Alexander Varshavsky

The BBVA Foundation Frontiers of Knowledge Award in the Biomedicine category has gone in this fourth edition to the Russian-born biochemist Alexander Varshavsky for discovering the mechanisms involved in protein degradation and their critical importance in biological systems.

Varshavsky, who is currently employed at California Institute of Technology (Caltech), showed that a type of protein known as ubiquitins act as labels tagging target proteins for destruction. “This system is essential for normal cellular functions, ranging from the control of gene transcription, protein synthesis and DNA repair to cell division and the response to stress,” in the words of the jury’s citation.

The work done by Varshavsky (Moscow, 1946) has spawned a whole new field in biomedicine, since we now know that defects in this protein degradation mechanism underlie a wide variety of human diseases.

His research, as such, has important implications for our understanding of cancers, immune system disorders and neurodegenerative conditions, “including Parkinson’s”, the citation points out. “It is likely that drugs that target components of the system will be of wide significance in medicine.”

While some proteins remain stable for days, others last only a matter of hours. The process of protein degradation is accordingly vital to the life cycle of the cell, and it was Alexander Varshavsky’s research that uncovered its inner workings.

In the 1980s, the new laureate discovered that ubiquitins attach themselves to proteins that are due to be destroyed through ubiquitin-ligases – a kind of enzyme of which we now know that there are many hundreds, whose role is to recognize specific proteins and target them selectively for degradation.

Varshavsky talked briefly about the impact of his discovery, after hearing of the award: “I feel privileged to have contributed to the birth of this field, and to partake in its later development. This arena grew rapidly in the 1990s and has become, by now, something vast and diverse.”

“One amazing thing about the ubiquitin field is that it refuses to age. After three decades of ever-expanding research, new directions of inquiry, new problems and new applications continue unabated.” In fact one of his recent contributions was a 2010 paper unveiling a new mechanism involved in protein degradation: N-terminal acetylation of cellular protein.

The search for ubiquitin-based therapies and drugs is a particularly thriving area. “There is a great deal of ongoing medical research, at both pharmaceutical companies and universities, to design small molecules that either inhibit or augment functional aspects of the ubiquitin system,” Varshavsky relates. In other words, translational research is drawing on his insights in order to activate or deactivate the degradation mechanism depending on the target condition.

Alexander Varshavsky was nominated for the award by the 2006 Nobel chemistry laureate Roger Kornberg, of Stanford School of Medicine (United States); Ulrich Hartl, of the Max Planck Institute of Biochemistry (Germany); and Elliot Meyerowitz, of California Institute of Technology (United States).

An early passion for science

Alexander Varshavsky was born in Moscow in 1946. The son of a physicist-chemist and a doctor, he grew up in a scientific environment. “So my interest, and later love for science were a case of ‘nature’ and ‘nurture’ together,” he remarks.

In his teenage years he was already familiar with the Moscow science world thanks to gatherings in his parents’ home. His excellent grades subsequently earned him a place at the prestigious Moscow State University, in the year 1964. He wanted to study biology, but also physics, mathematics and chemistry. After gaining five straight As in the entrance exam, he decided to take his degree in chemistry.

In January 1968 he published a paper in Russian journal “Molecular Biology”, a theoretical piece full of differential equations that described the behavior of circuits in which repressors regulated themselves; three years before such models were even considered in the English-language literature. 

Between 1970 and 1977, Varshavsky worked at the Institute of Molecular Biology. He obtained his PhD in biochemistry in 1973 and began to devote himself to the still mysterious structure and organization of chromosomes. One of his findings was written up in USSR journals but also in the west. The result was a series of invitations to give talks abroad, all of which were turned down except two from Communist-bloc countries: Bulgaria and the German Democratic Republic. Shortly, however, an invitation to London from the structural biologist Aaron Klug would change Varshavsky’s fate. With the OK of the IMB’s director, Vladimir Engelhardt, he flew from Moscow to London in 1977, returning on schedule so as not to let his mentor down. Thanks to this, he was allowed out again without too many restrictions. And it was on one of these occasions, at a conference in Helsinki, that he managed to escape by ferry to Stockholm and make his way to Frankfurt, where he got in touch with David Baltimore of Massachusetts Institute of Technology (MIT). Thanks to the mediation of the 1975 Nobel medicine laureate, he was granted a visa for the United States.

That same year he managed to get work done while still in the Soviet Union published in the journal Cell, an usual occurrence back then. (Bakayev, V. V., Bakayeva, T. G. and Varshavsky, A. (1977) "Nucleosomes and subnucleosomes: heterogeneity and composition". Cell 11, 619-630).

After delivering a seminar in MIT’s Department of Biology, the university offered him a post. From assistant professor (1977-1980), he progressed to associate professor (1980-1986) and finally full professor of biology. In 1992, he was appointed Howard & Gwen Laurie Smits Professor of Cell Biology in the Division of Biology at California Institute of Technology.

International jury

The jury in this category was chaired by Werner Arber, Nobel medicine laureate and Emeritus Professor of Molecular Microbiology at Biozentrum, an interdisciplinary research institute belonging to the University of Basel (Switzerland), with Robin Lovell-Badge, Head of the Division of Stem Cell Biology and Developmental Genetics at the MRC National Institute for Medical Research (United Kingdom), acting as secretary.

Remaining members were Adriano Aguzzi, Chairman of the Department of Pathology and Director of the Institute of Neuropathology at the University Hospital of Zurich (Switzerland); Dario Alessi, Deputy Director of the Protein Phosphorylation Unit, a Medical Research Council unit in the College of Life Sciences of Dundee University (United Kingdom); Francisco Sánchez Madrid, Scientific Director of the Instituto de Investigación Princesa, Professor of Immunology at the Universidad Autónoma de Madrid (UAM) and Head of the Department of Immunology in La Princesa University Hospital (Spain); Ursula Ravens, Head of the Department of Pharmacology and Toxicology at Dresden University of Technology (Germany); Angelika Schnieke, holder since 2003 of the Chair of Livestock Technology in the Department of Animal Science of the Technical University of Munich (Germany); and Bruce Whitelaw, Head of the Developmental Biology Division at The Roslin Institute in Edinburgh (United Kingdom).