A life devoted to protein research

“The time has simply flown by,” says Ruedi Aebersold, sitting behind the desk in his office. It’s hard to say if the tone of his voice is one of wistfulness, or simply amazement that his retirement is right around the corner, in January 2020. He will hold his farewell lecture on 9 December.

His retirement marks the end of an era for the influential biochemist: he is highly regarded in his field, his publications have been cited tens of thousands of times, and he has earned numerous awards and honours throughout his career. Several of these grace the walls of his office, in addition to two large-scale abstract artworks. “The one picture represents a family of five, much like my own, and I like the other one for its intense colour,” Aebersold explains. He adds, modestly, “I’m not particularly well-versed when it comes to art, and I can’t draw or paint well.”

Instead, his talent lies in science, specifically in the study of proteomics. This specialist field of biology looks at the totality of all proteins in an organism. Aebersold is a pioneer in this area and has set many milestones. He also played no small part in inspiring the many researchers around the world today who investigate the proteome of cells or even of entire organisms.

Years of fascination with proteins

“I became interested in proteins as a student,” Aebersold says. He studied cellular biology at the University of Basel’s Biozentrum, wrote his thesis on the activity of immune factors and delved further into this topic for his doctoral thesis. Working with proteins fostered his fascination for them. “My whole career has been about proteins. They turned out to be a stroke of luck for me.”

Most proteins are complex molecules. In the late 1970s, working with them was complicated and expensive. “We were able to work with only a very few proteins, as analysing them required huge quantities of each one in a highly pure form,” the ETH professor explains. Back then, working with DNA would have been more attractive, because it was possible to make more progress faster than working with proteins. But his doctoral advisor, biochemist Dietmar Braun from Ciba-Geigy, continued to pursue protein research and built up a group devoted to the topic at the pharmaceutical company.

“Ciba-Geigy had a strong protein chemical group that I was able to join even while I was still working on my master’s degree,” Aebersold recalls. The company had laboratory facilities that the Biozentrum didn’t. “There I was able to acquire skills in this niche that turned out to be very useful later on,” Aebersold says.

As a doctoral student, he had a book that contained all the known sequences of amino acids in proteins. It was a slim volume. Aebersold still has it today: “This book motivated me to refine techniques that we could use to determine amino acid sequences in proteins more easily than before.”

Diving into creative chaos

The laboratory that allowed him to do this was Lee Hood’s lab at Caltech in the United States. It was in the vanguard of laboratory automation and the development of analysis equipment. Aebersold remembers the special atmosphere Hood created: “It was creative chaos.” During his time in the lab, Aebersold collaborated with chemists and engineers to construct his first protein sequencing machine, which could automatically carry out the Edman degradation, a complicated chemical process.

After finishing his postdoc assignment, Ruedi Aebersold moved his wife and their three children to the University of British Columbia in Vancouver, where he was able to set up his first group as an assistant professor in the 1980s.

Mass spectrometry was undergoing a rapid transformation at this time. Another researcher, John Fenn, had just invented electrospray ionisation. This made it possible for the first time to ionise large, fragile molecules like proteins – in other words, giving them an electrical charge and transferring them into the vacuum system of a mass spectrometer. This meant scientists could determine the mass of these molecules and even their amino acid sequence in the mass spectrometer.

Aebersold procured a spectrometer and used it to analyse proteins, thus laying the foundation for his further work. “By coincidence, my education in protein biochemistry had put me in the perfect position to generate biologically relevant data and not just chemical/analytical data,” he says.

Productive period in Seattle

It was again Lee Hood who gave Aebersold’s career another boost. Hood had moved from California to Seattle in 1992 and was setting up a new department at the University of Washington. Hood needed professors for the department and tapped Aebersold for a position. He accepted, and he and his family moved from Vancouver to Seattle.

Today, Aebersold describes his time at the University of Washington as very productive. Milestones included the creation of two centres for genomics and the first ever centre for proteomics. An atmosphere of optimism pervaded the campus. However, the researchers didn’t make the desired progress, and the main reason for that was the structure of the department: “We were unable to expand our groups further due to a lack of space. The field of proteomics was downright exploding, and we didn’t have enough room for our groups to grow and the Department couldn’t recruit additional professors,” Aebersold recalls.

Co-founding a private institute

To escape the dead end of going down the university path, in 2000 Aebersold joined with Hood and immunologist Alan Aderem in resigning their university positions to found a private institute for systems biology in Seattle. “We had lifetime appointments plus families to take care of. We had to consider whether or not we could justify such a step, as it meant suddenly giving up a stable financial foundation,” Aebersold says, “but it was a calculated risk.” One they expected would pay off.

At this time, public policy was kindly disposed toward science and research, which provided the researchers with a certain advantage. Then US president Bill Clinton doubled the budget of the National Institutes of Health, so Aebersold and his colleagues were able to procure enough funding to finance the operations of their new institute.

Pioneers for proteomics at ETH

Aebersold also waxes enthusiastic about ETH’s financing model. Supported over the long term by sufficiently unrestricted research funds, professors are free to pursue new ideas or unusual observations. This means that ETH can allow its professors to conduct “risky” research, because they don’t need to worry about losing some or all of their funding through a single misstep. It is a different situation in the US, where research is often conducted only when the scientists are sure it will pan out, so that they can obtain continued funding for subsequent projects. “Research under those conditions will make hardly any fundamental progress,” Aebersold says. Many groundbreaking findings have resulted from unusual observations, he continues, “and at ETH we have the privilege of being able to pursue such lines of inquiry.”

Among the highlights of his time in Switzerland, Aebersold counts something that outsiders would perhaps not expect: SystemsX.ch, the country’s cross-university initiative for systems biology, which he helped set up. At the start it was a small association consisting of ETH Zurich and the Universities of Basel and Zurich; later, the programme was expanded to include research institutes across all of Switzerland. “With this programme, we reached over 2,000 researchers who achieved highly interesting results with above-average impact,” Aebersold says.