrich and allows scientists to “see” what they look like, to study and probe their structures, and to design drugs that inhibit them.

We talked to Professor Wüthrich over the phone right before he left for the Nobel Week in Stockholm.

PJ: What drew you into structural biology?

KW: My way is unusual because. I studied sport at the University, and I was teaching in high school for five years, early in my career. Then, it sounds a bit strange maybe, but because I was in sports, I was interested in oxygen uptake. So my first work in structural biology was with hemoglobin. That work attracted so much interest that I could no longer consider teaching in high school. I have never studied biology. I studied chemistry, physics and mathematics, where I have University degrees in addition to the sports degree. Hemoglobin was also attractive because it contains metal-ions. It all went very well together, considering that my Ph.D. degree is in inorganic chemistry.

PJ: In your opinion, what are the biggest unanswered questions in your field?

KW: There are many unsolved questions. The most important unsolved questions have probably not been asked, because if they were, somebody would long have jumped on it.

PJ: Were there any challenges or difficult times that you had to overcome before being awarded the Nobel Prize?

KW: We did not fortunately have major problems getting funded, and it was not too hard for me to get jobs. It was a matter of good luck to have been in the right place at the right time, trying to do the right thing, first alone, and then with the right students and collaborators. One thing was very important:  I was always in the very best places to work, such as at UC Berkeley, Bell Telephone Laboratories, and the ETH Zürich. It is very important that one is in top places for work.

PJ: What did you learn from your mentors?

KW: At UC Berkeley, I worked with Professor Robert E. Connick. He taught me discipline in science, and he taught me how to write papers. He was a very strict person, not accepting anything vague. He wanted facts, and that was a very important lesson for me.

PJ: Is it what you’re doing with your students? How do you try to mentor them?

KW: Well, on the one hand I try to let them do their thing without interfering too much.

On the other side, I am not afraid to put pressure on them if I feel that it is needed.

PJ: What keeps you motivated in your work?

KW: I’m curious! There are so many problems to solve! It is also nice to work with young students. Currently, I have a very young research group. Most of my students are only 22-25 years old. They are just starting their Ph.D. or finishing their master education. This is a very nice situation.

PJ: Do you always think and behave scientifically? Is Science always in your head?

KW: [Laugh] I’m afraid it is! Even in the most unlikely locations! I might be asleep and wake up with some great ideas on my research.

PJ: In your opinion, which of your qualities helped you in your career?

KW: I think I am able to identify good problems that I then try to solve. This is certainly important. And I am curious, very curious, in many different ways.

I have learned in sports to accept defeat, and to resume with increased effort after a defeat.

PJ: Do you have any advice for researchers who are just starting in the field?

KW: They should always do something that is fun for them, or that they feel that is fun. They should not work for superficial results, such as getting a prize. Such an outlook would make anyone unhappy.

We are grateful to Prof. Beutler and Prof. Wüthrich for taking the time to participate in this post and we congratulate the recipients of this year’s awards.




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