The protein pioneer

Rudolf Aebersold has dedicated his entire career to researching proteins. He co-founded two research areas, proteomics and systems biology. Today his findings are applied in the early detection of cancer and in personalised medicine. This year, Rudolf Aebersold will be awarded the Marcel Benoist Swiss Science Prize for his achievements.

Even after his retirement, his curiosity continues to drive him: Rudolf Aebersold, the Marcel Benoist Prize laureate, wishes to continue to actively contribute his knowledge in support of real-world applications. Photo: Daniel Rihs

Proteins are omnipresent in the human body: they are the main component of nails and hair; they act as hormones to regulate metabolic processes; they act as antibodies to ward off infections; and are used to transport substances. Every human cell contains eight to nine billion protein molecules, i.e. roughly the same number as there are people on earth. “No life without proteins,” summarises Rudolf Aebersold. The new Marcel Benoist Prize laureate has been working with proteins for 40 years and describes them as ‘the cell’s craftsmen’. Proteins are responsible for carrying out and controlling tens of thousands of biochemical reactions that take place in a cell and thus determine the cell's properties and functions.

Tedious and monotonous work
Although there are thousands of different types of protein, they are all comprised of a maximum of 20 types of amino acids arranged in different numbers and sequences depending on the type of protein. In order to understand the properties and functioning of a protein, you first need to know how these amino acids are arranged. This was exactly what Rudolf Aebersold set out to do when he started his scientific career.

Back in the early 1980s, Aebersold was a PhD student at the University of Basel’s Centre for Molecular Life Sciences and was working at Ciba-Geigy. It was at that time that he began sequencing individual proteins using chemical methods. His curiosity drove him on, but the work was laborious, slow and monotonous. In six months, he deciphered the composition of just a single protein. He was convinced that there had to be a faster way to do this! In 1984, after completing his PhD in cell biology, he therefore went to the renowned California Institute of Technology in Pasadena under a grant from the Swiss National Science Foundation. His vision: to improve and accelerate protein sequencing through automation. In the creative chaos of an interdisciplinary research group, Aebersold managed to take his analytical technique a big step forward and even discovered some unknown proteins along the way.

The proteomic revolution
His achievements drew the interest of several universities, which offered him a position as assistant professor. Aebersold chose the University of British Columbia. This was a comparatively low-profile choice from an academic standpoint, but he felt that life in Vancouver would be ideally suited for his family with three young children. The decision also proved to be a stroke of fortune from a professional standpoint, as he achieved his first scientific breakthrough in western Canada. He threw his former sequencing techniques out the window and began working with a mass spectrometer and quantitative methods. This enabled him to study proteins in new ways and determine their quantity and composition. This was a scientific revolution that laid the foundation for what is now known as modern proteomics.

In the mid-1990s, he moved back to the United States, accepting an associate professorship at the University of Washington in Seattle. At that time, the prevailing notion was that one simply had to know all genes and proteins in order to understand the processes taking place in a cell. Aebersold's methods, which he developed further in Seattle, were used to create comprehensive catalogues of existing proteins - an approach that he himself viewed with scepticism. He was convinced that it is not possible to understand a cell if one considers it to be a mere collection of individual molecules. “It is like language,” he explains. “You can collect all existing words in a book and learn them by heart. But you can't read or write texts with those words yet. You need syntax for that. Texts only really make sense when words are presented in the correct order and the connections between them are understood.”

Against all odds
Aebersold was convinced of the need to understand cells as systems whose properties are determined by networks of proteins connected by a kind of ‘syntax of life’. To achieve this, he had to systematically investigate how protein groups form, how they interact and how they change through influences. Because he was unable to make progress with in a university setting, he founded the Institute of Systems Biology in Seattle with his colleagues Leroy Hood and Alan Aderem, the first institute of its kind in the world. Aebersold's approaches were not always met with enthusiasm within the research community. The field of systems biology, which he helped to found, was sometimes considered just a fashionable trend. For years, Aebersold and his colleagues struggled to achieve acceptance of the new research discipline.

Over time, however, systems biology became established - also in Switzerland. In 2001 Aebersold became a part-time professor at the University of Zurich and in 2004 he was offered an additional professorship at ETH Zurich, where he established the Institute for Molecular Systems Biology (IMSB) in 2005. In Zurich, Aebersold and his research group developed a methodology to precisely identify and measure every protein in a human cell. The group was also able to show that the expression of a gene is usually not carried out by a single protein, but rather by hundreds of proteins arranged in a specific form and interacting with each other. They also showed that the various arrangements and interactions changed depending on the conditions.

From fundamental research to practice
With his pioneering work in proteomics and systems biology, Rudolf Aebersold has fundamentally changed the world’s understanding of organisms and biology. For this work, he has been awarded this year's Marcel Benoist Swiss Science Prize, only a few months after his retirement from the IMSB. However, Aebersold has no intention of sitting back and enjoying retirement. “My fascination with proteins has actually grown even more over the years,” he says. “With each new discovery, our questions have become even more exciting.”

This is also due to the fact that the findings from basic research are increasingly being applied in practice. Personalised medicine, for example, builds on Aebersold's work. The stated aim here is to use protein analyses to determine whether or not a given treatment is suitable for a patient before it begins. Another area of application is the early detection of diseases. Aebersold, who is considered among colleagues to be a fantastic mentor, supervised PhD student Ralph Schiess, who succeeded in developing a simple blood test for the reliable early detection of prostate cancer. Rudolf Aebersold himself is very keen to continue to actively contribute his knowledge in support of real-world applications. This is one of the reasons why he is heading the tumour profiling project, a joint initiative of ETH Zurich, the University of Zurich and the University Hospitals of Basel and Zurich, which will run until the end of 2023. His motivation: “There is still so much to discover!”