Dr. Carla Koehler: Studying Yeast Yields Important Data on How Human Cells Generate Energy
Dr. Carla Koehler2003 - Dr. Carla Koehler wants to know how the energy factory in every human cell assembles itself, and how that construction sometimes goes awry. Armed with this knowledge, it may be possible to design new drugs to correct the operational defects and, in the process, treat or prevent a host of diseases.
“All cells contain several hundred mitochondria—complex protein structures that produce most of a cell’s energy and perform various other vital functions,” says Dr. Koehler, a 2000 recipient of a Burroughs Wellcome Fund New Investigator Award in the Toxicological Sciences and an assistant professor of chemistry and biochemistry at the University of California-Los Angeles. “We are trying to understand the basic mechanisms of mitochondrial biogenesis, the process by which these powerhouses are constructed within cells, and also how one particular aspect of this process sometimes malfunctions to cause disease.”
Dr. Koehler focuses on how the inner of two membranes within mitochondria are constructed from proteins imported from the surrounding cytoplasm. “Very little is now known about the assembly and function of this inner membrane,” she says. “This is still an area ripe for experiment and discovery.”
Building on work she began as a postdoctoral fellow, she uses biochemical and genetic techniques to probe the details of mitochondrial biogenesis in Saccharomyces cerevisiae— baker’s yeast. “The process in yeast is very similar to that in humans, so this provides a useful model system,” she says. “Plus, it’s easy to grow lots of yeast, manipulate the cells genetically, purify lots of their mitochondria, and then apply a variety of biochemical tests to tease out the information we want.”
Of key importance, Dr. Koehler has identified a novel process that yeast mitochondria use in importing proteins and assembling their inner membranes. She also has shown that a specific genetic mutation in one of the components of this process causes a disease in humans— Mohr-Tranebjaerg syndrome—that leads to blindness, deafness, and an inability to move properly. “The cause of this disease had previously been unknown,” she says. “This is the first disease that has been directly attributable to a defect in the protein transport process that occurs in the inner membranes of mitochondria. So this really is opening a new field.”
Dr. Koehler also studies cells taken from patients with the disease, working jointly with one of the disease’s experts, Dr. Lisbeth Tranebjaerg of the University of Tromso, in Norway. “What’s particularly interesting is that we have identified additional patients with two other diseases that we suspect are caused by defects in mitochondrial protein transport,” Dr. Koehler says. “One is a type of cancer and the other is a type of Tourette’s syndrome, and we will be expanding our studies to include cultured cells from these patients as well.”
To build on these efforts, Dr. Koehler has been working to develop a mammalian model, using genetically engineered mice, for probing this novel protein transport process. “We can knock out a gene in mice in order to make them develop the disease,” she says. “Then we can study the mitochondria of the mice to better understand the fundamental molecular defects that give rise to the disease. Working in mice is slower and more difficult, but this will give us the opportunity to test the ideas that we gain from our work with yeast and cell cultures.”
Her group engineered a strain of mice that showed early promise but ultimately were unsuitable. “So we’re back to square one, in a sense,” she says. “But we learned a lot with our initial mouse model, and we hope to be able to apply this information in developing a new strain that has all the characteristics we need.”
The long-term goal is to learn enough about mitochondrial biogenesis to be able to develop new drugs or other therapeutic methods to fight disease. “We’ve only scratched the surface here,” Dr. Koehler says. “We already know of many diseases, including cancer, Parkinson’s disease, and Alzheimer’s disease, that are caused at least in part by mitochondrial malfunctions, and I believe that many other diseases—some common, some less so—will ultimately be linked to such problems. Finding drugs to treat these diseases will take a long time, but we won’t be able to really begin searching seriously until we’ve gained a better understanding of how mitochondria work.”
Growing up on a dairy farm in Wisconsin piqued Dr. Koehler’s interest in science. “I always seemed to be interested in how you might use genetics to breed cows that give more milk or have other desirable traits,” she says. Her farm-nurtured interests prompted her to major in biochemistry in college. She earned a B.S. from Iowa State University and then spent a year studying to become a veterinarian. “But I quickly found that I was more interested in basic research, so I switched back into biochemistry. I studied mitochondria in dairy cattle as part of my work for my master’s degree, and then for my doctorate I worked on developing more general models of how mitochondria function.” Along the way, she also received several Iowa State University Teaching Excellence awards.
Following her graduation in 1995, Dr. Koehler headed abroad for postgraduate work. “I studied with Dr. Gottfried Schatz at the University of Basel, in Switzerland—maybe not so far afield from Wisconsin’s dairy farms after all,” she says. “That’s where I first identified the protein import pathway in yeast that we are continuing to study in order to better understand mitochondrial biogenesis.”
Dr. Koehler moved to UCLA in 1999 and says her BWF award was instrumental in advancing her research. “The award was especially important in enabling me to extend my research into mammalian systems,” she says. “I didn’t have a long track record of working with mice, and so I lacked the preliminary data that the National Institutes of Health and most other granting agencies want to see. The award let me get my feet wet, based on the promise of my earlier work with yeast. As we’ve steadily gained experimental data, we have been able to win additional funding that will help us to continue these studies.” She now receives support from the National Institutes of Health, the Muscular Dystrophy Association, and the Beckman Foundation, among others.
“BWF’s award has helped me make the critical transition from starting up my own laboratory to becoming an ‘established investigator’ among my peers,” she says. “Based in large part on the research supported by the award, my department has recently nominated me for early tenure.”
She has reached another milestone as well: “My first four Ph.D. students are now going on to accept postdoctoral positions in other labs,” she says. “I’ll be very interested to watch their continued progress.”
Dr. Koehler stays in high gear both inside and outside the lab. “When I’m not in the lab, I’m usually on my bike,” she says.
Her bicycle has taken her into the world of elite racing: She’s the current national champion in the U.S. Cycling Federation’s Masters Team Pursuit event, which pits four-person teams of riders over age 30 against each other for a two-kilometer race on a cycling track. Not only did her team win, but Dr. Koehler also won the individual championship. In addition, she pedals in national competitions for a team sponsored by Minute Maid and Dasani. “We race to win, of course,” she says. “But we’re also trying to develop some younger women who will go on to ride for the U.S. national team or the Olympic team.”
In the community, Dr. Koehler periodically teaches science to third-graders in an inner-city school. “One of the members of my bike team teaches there, and she told me about the almost total lack of science education offered in her school,” she says. “So I’ve been going into her class and giving the kids presentations on microbiology. They seem to like it—and I know I do.”