An experiment using his own hemoglobin motivated a Nobel laureate in chemistry

In an interview with Agência FAPESP, Kurt Wüthrich talked about how he began to develop the award-winning technique of protein structural analysis, driven by the desire to improve his athletic performance.

By Karina Toledo, in Araraquara

Agência FAPESP – The stereotype of the coke-bottle-lens-wearing nerdy scientist, always at his laboratory bench, averse to any physical exercise, dissipates quickly when hearing the life story of Swiss-born Kurt Wüthrich, winner of the 2002 Nobel Prize in Chemistry.

The first in his family to earn a college diploma, Wüthrich received an undergraduate degree in chemistry, physics and mathematics from the University of Bern, Switzerland, where he studied from 1957 to 1962. At that time, he also got his first job as a high school physical education teacher, a position that he held for five years.

During the winter months of those early years, he worked as a ski instructor at resorts in the Swiss Alps. It was there that he met Marianne Briner, whom he married and with whom he had two children.

From 1962 to 1964, while pursuing his PhD in chemistry at Switzerland’s University of Basel, he spent an average of 25 hours per week engaging in intense physical exercise as well as taking courses in anatomy and physiology to earn a bachelor’s degree in Sports.

While a post-doctoral fellow at the University of California in Berkeley, he began to develop studies involving nuclear magnetic resonance (NMR). Some years later, driven by the desire to improve his sports performance, he decided to study the structure of his own hemoglobin, the protein found in the red blood cells responsible for carrying oxygen throughout the bloodstream.

In the mid-1970s, he began to develop a method that enabled him to use NMR to analyze proteins in a solution. Basically, the idea consists of bombarding the sample with strong electromagnetic waves.

The nuclei of certain atoms, such as hydrogen, respond by emitting their own electromagnetic waves that, upon analysis, offer clues about their molecular structure. Initially, the method worked only with small molecules.

The results of complex protein analysis were an indecipherable tangle of radio signals. Wüthrich found a way to determine the distance between the hydrogen atoms and thus to build a three-dimensional picture of the target molecule.

He attained his first success with the technique in 1984, when he elucidated the three-dimensional structure of a protein found in the blood of a bull. This accomplishment earned him a nomination for the Nobel Prize nearly 20 years later. It is estimated that 20% of the three-dimensional protein structures known by 2002 had been determined with NMR.

Wüthrich shared the prize with John Fenn (Virginia Commonwealth University) and Koichi Tanaka (Shimadzu Corp.). The latter two developed different methods to identify certain proteins in solution by measuring the weight of the molecules.

Wüthrich is currently a professor of structural biology at the Scripps Research Institute in the United States and a biophysics faculty member at Zurich Federal Polytechnic School (ETH) in Switzerland.

Since 2012, he has been a visiting professor with the Science Without Borders program as well as a visiting researcher at the National Institute of Science and Structural Biology and Bio-imagery Technology (INBEB) at the Federal University of Rio de Janeiro (UFRJ).

In an interview with Agência FAPESP, granted during the launch of the NMR Platform II at the Chemistry Institute of São Paulo State University (Unesp) in Araraquara, São Paulo, Brazil, Wüthrich talked about his current lines of research. One of his goals is to understand potentially infectious diseases caused by abnormal versions of proteins known as prions.

An example is Creutzfeldt-Jakob disease (CJD), which is characterized by the incidence of rapidly progressive dementia, rigid posture, epileptic seizures and facial paralysis that gives the victim the appearance of a grin. CJD is part of a group of diseases known as spongiform encephalopathies and is considered to be the human version of mad cow disease.

During the Araraquara event, the researcher presented a lecture that addressed the evolution of his research on NMR, prospects for the field and the importance of basic science driven by curiosity.
 

Agência FAPESP – During your lecture, you mentioned the importance of research driven by curiosity. Was this the case when you began studying the three-dimensional structure of proteins or did you have a more applied goal in mind, such as finding a cure for a particular disease?
Kurt Wüthrich – My case was rather special because I was an athlete. In all endurance sports, oxygen capture is a limiting factor. The first protein I studied was my own hemoglobin in an attempt to find something that could help me to better understand oxygen capture during exercise. I had the opportunity to work in this field and the curiosity to discover what my blood hemoglobin was like.

Agência FAPESP – Why is it so important to understand the three-dimensional structure of proteins?
Wüthrich – Under no circumstances is it possible to understand how proteins perform their various functions in the body without knowing the three-dimensional structure of these molecules. Proteins regulate all processes in the body, but they also form our hair and skin. The largest number of proteins in the body is in solution, and they cannot perform their functions if not dissolved in water, but, luckily, hair does not dissolve in water. You cannot understand these differences without understanding the three-dimensional structure.

Agência FAPESP – In studying protein structure, what advantage does NMR offer in relation to other structural techniques, such as crystallography?
Wüthrich – Crystallography is performed using protein crystals, and NMR allows us to work with solutions. Crystallography works at very low temperatures, whereas we work at body temperature. We can adjust our solutions to mimic bodily fluids. In the future, I hope that this allows us to study proteins in living cells.

Agência FAPESP – What is the current thrust of your research?
Wüthrich – In Zurich, I’m mainly studying diseases related to prion proteins, such as mad cow disease and human prion diseases, which include CJD. In the United States, I’m primarily studying G protein-coupled receptors (GPCRs). We have 826 of these receptors in our bodies, and they are related to almost everything: sense of smell, sense of taste, control of heartbeat, adrenaline. Everything is through the GPCRs. That is why today, nearly 40% of all prescription drugs are linked to GPCRs. The idea is to explain the mechanism of action of these receptors. They are found in the cell membrane, where they perceive drugs from the outside and activate signals inside the cell that then have an effect on the disease. We want to understand exactly how the drugs affect the signals inside the cell.

Agência FAPESP – When were you first in Brazil, and how has Brazilian science changed since then?
Wüthrich – The first time I was in Brazil was in 1973, and since then there have been a lot of highs and lows in Brazilian science. There have been very impressive findings and advances in genomics. At a virtual institute [the Organization for Nucleotide Analysis and Sequencing], Brazilian scientists discovered the genome of the bacterium Xanthomonas citri, which causes citrus disease.

Agência FAPESP – What topic of study would you recommend for a young scientist in your field today?
Wüthrich – First off, I would recommend choosing something they like to do because they will work very hard, and they have to enjoy the work they will be doing. That’s the most important thing. If you are driven by curiosity, it’s possible to obtain important results in any field. You also need to have a sense of where your field of interest is headed and to try to work at the cutting edge. I think there will be huge advances in high-resolution imaging techniques and extremely interesting applications of functional magnetic resonance imaging. I hope that the next generation will be able to observe proteins in living cells and that this is not necessarily limited to NMR techniques. There are also optical techniques, such as the one that won the 2014 Nobel Prize in Chemistry, that allow us to obtain super-high-resolution images from inside cells. This would overturn an old law of microscopy that says it is not possible to observe anything smaller than half the length of a light wave [0.2 micrometers].

Agência FAPESP – Do you think that teaching is an important part of a science career?
Wüthrich – I taught sports in high school for five years. That’s a long time. I taught skiing for 10 years. I like to teach. I think that top-quality universities need to have researchers teach the students; otherwise, they will never really know what science is about. Getting back to sports, I always trained with the best, with Olympic athletes. Only when we are among the best of the best do we have a chance to rise to the top. I know that many Brazilian colleges have professors on staff who do not have PhDs. I think this needs to change if Brazil really wants to become an important actor in basic research, which of course it can be.