I, Cannibal: The Critical Role of Autophagy In Human Physiology

On October 3, 2016, much of the world woke up to discover a word and a concept that had previously been relatively obscure outside of scientific circles.

“Yoshinori Ohsumi wins Nobel prize in medicine for work on autophagy,” shouted one headline from the Guardian [1]. “Yoshinori Ohsumi of Japan Wins Nobel Prize for Study of ‘Self Eating’ Cells,” explained another headline from the New York Times [2]. Intrigued by the concept of cannibalistic cells, morning commuters took to Google to learn more (Figure 1). And just like that, autophagy (pronounced ah-TAH-fuh-gee) earned its well-deserved place in the public lexicon.

Figure 1. Google trends data for searches of “autophagy” from September 26-October 3, 2016.


Now that the world is aware of this strange scientific term and Hollywood filmmakers have begun dreaming up ways to incorporate the terrifying idea of cellular cannibalism into their latest blockbuster horror films, the time seems right to answer some pressing questions about autophagy, and why it is important enough to have been honored with the 2016 Nobel prize in medicine.

“What the heck is autophagy anyway?”

Autophagy refers to the process of cellular self-digestion [3]. Although this may sound undesirable, it is actually crucial for the normal functioning of many different cell types across different kingdoms of life. Autophagy makes it possible for cells to recycle components they no longer need, to obtain energy when they are starved, and to protect themselves from infection, among many other functions.

“Oh, I see. So Ohsumi discovered autophagy?”

Not exactly. Autophagy was first discovered in the 1960s when researchers found that many of the cell’s compartments for breaking down nutrients obtained from the environment also contained some components of the cells themselves [4]. The compartments that contained these cellular components were called autophagosomes, or self-eating compartments, since they appeared to be using their own cellular components as food. However, researchers lacked the genetic tools to effectively study autophagosomes in mammalian cells.

Figure 2. Yeast cells with a buildup of autophagosomes (small dark circles within light circle). Image taken from from Ref. 5. ©Takeshige, K. et al., 1992. Originally published in Journal of Cell Biology. 119, 306.

Then, in 1988, Ohsumi discovered that by blocking the ‘digestive’ process in yeast cells while simultaneously starving them of external nutrients, he could observe the buildup of many large autophagosomes inside the cells that were visible under the microscope (Figure 2) [5]. This observation became a valuable tool that could then be used to study the cellular components required for autophagy. In subsequent experiments, Ohsumi used various chemicals to disrupt different genes in yeast, and then looked for the presence of autophagosomes under the microscope [6]. In this way, he could find out what genes were important for the process of autophagy. Through this line of study, Ohsumi discovered many of the genes that are important for autophagy. Though his work was done in yeast where it is easier to disrupt many different genes, many of the components important for autophagy in yeast have been shown to also be important in humans and other mammals.

“Neat! But I thought you said this was the Nobel prize for medicine. Did Ohsumi’s discoveries lead to any cures?”

Although Ohsumi did not set out to cure any specific disease when he started working on autophagy, the discovery of the genes important for autophagy has led to a fundamental shift in our understanding of human biology, including many important diseases. We now know that autophagy is important for the normal functioning of cells. For example, on a daily basis our liver cells undergo autophagy in between meals, and this nutritious snack gives the liver enough energy to maintain its normal functions without us constantly eating to provide it with energy [3].

Because autophagy is so important in the normal functions of cells throughout our body, many diseases can be traced back to defects in autophagy. For example, deficiencies in autophagy have been shown in Parkinson’s disease, cancer, type II diabetes, microbial infection, Alzheimer's, and more [3]. Because of this, researchers are working to determine whether activating autophagy can help prevent or treat these diseases.

Clinical trials are currently underway to determine whether activators of autophagy can be effective in treating various cancers including breast, pancreatic, and lung cancer [7]. Just last week, the FDA announced that it had approved an autophagy activating drug for phase II clinical trials in the treatment of Alzheimer's [8]. In the very near future, we could begin to see the rolling out of drugs targeting autophagy that provide much needed treatments for previously untreatable illnesses.

“Wow, that’s exciting!”

Yes, it is. And apparently the Nobel prize committee agrees. Congratulations, Dr. Ohsumi. Thanks to you, we’ve come to understand that we all have a little cannibal in us - and it turns out that's a good thing.

Jeff Maloy (@JeffreyMaloy)
Staff Writer, Signal to Noise Magazine
Ph.D. Candidate, Microbiology


References
[1] Devlin, H. & Sample, I. Yoshinori Ohsumi wins Nobel prize in medicine for work on autophagy. The Guardian (2016). https://www.theguardian.com/science/2016/oct/03/yoshinori-ohsumi-wins-nobel-prize-in-medicine
[2] Chan, G. Yoshinori Ohsumi of Japan Wins Nobel Prize for Study of ‘Self-Eating’ Cells. Nytimes.com (2016). http://www.nytimes.com/2016/10/04/science/yoshinori-ohsumi-nobel-prize-medicine.html
[3] Mizushima, N., Levine, B., Cuervo, A. & Klionsky, D. Autophagy fights disease through cellular self-digestion. Nature 451, 1069-1075 (2008).
[4] de Duve, C. & Wattiaux, R. Functions of Lysosomes. Annual Review of Physiology 28, 435-492 (1966).
[5] Takeshige, K. Autophagy in yeast demonstrated with proteinase-deficient mutants and conditions for its induction. The Journal of Cell Biology 119, 301-311 (1992).
[6] Tsukada, M. & Ohsumi, Y. Isolation and characterization of autophagy-defective mutants of Saccharomyces cerevisiae. FEBS Letters 333, 169-174 (1993).
[7] Jiang, P. & Mizushima, N. Autophagy and human diseases. Cell Research 24, 69-79 (2013).
[8] Georgetown Receives FDA Clearance to Conduct Clinical Trial with Nilotinib in Alzheimer’s Disease. Gumc.georgetown.edu (2016). https://gumc.georgetown.edu/news/georgetown-receives-FDA-clearance-to-conduct-clinical-trial-with-nilotinib-in-alzheimers-disease