Today’s Nobel Prize in Medicine has been awarded to Japan’s Yoshinori Ohsumi for his work in understanding a fundamental biological process by which the cell digests damaged or unnecessary components. The process, called “autophagy,” or self-eating, allows cells to survive periods of stress or starvation or adapt to changing conditions or needs. Disturbances in autophagy have been linked to both cancer and neurodegenerative diseases.
As with many previous winners, Ohsumi seems to have had the right ideas at the right time. In the 1950s, former Nobel laureate Christian de Duve identified small structures in cells that contain many digestive enzymes. Others recognized that these structures were involved in situations where cells digest parts of their own internal membranes, freeing up raw materials for reuse. A decade later, the term autophagy was coined and people recognized it as a normal process in cells.
But in the decades that followed, understanding how it worked was slow, partly because typically complex eukaryotic cells are filled with tiny bits of membrane, and partly because the process was transient, rapidly digesting the material it received. We knew it was happening, but we didn’t know when or how it was triggered. This left the field open for Ohsumi, who started working on it in the 1990s.
Ohsumi decided to work on yeast cells (the same yeast that makes our bread and beer) because they are simpler and genetically traceable. Here the interior is a lot less complex, albeit smaller, and individual components tend to be more difficult to identify. An exception to this is the vacuole, a large permanent structure filled with digestive enzymes that processes the cell’s waste and toxins. In that way, it is the equivalent of the small, membrane-bound bundles of digestive enzymes that have been observed in human cells.
To show that it was actually the equivalent, Ohsumi did an experiment that ended up giving him a very useful tool. He eliminated the genes for three digestive enzymes known to be located in the vacuole, reasoning that this would block the processing of material there. He then starved these mutated yeast, putting them under stress that would normally cause them to digest some of the structures that could no longer support them. But the mutations prevented them from being digested. Instead, many membrane structures began to accumulate in the vacuole – so much that the defect could be seen with a standard light microscope.
This showed that in yeast, the vacuole is where autophagy takes place. But more importantly, it gave Ohsumi a handle on the process itself. In his mutated yeast, autophagy fails at the very last step, when the target material is digested, leading to the accumulation of material in the vacuole. If an additional mutation interfered with the process, the material would never be able to get to the vacuole in the first place. As a result, you would no longer see the accumulation of material in the vacuole.
Ohsumi used this as the basis for a genetic screen, eventually identifying 15 different genes needed to target material for autophagy. (Especially instead of appearing in a high-profile publication like Science or Naturethis article was in a smaller magazine called FEBS letters.) Since the process is potentially dangerous if it were to occur in an uncontrolled manner, many of these genes are involved in regulating it. For autophagy to take place, a complex of different proteins must be assembled and interacted with, a process that is regulated in part by proteins that sense the cell’s nutritional status.
Most of these same genes are involved in regulating autophagy in mammalian cells, and Ohsumi helped identify and characterize them. Several are critical to embryonic development, with cells often changing their interior when they take on a specific identity, such as a neuron or a liver cell. Others have shown that the pathway he identified is just one of many ways cells can target parts of themselves for destruction and recycling.
And that’s where the story comes back to medicine. One of the human versions of a gene Ohsumi originally identified has been found to be mutated in many breast and ovarian cancers. Loss of one of the two others from the brains of mice causes neurodegeneration. In fact, there are now several human neurological diseases involving autophagy, including Alzheimer’s and Parkinson’s disease.
Knowing that autophagy is involved does not always provide an obvious route to developing a therapy. But the Nobel Committee has made it clear many times that simply understanding the basic science that helps us understand a disease deserves recognition.