Nobel Honors Discoveries on How Cells EAT Themselves

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This year’s Nobel Prize in Physiology or Medicine has been awarded to Yoshinori Ohsumi, a cell biologist at the Tokyo Institute of Technology’s Frontier Research Center, for his work on autophagy, the process in which cells degrade and recycle cellular components.

“Ohsumi’s discoveries led to a new paradigm in our understanding of how the cell recycles its content,” a press release by the Nobel Assembly at the Karolinska Institute (KI) in Stockholm says. “His discoveries opened the path to understanding the fundamental importance of autophagy in many physiological processes, such as in the adaptation to starvation or response to infection. Mutations in autophagy genes can cause disease, and the autophagic process is involved in several conditions including cancer and neurological disease.”

 “Of course for a researcher, there is no higher honor,” Ohsumi said this evening at a hastily called press conference on the campus of the Tokyo Institute of Technology.

“This is an excellent decision,” biochemist Volker Haucke of the Leibniz Institute for Molecular Pharmacology said at a meeting this morning in Berlin, where scientists watched the announcement live. “With Ohsumi, they have awarded the prize to a scientist who investigated a phenomenon in yeast that was seen as a side phenomenon, but that turned out to be central to molecular medicine,” Haucke said. “It’s very well deserved. … He is a prime example of someone who did basic research and discovered a process that otherwise might have stayed hidden for decades.”

In the 1950s and 1960s, researchers recognized that some animal cells use autophagy to recycle proteins and other cellular machinery. They knew that the process was especially active when the cell was under stress, for example when nutrients were in short supply or when the organism was fighting off an infection. But how the process worked—and even which cells used the method—was unclear.

Ohsumi and his colleagues set out to explore whether yeast, a single-celled organism that nevertheless uses many of the same biochemical processes as animal cells, could help answer some of the outstanding questions. (“I thought of trying something others weren’t working on, so I started research into yeast,” he explained at his press conference.) Ohsumi developed strains of yeast that lacked key enzymes suspected of playing a role in autophagy, hoping to see what happened to the cells when the process didn’t work as it should. When they starved the yeast, the scientists found that the cells developed unusually large vacuoles, the cellular garbage dumps that collect materials to be recycled. Usually yeast vacuoles were too small to see under the light microscope, but in the mutant yeast, they grew so large they were easy to observe.

Ohsumi then used chemicals to induce more mutations in the yeast strains, looking for cells that failed to form visible vacuoles even when they were starving. Such cells, he reasoned, lacked genes that were important for autophagy to work properly. In a key paper published inFEBS Letters in 1993, Ohsumi and and his team identified 15 essential genes involved in the process. Further studies showed that very similar genes controlled the process in animal and human cells, and also helped piece together how the genes work together to keep the cell’s recycling centers running.

Since then, Ohsumi and others have shown that autophagy plays a crucial role in embryo development, cell differentiation, and the immune system. A breakdown in autophagy can lead to a wide variety of diseases, including cancer, diabetes, and Huntington disease. A healthy autophagy system is correlated with longevity, and a faulty one can accelerate symptoms of aging.

“One reason autophagy has become so important is the realization that it is a highly regulated process, not just some automatic breakdown,” says Peter-Michael Kloetzel, head of the Laboratory for Proteolytic Systems at the Charité university medical center in Berlin. As Daniel Klionsky, a researcher at the University of Michigan, Ann Arbor, explains it in this playful art and science video about autophagy, “the cell carries out a dance of spring cleaning 365 days a year.”

“I think Ohsumi is the right person” to win the Nobel, says David Rubinsztein, who studies the role of autophagy in neurodegenerative diseases at the University of Cambridge Institute for Medical Research in the United Kingdom. “While there are many other people who have made important contributions to the field, he is justifiably considered the father of the field,” he says. “His lab was the first to identify yeast genes that regulate autophagy. Those discoveries have allowed us to then understand how autophagy is important in mammalian systems, because the yeast genes are very well conserved.”

“Of course, this kind of research is not something only one person can do,” Ohsumi said today, thanking the graduate students, postdocs, and staff who “strove mightily” in his lab for 27 years. (Ohsumi is “a very modest man,” Haucke said at the Berlin meeting.) Some of the follow-up work on mammalian autophagy was done by people who trained in Ohsumi’s lab, such as Tamotsu Yoshimori at Osaka University in Japan and Noboru Mizushima at the University of Tokyo. Both have “really been influential,” Rubinsztein says. “One thing that Ohsumi should get credit for is being a very good mentor,” he says. “I couldn’t be happier,” seeing others build on his basic work, Ohsumi said today, adding, “I’m looking forward to seeing more and more light shed on this phenomenon.”

The award comes at a rocky time for KI’s Nobel Assembly, a group of 50 KI professors that picks the winners of the physiology or medicine Nobel every year. In February, developmental geneticist Urban Lendahl stepped down as the assembly’s secretary-general because he expected to be investigated in the scandal around former KI surgeon Paolo Macchiarini. Anders Hamsten and Harriet Wallberg-Henriksson, two former vice-chancellors at KI who were involved in the Macchiarini affair as well, announced earlier this year that they would skip the deliberations for the 2016 prize; Hamsten and Wallberg-Henriksson were both asked to resign from the assembly on 6 September, but both still appear on the list of assembly members. Katarina Le Blanc, an immunologist who was a co-author on a key Macchiarini paper, and Hans-Gustaf Ljunggren, a former KI dean of research, have also said they would not participate in the prize deliberations this year.

Today’s announcement is the first in a week full of tightly scripted Nobel suspense. Winners in physics will be revealed tomorrow, and in chemistry on Wednesday; the Nobel Peace Prize and the Prize in Economic Sciences will follow on Friday and Monday, respectively. (No date has been set for the announcement of the 2016 Literature Prize.)

Published by: sciencemag

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