Dr. Ohsumi has achieved world-leading results in his genetic study of autophagy in yeast, a cellular process that degrades proteins in order to adapt to the nutritional environment and other factors. He has made groundbreaking contributions toward elucidating of the molecular mechanisms of autophagy and its physiological significance.
A Ubiquitin-like System Mediates Protein Lipidation (Ichimura, Y. et al.), Nature 408: 488-492, 2000
The Pre-Autophagosomal Structure Organized by Concerted Functions of APG Genes Is Essential for Autophagosome Formation (Suzuki, K. et al.), EMBO J. 20: 5971-5981, 2001
Atg8, a Ubiquitin-like Protein Required for Autophagosome Formation, Mediates Membrane Tethering and Hemifusion (Nakatogawa, H., Ichimura, Y. and Ohsumi, Y.), Cell 130: 165-178, 2007
Dr. Yoshinori Ohsumi has made groundbreaking contributions to science in his cellular genetic study of autophagy (also known as “cellular self-cannibalization”) in yeast, a cellular process that degrades proteins in order to adapt to the nutritional environment and other factors. Autophagy was first proposed in the early 1960s, having been inferred from the observation that cytosolic components such as mitochondria and endoplasmic reticulum are found in single-layered membranes within the lysosome, known as the food vacuole or phagosome in animal cells. The term autophagy refers to a process whereby intracellular components and organelles are incorporated into the lysosome for degradation. For some time, the phenomenon was reported to occur in a variety of cells and some organs, but the molecular mechanism and physiological significance remained unclear. In 1992, while studying the function of vacuoles using the budding yeast, Saccharomyces cerevisiae, Dr. Ohsumi discovered that intracellular components and organelles enclosed by single-layered membranes appeared within the vacuole if proteinase B-deficient strains were exposed to a low-nutrient culture medium. This was the first demonstration that autophagy could be induced in yeast. By following this observation, Dr. Ohsumi then isolated a number of mutants in which autophagy is not induced even if proteases are inhibited and nutrients are depleted. His discovery of autophagy in yeast and these mutants paved the way for analysis of the molecular mechanisms involved in autophagy. Thus far, his findings have led to the identification of several dozen molecules involved in autophagy, and functional analysis of these molecules is shedding light on the pathway determining how the de novo formation of a membrane structure containing intracellular components and organelles, and its fusion with a lysosome, take place in response to starvation and other stimuli.
The discovery of factors involved in the autophagic process in yeast has also helped to identify their homologs in mammalian and other animal cells. This has, in turn, enabled many researchers to reveal the broad physiological significance of autophagy in animals—namely, that autophagy is essential for neonates to adapt to the starvation state at birth; that autophagy is necessary to prevent neural cell death, as it hinders the accumulation of abnormal proteins in nerves; and that metabolic turnover via autophagy is vital to the maintenance of myocardial contraction.
Dr. Ohsumi’s contributions to this field deserve high recognition, as he has opened the door to elucidating the molecular mechanisms and physiological significance of autophagy—a cellular self-cannibalization system that represents a vital and fundamental process in living organisms.
For these reasons, the Inamori Foundation is pleased to present the 2012 Kyoto Prize in Basic Sciences to Dr. Yoshinori Ohsumi.
I was born in Fukuoka, Japan, in 1945, just half a year before the Second World War came to a close, and so I have lived through the post-WWII period of this country. My coming up to 45-year career as a researcher has never been a smooth run, and I have followed a truly narrow path. Nonetheless, I was fortunate to be blessed with many happy coincidences and encounters along the way. I have come to realize that science is a system of intellect built upon the persistent efforts of humanity. In that sense, I feel that my own existence is also a very social one.
My college and graduate school years coincided with the period when molecular biology was being established as an academic discipline, and this led me to choose biology rather than chemistry which I had been aiming to study. The fact that I began my career as a young researcher studying protein biosynthesis would have profound impact on my cell studies in later years. My involvement with yeast—which would become the subject of my lifelong research activities—dates back to when I was studying in the laboratory of Nobel Prize-winning biologist Dr. Gerald Edelman at the Rockefeller University. I started out working on fertilization in mice but soon transitioned to working on yeast as a model. Upon my return to Japan, Professor Yasuhiro Anraku of the University of Tokyo’s Graduate School of Science was kind enough to supervise me as I began my earnest study of yeast, which has played a decisive role in modern biology, and focused on vacuoles of yeast. Since I do not enjoy doing research work in a competitive field, I have a solid belief to deliberately choose something that others are not researching. Hence, I began analyzing vacuoles, which by that time had been widely recognized as the garbage bin of the cell, to reveal that they are active organelles that perform important functions.
In 1988, I set up what I believe was the smallest lab at the University of Tokyo’s College of Arts and Sciences with the idea of studying another function of vacuoles— degradation—and it was the microscopic observation which I immediately initiated that would determine everything I would do from that time on. The phenomenon of autophagy, or the process of cellular self-degradation, had been identified in animal cells some fifty years earlier but little progress had been made on the subject since that time. However, I was able to demonstrate that the degradation process in the vacuoles of yeast was an excellent model of that cellular process. Using a molecular genetic approach, I was also able to identify the genes involved in autophagy. As such genes of everything from yeast to humans were extensively preserved, autophagy research suddenly began to accelerate to the point where research on its physiological roles in higher animals and plants is now undergoing an explosive evolution. One may think that degradation is a somewhat negative process but, in fact, it plays a role in the lives of organisms that is just as important as synthesis.
I believe that our understanding will continue to expand if we confront natural phenomena without preconceptions and if we do not allow ourselves to be overwhelmed by vast amounts of information.
Today, no single biologist can expect to accomplish anything on his or her own. The research work for which I am being honored is the fruit of unremitting efforts by a total of 80 joint researchers, and I am truly proud of these brilliant colleagues. It gives me great pleasure to know that the researchers with whom I have worked in my lab are taking the lead in international autophagy research.