Autophagy Researcher Wins Nobel Prize for Medicine

October 03, 2016

A Japanese scientist was awarded the 2016 Nobel Prize in medicine today for research on how cells break down and recycle their contents, a metabolic process involved in cancer, diabetes, and neurologic disorders, and one amenable to therapeutic manipulation.

For almost 3 decades, Yoshinori Ohsumi, PhD, has characterized autophagy, or "self-eating," in baker's yeast and has demonstrated that it works almost the same way in human cells. In an interview posted on the Nobel Prize website, Dr Ohsumi recalled that when he started out, published research on autophagy amounted to fewer than 20 articles a year.

"Now [it's] more than 5000, or something like that," said Dr Ohsumi, a cell biologist at the Toyko Institute of Technology. "It's a huge change."

Pediatrician David Perlmutter, MD, one of the many scientists who are attempting to translate autophagy bench science into new treatments, told Medscape Medical News that Dr Ohsumi "gave us the tools to exploit this.

"It's a beautiful example of how basic scientific research can be capitalized on for understanding and treating disease," said Dr Perlmutter, executive vice chancellor for medical affairs and dean of the Washington University School of Medicine in St. Louis, Missouri. "The [autophagy] process has now exploded in biomedical research."

Autophagy is essential for cell survival in a number of ways. It serves as a recycling service for damaged proteins and organelles. A sacklike structure called an autophagosome engulfs this cellular waste and transports it to a lysosome, where enzymes break it down into nutrients and cellular building blocks. Cells use these same tools to capture and eliminate invading bacteria and viruses. And perhaps in an evolutionary response to starvation, cells can obtain emergency fuel through autophagy by essentially eating themselves.

But these metabolic processes can go awry, particularly when cellular waste goes unrecycled and accumulates. Disruptions in autophagy have been linked to cancer as well as disorders such as Parkinson's disease and type 2 diabetes that develop with aging. Scrambled genes that code for autophagy also can trigger disease.

Dr Ohsumi's research pointed to possible therapies by identifying the genes that code for autophagy and the chain reaction of proteins and protein complexes that carry it out. This knowledge gives researchers clues on how to manipulate the process through drugs and gene therapy. A study recently published in PLOS Biology, for example, showed that a protein that promotes autophagy helped repair damaged heart tissue in mice after myocardial infarction.

Likewise, a research group headed by Dr Perlmutter reversed liver cirrhosis caused by alpha-1-antitrypsin deficiency (ATD) in mice by administering carbamazepine, an anticonvulsant and mood stabilizer, to stimulate autophagy. The therapy worked by cleaning up misfolded — and toxic — apha-1-antitrypsin proteins that accumulate in liver cells. The team is now conducting a phase 2 clinical trial to treat patients with severe ATD liver disease this way and avoid a transplant.

For all the progress made, Dr Ohsumi sees much more basic research on autophagy ahead. "Still we have so many questions," he said. "Even now we have more questions than when I started."

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