Of yeast and men. How to survive starvation and infectious disease.

By Dr. Hans Clevers, M.D. Ph.D.

Sixty years ago, Christian de Duve, an iconic 20th century cell biologist from Belgium, discovered the lysosome. Lysosomes serve as intracellular trash cans, in which cells can dispose of all kinds of biological debris taken up from the outside. Some years later he noted that cells can also discard parts of themselves into these little demolishing machines, presumably to remove worn-out structures and to recycle their building blocks. He coined the term "autophagy" for the process by which cytoplasmic constituents are transported to and degraded in the lysosome. These observations have appeared prominently in the high-school textbooks ever since, but how exactly cells would selectively cannibalize little bits of themselves remained an enigma for several decades. This somewhat esoteric question was taken up 25 years ago by Yoshinori Ohsumi, a scientist at the Tokyo Institute of Technology and now in his seventies.

Ohsumi realized that yeast cells and human cells go about many daily challenges in much the same way, even if the common yeast-human ancestor may have lived more than a billion years ago. Since free-living yeast cells are quite a bit simpler than our own cells, he reasoned that yeast might represent just the right system to address his question. As a first crucial discovery, he noted that yeast cells employ autophagy –they literally start eating themselves- when starved of nitrogen. He then performed a genetic screen to dissect the autophagic process. In other words, he found mutant yeast strains in which the autophagy process was disturbed in one way or another. With the explosion of molecular technology, it was not too difficult to find out which genes were mutant in these strains: He thus rapidly found 15 autophagy-related genes, now called ATG genes. With these genes in hand, he then started working out how they –in concert- allow a yeast cell to mark, transport and digest small intracellular components.

The first striking discovery revealed that a biochemical process that rose to prominence in the 80s, the ubiquitin conjugation system, kick-starts autophagy. Working together with a lipid conjugation system, it builds specialized vesicles (‘autophagosomes’) that have the unique property to engulf intracellular components for delivery to and destruction by de Duve’s lysosome. With these and other discoveries, Ohsumi unveiled almost all components of the autophagy pathway and defined the principles by which these components work together to remove and recycle the right cellular component at the right time. A new field was born. His junior co-workers Noboru Mizushima and Tamotsu Yoshimori as well as others around the globe went on to demonstrate that mammalian cells use the same autophagy genes as yeast – exactly as predicted by Ohsumi.

Now, autophagy is recognized as much more than 'just' a mechanism for turnover of cell parts. It is a central player in some of the most important health threats of current times. Autophagy is a crucial mechanism to survive periods of starvation, from yeast to mammals, while its role in the opposite phenomenon –obesity- is intensively scrutinized. Cells also have learned to utilize the autophagy system to remove unwanted bacterial visitors. The list of these party crashers is impressive and includes tuberculosis, salmonella, Shigella, Coxiella and Listeria, responsible for some of the most frightful infectious diseases on our planet. The role of autophagy in neurological afflictions such as Alzheimer’s and Parkinson is also intensively investigated. Indeed, in one rare hereditary form of Parkinson’s, the gene Parkin is mutated. In healthy cells, Parkin is essential for the autophagy of worn-out mitochondria, the miniature power plants inside cells.

We scientists build on work from others. We are trained to work in established fields. We add details, find new links. We correct mistakes in our own work or in that from others. A rare breed of scientists is different. They are individuals who start new fields, open new horizons. They are the giants on whose shoulders we stand. There are not many. Yoshinori Ohsumi, the winner of this year’s Dr. Paul Janssen Award, is one.

hans_cleversHans Clevers, M.D. Ph.D., is professor of molecular genetics at the Hubrecht Institute and Research-Director of the Princess Máxima Centre for Paediatric Oncology. Dr. Clevers is also part of the Dr. Paul Janssen Award Selection Committee.