Dartmouth Chemist Studies Autophagy, or Cannibalism in Cells

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The process Michael Ragusa studies is important in the operational maintenance of cells.

Professor Michael Ragusa and Postdoctoral Research Associate Sarah Katzenell
Postdoctoral Research Associate Sarah Katzenell and Assistant Professor Michael Ragusa look at a membrane plot that shows interactions among autophagy proteins. (Photo by Eli Burakian ’00)

Assistant Professor of Chemistry Michael Ragusa looks at a cell the way a mechanic looks at a car: Both are complex and have many moving parts that wear out over time.

“Like cars, cells have different components that perform specific tasks, and when things stop working, you need to pull them out,” he says.

Ragusa studies the cannibalism that goes on perpetually inside our cells. Known as autophagy, it means “self-eating” and is crucial to keeping things on track in cells. Studying this complex maintenance process is challenging for his staff and students and helps chart a path for undergraduate researchers.

Gaining an understanding of the molecular mechanisms of autophagy could facilitate the development of novel therapeutics for the treatment of cancer as well as neurodegenerative and infectious diseases, Ragusa says.

The cellular-level process is much more than just taking out the trash. “There isn’t really a place in the cell to put what is left over, so this becomes more of a recycling process,” says Ragusa. “If you can’t dispose of the old parts, they just hang out and take up space, and sometimes they can be really toxic and cause a whole host of diseases.”

Everything in a cell must eventually be broken down, reproduced, and then replaced. Fortunately, most of the residue can be dismantled and funneled back to the cell as nutrients or metabolites.

Assistant Professor Michael Ragusa and graduate student ​Xue “Sherry” Xia
Assistant Professor Michael Ragusa and graduate student ​Xue “Sherry” Xia discuss the structure of a protein and possible mutations they can make to test new hypotheses about its mode of action. (Photo by Eli Burakian ’00)

Ragusa’s group is interested in the fundamental “how”—the mechanics of autophagy. In this process, the cell must first target what it needs to recycle, isolate the material, and then direct it to the recycling machinery. Autophagy can take care of essentially anything in the cell related to maintenance and also fend off disease-causing microorganisms such as bacteria that may have infected a cell, Ragusa says.

“From our work, there isn’t a direct path to treat diseases per se,” he says, “but we are trying to help the people more directly connected with those lines of research by showing them exactly what is going on at the molecular and atomic levels.”

Proteins, the molecular workhorses of the cells, play integral roles in autophagy, particularly in the recycling process. Ragusa says that to understand just what they are doing, one must first understand what they look like. In the lab, his team employs sophisticated techniques such as X-ray crystallography and nuclear magnetic resonance spectroscopy—methods that provide windows into the atomic structure of these proteins. With a protein’s structure in hand, they can compare it to similar proteins and potentially deduce its function.

Ragusa shares many of these complex technologies with students through his graduate courses in protein crystallography, and protein structure and dynamics, and a biophysical chemistry course for seniors.

Many of the undergraduates in his lab are effectively doing graduate level projects, he says. “Because of the nature of what we do, there are no easy projects, so everything has a very high bar.”

At first, they work with a graduate student for a term or two, and then they begin their own research projects. Once they have demonstrated a level of independence, they are on their own.

“We try to give them the freedom to really run with it and explore their own science,” says Ragusa. “It is important to demonstrate to them not just the challenges of science, but also the successes, which is why we do this. We do it because it is exciting, and because it can be very impactful.”

Joseph Blumberg can be reached at joseph.e.blumberg@dartmouth.edu.

Joseph Blumberg