Japanese cell biologist Yoshinori Ohsumi, PhD, was awarded this year's Nobel Prize in Physiology or Medicine for his discovery of autophagy. His groundbreaking studies in yeast cells illuminated how cells break down and recycle damaged material, a process that is critical to the survival of both normal cells and some cancer cells.
Japanese cell biologist Yoshinori Ohsumi, PhD, has been awarded this year's Nobel Prize in Physiology or Medicine for his discovery of autophagy. His groundbreaking studies in yeast illuminated how cells collect and break down intracellular proteins and organelles, a process that is critical to the survival of both normal cells and some cancerous ones.
“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,” noted the Nobel Committee in announcing the award in October.
The concept of autophagy was first observed in the 1960s, but little was known about its underlying mechanisms until Ohsumi conducted a series of experiments with baker's yeast in the early 1990s. Those studies eventually led him to identify the genes—and the proteins they encode—that control autophagy, and to show that a corresponding mechanism exists in humans.
Autophagy is a self-defense mechanism that prevents the accumulation of garbage or potentially toxic material in cells, such as damaged proteins and organelles. In normal cells, it serves as a buffer during metabolic stress by recycling intracellular components. It also helps to eliminate invading bacteria and viruses following infection, promote embryo development and cell differentiation, and counteract the negative consequences of aging.
Ohsumi verified that the process exists in yeast cells by studying how autophagy delivers cargo for degradation in the vacuole. (In human cells, similarly, autophagosomes fuse with lysosomes, which contain enzymes that degrade proteins and organelles.) He then cultivated cells that lacked vacuolar degradation enzymes, starved them, and was able to observe the vacuoles fill with small vesicles holding proteins to be degraded—known as autophagosomes.
In another set of experiments, Ohsumi exposed engineered yeast cells to a chemical that randomly introduced mutations in many genes, then induced autophagy. As a result, he identified many different proteins and protein complexes that regulate distinct stages of autophagosome initiation and formation.
“Ohsumi used yeast as a model system to identify the mechanisms it uses to survive nitrogen starvation and the genes essential for the autophagy pathway,” says Eileen White, PhD, professor of molecular biology and biochemistry at Rutgers University and deputy director and associate director for Basic Science at Rutgers Cancer Institute of New Jersey, in New Brunswick. “By doing this, he opened up a whole new field of investigation.”
Recent research has revealed that some cancer cells in hypoxic regions also use autophagy to survive metabolic stress, suggesting that the process may be a viable drug target, says White. Companies are now working on autophagy inhibitors, possibly to augment the activity of targeted drugs. Multiple clinical trials are testing hydroxychloroquine (HCQ), an antimalarial drug that interferes with lysosome function, in combination cancer therapy. For example, a phase II trial is assessing HCQ combined with the BRAF inhibitor dabrafenib (Tafinlar; Novartis) and trametinib, a MEK inhibitor (Mekinist; Novartis), in patients with advanced BRAF-mutant melanoma.
“The discovery of autophagy genes and how they enable lysosomal degradation and recycling of organelles and proteins has provided a critical platform for understanding how autophagy plays a role in resistance to cancer therapy,” says Ravi Amaravadi, MD, a medical oncologist at the University of Pennsylvania in Philadelphia, who led a series of early-phase clinical trials testing HCQ in combination with targeted therapies. “Ohsumi's work provided the framework to propose biomarkers and targets for drug discovery that could improve the efficacy of cancer therapies in a number of cancers.” –Janet Colwell
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