Q&A: The fits and starts of science

Three scientists in a lab
Robert Farese, Jr., left, Tobias Walther, Jeeyun Chung

January 21, 2020—It’s been a busy year for Robert Farese, Jr. In January 2019, Farese was appointed chair of the Department of Genetics and Complex Diseases—now known as the Department of Molecular Metabolism—and he continues to co-run a laboratory with Tobias Walther, also professor of molecular metabolism. Farese sat down to discuss his new research, the fits and starts of doing science, and his first full year as department chair.

How has becoming chair changed your understanding of the department and wider Harvard Chan research community?

Becoming chair made me reflect a lot on why we exist as a department and what our mission is. Since the beginning of the Harvard School of Public Health in 1913, basic science has been an integral component across the School’s departments, which is part of what attracted me here in 2014. The Genetics and Complex Diseases department was founded approximately 15 years ago on the premise that metabolic diseases— obesity, diabetes, fatty liver disease—are significant public health problems.

The way I see it now is that if we look at non-communicable diseases as public health problems, the major burdens are metabolic diseases, cancer, and neurodegeneration. The expertise of our department is in metabolism, and by unraveling the metabolic underpinnings of these diseases, our researchers could potentially make huge improvements in public health. In thinking about all of that, we decided that for a variety of reasons that the name of the department should play more to our strengths and our expertise in metabolism.

You mentioned neurodegenerative diseases. How do you see the type of basic science your department does evolving on that front? 

The brain is 60% fats or lipids by mass. And there is a huge area of biology that is relatively underexplored, which is lipid metabolism in the brain. In particular, the brain is rich in a kind of lipids called sphingolipids. We already know that abnormalities in lipid metabolism underlie many childhood diseases, and we believe it’s important to understand the contribution of brain lipid metabolism to adult neurodegenerative diseases. I think research in this area will take off as people increasingly recognize its importance. It’s a challenging subject. The brain is incredibly complicated and lipid metabolism is incredibly complicated. To be able to work at the intersection of them requires considerable training and we’re eager to build an enterprise for investigating brain lipid metabolism and metabolism in general.

In addition to your duties as chair, you’re still a professor who runs a lab and publishes frequently. You and Walther recently co-authored a study in Developmental Cell identifying new cellular machinery involved in cellular lipid storage. What was the thrust of the research and what excites you about it?

The paper you mention focuses on how oils and fats are synthesized and stored in cells, a problem that has fascinated me and Tobi for a long time now. Specifically, it identified a protein that we’ve called lipid droplet-assembly factor 1, or LDAF1, which is an important part of the cellular machinery that allows oils and fats to be produced and stored.

This has a couple of significant implications. One is just from a basic life standpoint because all life forms have to store energy and they do it mostly in the form of fats or oils. That’s the best, most efficient way to store energy, and understanding the machinery that allows for this is really important. Second, the process of storing fats underlies a lot of disease processes that are big public health problems, such as metabolic disease and fatty liver disease, and it relates to cardiovascular disease and atherosclerosis. And third, one of the huge problems in the world is energy production, and the process we’re focused on could have industrial applications when it comes to making seed oils or biofuels. So it’s a paper that has broad and fundamental implications for many areas of biology.

What does the process of making this type of discovery look like? Is it a slow burn, like putting together a jigsaw puzzle where things gradually come into focus? Or is it a sudden eureka moment where everyone yells huzzah and champagne is popped?

That’s an interesting question that gets to the nature of basic science research. It is kind of a slow chugging along, fueled by perseverance and belief. And then there are fits and starts of great insight.

Take for example the paper you just mentioned on LDAF1. Before that paper, we knew that a protein called seipin was important in lipid storage. Seipin was recognized about a decade ago as being potentially important in how oil droplets are produced in cells, and many laboratories, including ours, have contributed to understanding how seipin works. Two years ago, our lab and one other lab obtained a molecular structure of seipin, or a picture of it, so that we could actually see for the first time what seipin looks like. However, it seemed to us that something was missing, that maybe we were just seeing part of the machinery. So Jeeyun Chung, an outstanding postdoctoral research fellow in our lab, struck out on a project to try to identify other components of the machinery. And lo and behold, she found the LDAF1 protein and worked out its involvement in fat storage. So that’s an example of one of those fits and starts where we get very excited because we’ve gained new insight into how something works. But then, of course, it takes another couple of years to test all your hypotheses about it.

When you were a younger researcher, did you appreciate the scale of time that science works on, or was there an urgency and pressure to get to the discovery so you could prove yourself?

Science oft-times moves slowly. Life, and a career, is short at the end of the day, so we always feel urgency. At this point in my career, what science has taught me—and it applies to many things in life—is that it’s nice to figure out what you think is important for the next two to three years and set a general course of direction. In science, you identify a problem, the general direction you want to go to solve it, and then you sort of figure out where you want to dig. And I think then keeping your eyes open is really important because you have to give serendipity a chance in your endeavors. Things come up, and one of them could be life changing. That’s very true in science and it’s also true with in life.

photo: Kent Dayton

Chris Sweeney