Kurt Wüthrich

Interview

Interview, May 2014

Interview with 2002 Nobel Laureate in Chemistry Kurt Wüthrich, 27 May 2014.

Trading swimming lessons for lab time.

Grabbing Max Perutz’ attention.

Kurt Wüthrich’s intense collaboration with Richard Ernst.

Kurt Wüthrich’s work in simple terms.

“Breakthroughs are unexpected.”

Doubts and criticism from other scientists.

Being awarded the Nobel Prize.

“The greatest week in a scientist’s life.”

The difference between doing sports and science.

“Sabbaticals are not meant to be vacations.”


Interview, December 2002

Interview with Professor Kurt Wüthrich by Joanna Rose, science writer, 12 December 2002.

Professor Wüthrich talks about how he started in the field of magnetic resonance imaging; explains his work with proteins (3:58); talks about the development of X-ray diffraction (10:46); future goals in proteomics (12:46); business companies’ interest for proteins (15:00); and challenges in his field of research (20:13).

Interview transcript

Professor Kurt Wüthrich, my congratulations to the prize.

Kurt Wüthrich: Thank you.

You have been, for a very long time, in the field of proteins and nuclear resonance. I wonder, how did you start in this field?

Kurt Wüthrich: I started in the field of magnetic resonance spectroscopy when I was 22 years old.

So it’s quite a long time.

Kurt Wüthrich: It was in 1960 and I was using electron paramagnetic resonance during my PhD thesis to study metal lines.

It sounds like a very ancient method. Was it?

Kurt Wüthrich: It was a very new method at the time.

But today?

Kurt Wüthrich: It actually turned out that I was the first scientist in Switzerland to ever record ESR, as you say, or EPR, Electron Paramagnetic Resonance spectra of metal complexes in solution. This I did not even know at that time but it was found out by historians later on.

And now you are in the field of proteomics, which is a very new field in science, I would say, at least the name is new?

Kurt Wüthrich: We have been working with proteins. I’ve started to work with proteins in 1967 and the transition from working in structural biology with proteins to working in proteomics is as much a semantic transition, as it is also a transition which is substantial.

In what way?

Kurt Wüthrich: In structural biology, we would typically investigate molecules of which function had been studied, usually in the classical structural biology project. We would come in at the late stage when biochemists had investigated a lot of functional properties. We would then end up getting 3-dimensional structure and use it to rationalise all the data that had been accumulated on this protein or this system of the protein interacting with other molecules. In proteomics you rather aim for proteins that are encoded by so far unknown genes. These parts of the genome, which have no function attached to them yet and so we would express these polypeptite chains determine the 3-dimensional structure and then use this as a starting point for obtaining information on possible functional properties.

When one looks how this is like, I could at least believe that you work with it because it is so beautiful, it’s like a piece of art. That is one protein?

Kurt Wüthrich: Well, this is one system of protein with a very important reaction partner, in this case the reaction partner is shown in red, blue and grey colours. These are what we would refer to as functional colours whereas the receptor protein, that is the protein inside the cell, that would bind this smaller effector molecule is shown in light blue.

What does it do, this reaction part?

Kurt Wüthrich: This is cyclosporin A. Cyclosporin A is a drug that prevents rejection of foreign tissue after an organ transplantation. It is sold under the name Sandimmun, it used to be a major product of the Sandoz pharmaceutical company. When we studied this structure, we had what is perhaps the biggest surprise I ever had in my career, we obtained the structure in which that molecule, after binding to its target in the cell looked when compared to its structure in the free state, looked that if a glove that has been ripped off your hand, with the inside coming out. A very big surprise which then gave important new information on possible modes of interaction of this drug molecule with its receptor and thus, in the next step, new guidelines for further research on this system.

Here we have another protein, it looks differently.

Kurt Wüthrich: This is very different presentation of another result from a NMR study. It may be helpful if you hold the two side by side. You see, on the left we have a surface view. The atoms are represented by small balls that represent their actual volume whereas on the right, we connect volume less points which represent the location of the atoms with lines that represent the bonds. This is not the realistic picture of the surface of the molecule, but it enables us to look through the molecule and to see what the architecture is that spans this surface that we see on the left.

How are they so beautiful, colourful, when you look at them?

Kurt Wüthrich: This is what we add to our results. Proteins per se do not appear coloured to our eyes, except when they are combined with certain functional groups that are not of protein character and that may be visibly coloured.

So this is the artistic part of your work?

Kurt Wüthrich: This is an important part of our work. We have spent a lot of time as /- – -/ in writing software that would enable to make pleasing and informative pictures of our results.

We have another picture here which is more like this. How should I keep it? Like this?

Kurt Wüthrich: Yes, I think you would best hold it like this. Here again, this is another step up from the picture that we see on the right.

Your right.

Kurt Wüthrich: On my right, I mean on this side we have a drawing which shows all the atoms without their volume, but it shows the correct position, and it shows how the atom positions are linked. Here on the left, this drawing has been made more easy to read in that we leave off the so called site chains, we only see the backbone of the protein and parts of the architecture which are only present in globular proteins, in particular helical structures and so called sheet structures which span planes of material inside the protein structure. These are easy to recognise. I do not believe that a layperson can readily distinguish helical and beta sheet regions from irregular folds, whereas here, this is readily obvious. Of course, this is no longer a precise representation of the molecular structure, it is an adaptation that should help to transmit knowledge about a structure to a wider audience.

With this long perspective on protein studies, can you tell us what you consider the most important thing that happened during this history, the most important invention or discovery?

Kurt Wüthrich: During the last …?

During the last 40 years or 50 years. Half a century, I would say.

Kurt Wüthrich: 50 years. Such pictures of protein molecules can be obtained by NMR spectroscopy, where we can study the molecules in solution or by x-ray diffraction, where the molecules can be studied in single crystals. This development of x-ray diffraction techniques and of NMR spectroscopy, to the level where these methods can be used to determine structures of such complex molecules as proteins and nucleic acids is certainly key developments during the last five decades. There are other methods, electron microscopy or electron diffraction techniques have been used in a few cases to obtain similar results and then of course we have mass spectrometry which has been included in this year’s Nobel Prize which is entirely complimentary to these structural determination methods. We would use mass spectrometry in daily practice as an analytical tool, to make sure that we use our expensive and labour-intensive technology on samples that are properly composed thus we can in a fast and inexpensive way, determine by mass spectrometry.

One of the goals of proteomics is to make a full list of all the proteins, is it right?

Kurt Wüthrich: This is what has originally been proposed as the goal of what is called structural genomics. I think we should no longer talk about structural genomics, we should talk about proteomics and structural proteomics. I believe that the goals of structural proteomics have been rephrased, in particular on the side of the commercial enterprises who have also entered this field in that one has rather gone away from the idea of establishing a complete atlas of all three-dimensional proteins folds but rather focuses on certain classes of proteins and performs in depth studies that would go far beyond full determination and would include information relating to the functional properties of these proteins. It has also been clearly shown that the high- throughput  technology, which is of course one of the key gadgets that have been introduced with structural proteomics, are particularly easy and efficient to be used for serial investigations of closely similar proteinic systems. For example, given protein receptor studied with a large library of small ligand molecules that bind to it in order to get lead information for drug design, for example.

Why is it so interesting with proteins for business I would say, for the companies?

Kurt Wüthrich: Well, you see, we have been very much impressed by the fact that the genome has been the genome of many organisms, more than 50 organisms so far…

… and the human.

Kurt Wüthrich: … including the human genome have been determined in an amazingly short time, but we now have to see very clearly that one needs more information than just a linear sequence of the DNA and this information that we need to add to this sequence information consists primarily in a description of the expression of this genomic information and the expression of the genomic information consists primarily of protein molecules, to some extent of ribonucleic acid molecules. Now it has been estimated that the human genome consists of approximately 30,000 genes plus a lot of regions on the DNA that are used probably for the purpose of regulation of the use of the different parts of the genome. Now each of these 30,000 genes can potentially yield an infinite number of different proteins because you may have post-translational modifications of the polypeptide chains that are read off from a given gene and that’s where mass spectrometry comes in. Mass spectrometry can give us an initial information on the level at which the proteins that derive from individual genes are expressed to what extent modifications of these proteins are produced after the process of translation. The mass spectrometry can give us indications about up regulation, down regulation, of certain forms of proteins during health and disease and that’s where mass spectrometry has been found to be a particularly powerful method, but mass spectrometry will not provide us with the basis for understanding protein function, there we need the three-dimensional structure.

You have to know the structure

Kurt Wüthrich: We have to know how it looks, what you have seen on these pictures and that’s where x-ray crystallography and nuclear magnetic resonance spectroscopy come in.

So how many proteins are there, if there are 30,000 genes. It’s just billions?

Kurt Wüthrich: Well, I said an infinite number in principle. This of course is an exaggeration, but it can be a very large number. I mean, the proteins that are combined with carbohydrate moieties, they’re made typically from one gene, you may get tens of thousands of very slightly different carbohydrate moieties attached to the protein in the so-called glycol proteins. It is well known that the carbohydrate parts are highly heterogeneous so you may have very wide variety there.

So the atlases may be nothing to think about.

Kurt Wüthrich: I do not believe that the idea of the atlas was to include those post- translational modifications. The idea was that if we discard as an approximation the post-translational modifications, we should be able to span the whole atlas of three-dimensional folds based on, at some point it was believed maybe 300 folds, then it was 10,000 folds and we don’t really know how many folds we will need to span the universe of protein structures.

My final question would be, what do you think will be the next big discovery in this field?

Kurt Wüthrich: You see, in structural proteomics, we are faced with an enormous task of characterising not only one product per gene but a large multitude of gene products per gene and right now, it appears that we have to accumulate a large number of data. I mean in a typical proteomics project, we will no longer focus on one protein structure and try to make sense out of that structure, we would rather try to determine dozens or hundreds of structures and then from comparison of this data, derive novel information. This all looks extremely complicated, it looks as if an incredibly large amount of work will be needed and I think that a big breakthrough to be anticipated is that we will find simplicity in this very complex material that by getting a sufficiently large sample of experimental data, someone will all of a sudden again see common simplifying lines which might then enable us to handle the complexity of the proteome without undue demands on time, labour and money.

You will find the principle.

Kurt Wüthrich: Yes, I think we are still lacking the principle that’s behind what we refer to as proteomics, behind the relations between the concentration of proteins and body fluids, the structures of protein molecules in body fluids and the outcome of the combined action of the very large number of different proteins.

I wish you good luck. Thank you very much.

Kurt Wüthrich: Thank you.

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MLA style: Kurt Wüthrich – Interview. NobelPrize.org. Nobel Prize Outreach AB 2021. Mon. 20 Sep 2021. <https://www.nobelprize.org/prizes/chemistry/2002/wuthrich/interview/>

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