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Peter Espenshade


Peter Espenshade
on how the body senses cholesterol, research surprises, and the future of medical research

Has basic research changed over the years?

ESPENSHADE: It appears as though there's a push towards more results-there's a drive to get cures as quickly as possible. It's a good thing, though; it makes people think harder about what they're doing. Researchers really have to sit down and think about the questions they're trying to answer and their priorities for discovery.

There is an essential role for discovery-based work in this process, but I think you'll see more teaming-up of people who are interested in how things work and, on the clinical side, people who have knowledge of important diseases. If more basic and clinical researchers interface, we'll see a lot of progress in medical breakthroughs. Technology has increased the speed of experiments, which continues to accelerate. As investigators, we will be able to study many different things during our careers instead of just looking at a single problem. The drive for disease cures also raises the question of how broadly versus how deeply we research something and when it is time to switch to new projects.

Tell me about your research.

ESPENSHADE: My lab is interested in understanding how cells measure the concentration of cholesterol within the body. It's sort of the Goldilocks problem: if they have too much, it's bad; if they have too little, it's bad; and so there is a sweet spot with just the right amount. We're interested in cellular processes that act like thermostats, measuring the amount of a given compound and turning the production up or down. Knowing how cholesterol is measured has important implications, because too much cholesterol in the blood is a risk factor for heart disease.

In mammalian cells, there's a protein, SCAP, which binds and senses cholesterol, changing its shape when there is too little. It sits in the endoplasmic reticulum, the area of the cell where cholesterol is made, which is a good location because it's also where cholesterol that comes from the blood ends up. When SCAP indicates that there's too little cholesterol, it frees another protein, SREBP, from the membrane. SREBP then goes and binds to DNA, turning on the genes that increase the production of cholesterol in the cell, as well as creating receptors to take cholesterol into the cell from the bloodstream. A cholesterol-lowering drug that targeted SCAP could work by making the body think there was low cholesterol in the cell, which would make the cells pull cholesterol out of the blood. Less cholesterol in the blood means less risk of clogged arteries and heart disease.

How do you study this?

ESPENSHADE: A common approach in basic science is to use a model organism that's simpler than a human but uses a similar process to the one that you're investigating and then work back to the full system in humans. We started by studying a yeast cell, which we knew sensed cholesterol. We've found that fission yeast cells-different from the yeast used in making beer or bread-use similar versions of SCAP and SREBP in their own cholesterol-sensing systems. We have a lot of data from yeast cells and from mammalian cells, and our next step is to see if the pathway works the same in whole animals-mice. Of course, the work in yeast cells also led to a new surprise. That's the great thing about basic science research, you always find new questions.

What was the surprise?

ESPENSHADE: The big surprise was, in mammalian cells SCAP and SREBP only regulate cholesterol, but in yeast they also turn on genes that control growing in low oxygen. It turns out that the yeast also uses the system to respond to how much oxygen is in the environment. A large amount of oxygen is required for the yeast to make cholesterol, and when there is insufficient oxygen it will not be created. So when SCAP senses low cholesterol, it also means that there is very low oxygen available, and the fungus can use this knowledge to adjust its growth conditions for less oxygen.

It turns out that this pathway exists in a number of different fungi-importantly, it happens in many fungi that cause disease. When these pathogenic fungi enter the human host, they experience limited oxygen and rely on this low oxygen sensor to survive in the host. We can use this system as a drug target to try and stop dangerous fungal infections. It's a really good example of how basic science-trying to ask basic questions of how something works, like how a cell senses cholesterol-can lead you into important questions that will eventually lead to treatment of disease.

--Interviewed by Vanessa McMains, written by Sarah Lewin

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