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Wüthrich, who is The Scripps Research Institute (TSRI) Cecil H. and Ida M. Green Visiting Professor of Structural Biology, member of TSRI's Skaggs Institute for Chemical Biology, and Professor of Biophysics at Eidgenössische Technische Hochschule Zürich (ETHZ), Switzerland, spoke with Endeavor magazine shortly after the prize was announced.
Many people have described your accomplishments recently; I was wondering if you could describe, in your own words, the work for which you were awarded the Nobel Prize.
Well, we succeeded in establishing one-to-one relations between the individual peaks in the highly complex NMR spectra of proteins and the individual atoms within those proteins. This was the turning point in the field of NMR with proteins. From there on, the avenue was outlined for obtaining de novo three-dimensional protein structures. Getting sequence-specific NMR assignments in the early 1980s was about equivalent to solving the phase problem in x-ray crystallography by heavy atom replacements in the 1950s.
How important was it that you were recognized both for the technology and for the structures which you solved?
This probably reflects quite faithfully what happened. It was very important throughout the last three decades that our efforts in methods development were always guided by open questions that arose from working on interesting biological questions. The methodology to entertain these questions was often not available, so we were again and again motivated to return to methods development. Of course, I like to work with physicists on methods development. I also like to work with mathematical physicists and specialists in informatics to develop the software that is needed. But it was important that these activities did not turn into a hobby, and that our methods development was, at all times, guided by the need to solve yet another biological problem.
As a graduate student today one often hears the advice to "choose a system" rather than a technology. But you chose a technology and applied it to many systems through the years. Do you think the same choice would be wise today?
I think both choices can be the starting platform for a highly rewarding and successful career. Although focusing on a particular technique and on developing this technique further and further may appear to be a very limited project to pursue for a lifetime, I have, by the fact that we applied the technique in many different fields, had the chance to also gain knowledge and experience in biology and the biomedical sciences over the years. We would solve an important problem in immune suppression, and I would find myself a featured speaker at medical conferences on the subject. Or we would solve the structure of the homeodomainDNA complex, and I would be a featured speaker at cell biology conferences. Then we would solve the structure of prion proteins, and I would find myself speaking to politicians, nutritional scientists, and again to medical doctors. This is all, of course, in addition to participating in specialized NMR meetings, since NMR is the trade that we bring to these other disciplines.
Describe the moment when you realized that you would be able to solve a structure with NMR.
Well, this moment extended over a few years. I started NMR with proteins in 1967, when there were fewer than 10 papers in the field. About seven years later, in 1974, there were about 500 papers, but I felt that we were not making progress. At that point, I wrote the monograph, "NMR in Biological Research: Peptides and Proteins." The field was still so small that I could review the entire literature. And, by that, I recognized that we could not possibly ever solve a protein structure with the attempts that had been made--in my labora-tory or in the others active in the field at the time. About a year after I had published this book, we worked with what is called the nuclear Overhauser effect (NOE). This is a physical phenomenon that depends on dipole-dipole couplings between individual nuclei and which obeys different rules in large molecules, which tumble slowly in solution, as compared to small molecules, which tumble rapidly. NOEs had previously been employed on a limited basis, and mostly with small molecules. The results that we obtained in 1976-77, using nuclear Overhauser effects, made it clear to me how we would determine de novo protein structures in solution.
Thus, while there is little mention of NOEs in my 1976 book, which was written in 1974-75, two years later it was clear to me how solving structures using NOE could be done. We actually went a long way with this in 1978, using the then-available one-dimensional NMR techniques. We were just doing bits and pieces of structures, but it was clear that the technique was going to work. It took another six years to develop, in collaboration with Richard Ernst (Nobel Prize in Chemistry, 1991), two-dimensional NMR methods for use with large molecules and then to develop the mathematical algorithms needed to compute three-dimensional protein structures from NMR data.
In 1984, we had arrived and solved the first structure.
Which was--
BUSI. Bull seminal trypsin inhibitor.
Where would biology be today without NMR as a structural tool?
There would be 3,000 fewer structures in the protein data bank. We would have quite a different feeling for the way protein molecules behave. We would not have any hands-on information on details of internal dynamics. We would have much less information on folding pathways of proteins, where much of the ground-breaking work has been done at TSRI by the groups of Peter Wright and Jane Dyson. We would not know about solvation of proteins in solution. Quite generally, we would miss a lot of information that is complementary to the data from structure determination by x-ray diffraction in single crystals.
You've always sought to expand the horizons of NMR, pushing the development of technology not just for your own research, but for the field in general. What are NMR's current horizons? Where is it going in the next 10, 20 years?
We have recently recorded NMR spectra of structures with a size close to one million Daltons, as documented in a Nature article about three months ago. So we now know that the spin physics enables us to use solution NMR over the entire size range from a water molecule to molecular structures with a mass of about one million Daltons.
Whether or not this size barrier will be further increased in the near future I would not want to guess; it is certainly not impossible. But it seems rather unlikely that there will soon be another step of a tenfold increase. Therefore, I think it will now be important to consolidate and to appreciate the available large window that includes a vast majority of all biological systems--considering just the size, of course. It will be a matter of refining the NMR techniques for large systems and of developing biochemical methods to prepare exciting systems for studies with NMR. There is now an incentive to introduce biochemical methods for partial isotope-labeling of proteins that were of no interest a few years ago, because one could not have studied, for example, segmentally labeled, very large molecular structures by NMR.
So with so many targets to choose from, how do you select which targets you're going to try to solve?
Well, my group is focusing on the emerging field of structural genomics. In this field, one typically works with gene products for which no information on function is available. Therefore, it will be more and more important that, in addition to the determination of new protein structures with novel polypeptide folds, we are also able to obtain measurements that relate to the function of these molecules. I think the most important type of such information is data on intermolecular interactions with partners in the cell. NMR is a very powerful technique for such studies--thermo-dynamic measurements as well as kinetic measurements --in addition to structure determination.
Why did you choose to come to Scripps?
Well, my wife and I have always liked to live in California. We were at UC Berkeley as postdoctoral fellows in the 1960s. We have been back many times--here at Scripps, at Cal Tech, at Berkeley, at Stanford. Among all these distinguished schools, Scripps is a particularly attractive workplace for me and La Jolla is a very attractive place for my wife and myself to live.
Speaking of your family, how do you balance your scientific career with a busy family life?
With my wife, I have an agreement that we do not take vacations. In turn, she often travels with me to scientific meetings. There are always days when there is free time for leisure activities, and I make special efforts that traveling to a scientific meeting with me is usually done at a comfort level that we would not necessarily afford if we took a private vacation. There is a mix of things that work this way, but I would definitely be very unhappy about "vacations" that would separate me for any length of time from my research activities.
How did you become interested in science?
This was much discussed in the Swiss press these last two weeks, because I also have a diploma as a sports instructor. In my youth, I taught skiing for many seasons; I was a swimming instructor; I taught sports in high school. I also taught physics in high school, and was planning to be a high school teacher in physics and sports.
Doing sports and scientific research, I had some interesting things happening to me in the laboratory, so much so that I became a professor at the ETH Zürich at the age of 33. Before that I had been at Bell Telephone Laboratories in New Jersey, which was an excellent place to do research and where I also organized a soccer league. You see, over a time span of a few years I was sort of sucked out of sports into science.
Are you looking forward to the Nobel ceremony on December 10?
Oh yes, of course. That will be a high point in my life.
How has winning the Nobel Prize changed your life?
I think it has not changed my life in important ways up to this point, except that I am giving interviews more often than I have given interviews on average over the last few years. How it will be long-term, maybe we should talk about this two years from now...
What are your favorite books?
I read the memoirs of Winston Churchill and memoirs of many famous scientists when I was in high school.
The Churchill memoirs are very thick.
Oh, I think 16 volumes.
You read the entire series?
Oh yes. But that was when I was in high school.
Churchill won a Nobel Prize in literature for those memoirs in 1953, I think.
Yeah? Very good. These last few years I have not been reading books very much. I mean, I'm using books a lot, but I'm not reading books. That's not the same thing.
Having worked with many scientists in your career, being a scientist yourself, and having trained many scientists, what are the characteristics that make a person a good scientist --or are there such characteristics?
Well, I believe that a person who wants to become a good scientist has to have the moral strength of identifying with the project under study and of attaching utmost importance to the daily work, without taking his/her person too seriously.
Is there anything else that we missed?
If there is anything to add, then it is just to say that it's great to have the opportunity to be at Scripps. It has been a great experience. I look forward to moving here permanently in 18 months and continuing my scientific work.
Well, thank you very much. It's been a real pleasure.
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