Health

How Yoshinori Ohsumi’s Stroke of Genius Empowered 21st Century Medicine

2016 Nobel Laureate Yoshinori Ohsumi’s experiments sparked off a revolution in research that has made it possible to develop drugs that can target autophagy and treat diseases

Yoshinori Ohsumi. Credit: 大臣官房人事課/Wikimedia Commons, CC BY 4.0

Yoshinori Ohsumi. Credit: 大臣官房人事課/Wikimedia Commons, CC BY 4.0

Cells may be the basic units of life, but a single cell itself is composed of sub-cellular compartments called organelles. Each of them performs some specialised function in, and for, the cell. The lysosome is one such organelle. When it was discovered by the Belgian scientist Christian de Duve in the 1950s, it was recognised as being an organelle that contained digestive enzymes. Lysosomes, to put it simply, are where dysfunctional and redundant cell material go to ‘die’. The enzymes present in them break down useless proteins, carbohydrates and lipids, generating energy that is useful to the cell.

In the 1960s, scientists began to look more closely into the activities of the lysosome. Again, it was de Duve who found that unwanted material in the cell would get enclosed in a membranous bubble called a vesicle. This vesicle would then get moved to the lysosome where its constituents are degraded. This explained why so much cellular debris and sometimes even full organelles were found inside the lysosome. de Duve named this process autophagy and the vesicles are now known as autophagosomes. He won the Nobel Prize in physiology or medicine for his findings in 1974.

However, over the next couple decades, progress in the field was negligible. Nobody was able to understand how exactly autophagy worked – nor did anyone have any ideas about how to go about studying it. So the phenomenon was still shrouded in mystery when, in 1988, a cell biologist in Tokyo University decided to take over from where de Duve left off.

Working with yeast

Yoshinori Ohsumi used yeast cells to investigate autophagy. Yeast was and remains a popular model organism and particularly useful to identify genes responsible for specific cellular pathways. At the same time, it posed several concerns to Ohsumi. First: did autophagy even exist in unicellular organisms like yeast? He suspected it did; after all, even yeast would need to dispose cellular waste somehow. And he guessed that if it did exist, the autophagosomes carrying the waste would probably end up in the vacuole, an organelle in yeast that was the equivalent of lysosomes in humans.

So far so good. But wait, how was Ohsumi supposed to observe the goings-on inside the vacuole? Being small in size, yeast cells and their organelles are not easy to distinguish under a light microscope. Moreover, the autophagosomes last only for 10 to 20 minutes before they fuse into the lysosome. It is during this bout of troubleshooting that Ohsumi had a stroke of genius that won him the Nobel Prize earlier today.

All he did was grow mutant yeast and starve them. Why? The mutant yeast cells were engineered to lack the digestive enzymes required by vacuoles to break down cell waste. The mutant cells were grown in a medium that was nutrient-deprived. This is a tactic to trigger autophagy by making the cell energy-hungry and resort to digesting its own cellular material to generate energy. Ohsumi predicted that without the enzymes, the autophagosomes would just accumulate inside the vacuole, now unequipped to digest them. He was right.

The stage is set

In all of a few hours, the autophagosomes accumulated in the vacuole and, in this relatively massive form, was visible under a microscope. With this, Ohsumi not only proved that autophagy exists in yeast (and by corollary, probably in other organisms, too), but also managed to assemble all the participants of this process on a stage for the world to see and study.

And now that the stage was set, Ohsumi could proceed to the bigger question: What are the genes that control autophagy? For this, he played around by creating more sets of mutants by exposing the yeast to a chemical. These mutants had random genes inactivated. The accumulation of autophagosomes in the vacuole was the sign that autophagy was occurring. If he could create mutants in which accumulation did not occur, he would be able to identify the gene that was inactivated in that mutant as an autophagy gene (ATG). In this manner, thousands of mutants later, Ohsumi identified 15 ATGs. He went on to characterise the proteins that each of these genes encoded and presented the cascade of events that went on behind autophagy.

The significance of Ohsumi’s work was established when it became more evident that that identical mechanism underlies autophagy in all life-forms. The fact that a specific cellular process survived evolution is a sign of how crucial it is to life. Autophagy is required for generating energy (in times of starvation), recycling old cell parts (especially during ageing), eliminating invaders (in cases of infection) and cell differentiation (during embryo development). Consequently, flaws in the mechanism play a role in several diseases such as cancer, Parkinson’s disease, type-2 diabetes and genetic diseases. Ohsumi’s experiments sparked off a revolution in autophagy research that has now made it possible to develop drugs that can target autophagy to treat diseases.

Only two weeks ago, Ohsumi had been honoured by the New York Academy of Sciences for his work. There, he stressed on the importance of uncovering the late steps of autophagy in order obtain a complete understanding of the phenomenon. Interestingly, Ohsumi was predicted to win the prize in 2013, but along with his labmate Noboru Mizushima and American scientist Daniel J. Klionsky. Both of them made significant additions to the body of autophagy research.

As it turned out, the committee has conferred the prize to Ohsumi alone, making him one of the only 38 (out of 211) recipients of an unshared Nobel Prize in Physiology or Medicine. The last person to be a sole winner of the award was Robert G. Edwards in 2010 for the development of in-vitro fertilisation.