Interview with Dr. Stahl

by Bowoo Lee

You conduct research in metabolic biology, particularly adipose tissue and its relationship to obesity-related disorders. How did you become interested in these topics?

I originally was interested in cancer research, primarily because there were some cases regarding cancer that I thought would be interesting to study. I started out my diploma thesis, the equivalent of a master’s thesis, in Germany working on cancer research and launched a Ph.D. research program at the Scripps Research Institute in La Jolla also working on cancer, particularly melanoma and cell biological aspects of how cancer cells are able to spread throughout the body. Around the time of my post-doc, it became clear that metabolism, which up to that point I had a straightforward textbook understanding of, really was not what we had previously thought. Ideas like new potential hormones that may be secreted from adipose tissues called into question what we had seen in textbooks. I thought, “Wow, this is an area that we took for granted,” and I got launched onto a path of becoming interested in metabolism and diseases related to fatty acids. 

What is the overarching goal of your research?

So currently, I would define the overarching goal of the lab as an attempt to re-engineer metabolic fluxes in order to further human health. By doing this, we are protecting certain tissues from lipid overload, which is one of the key aspects of obesity that can drive organ dysfunction, particularly in the liver and the heart, as well as providing a venue for excess calories to be consumed, particularly through bioengineering-based approaches to expand and activate of brown adipose tissue, which releases energy in the form of heat. These are complementary approaches that work together to combat while actively protecting our body from lipid overload. 

You’ve mentioned that you are developing ways to expand and activate brown adipose tissue. Why would you take this approach over other ones in order to fight obesity-related diseases?

The most important step is to come up with novel anti-obesity strategies. As you know, obesity is a worldwide problem, and obesity rates really haven’t been dropping in spite of many efforts to educate the public, so I would argue that we still need to find a way to combine nutritional approaches with some kind of pharmacological intervention. Although there have been some drugs that were effective, such as fenfluramine-phentermine, they had tremendous side effects. However, the ideas behind fen-phen, which was a combination of two compounds, one that inhibits appetite and another other that increases the utilization of calories by increasing the metabolic rate, struck a lot of people as an attractive approach. To find a safe way of expanding brown fat, which would achieve the same effect as fen-phen of utilizing excess calories so that they aren’t stored, is still a very interesting approach in my mind to combat obesity.

We tend to associate obesity with an “excess of fat.” However, those in your line of research would argue that increased adipogenesis is not the sole explanation for obesity. Can you elaborate on this?

This brings us to the fact that fat is not equal to “being fat.” There are different kinds of fat, including white fat, brown fat, and beige fat, which lies somewhere in between. The white fact functions mostly to store excess calories. The function of brown fat is to generate heat through uncoupled respiration, which is the process where the mitochondrial respiration chain functions normally, but the outcome is not the production of ATP; instead, the proton gradient is dissipated by a protein that sends the protons back to the inner mitochondrial matrix, which then produces heat rather than chemical energy. So this is called non-shivering thermogenesis, which plays an important role in most mammals, including newborn humans. Beige fat is inducible brown fat within white fat depots. Stem cells within white fat can make a decision of differentiating into white fat or beige fat, and prolonged cold exposure induces beige fat differentiation. So these are all the different flavors of fat, and there may be even more, which is an active area of investigation. 

To answer your question, we have to look at white fat primarily. White fat differs in its metabolic functions, and the major differences seem to come about in terms of where the fat is localized. One large area of fat accumulation is called subcutaneous adipose tissue. Another area where you can accumulate fat is within the intraperitoneal cavity and around the gut. These two fat depots behave very differently in terms of impacting insulin sensitivity, the hallmark of obesity. The expansion of white fat depots in the subcutaneous are often associated with the maintenance of insulin sensitivity and a “pear” body shape, with fat accumulated in the legs, arms, buttocks. These people may be overweight but they may be able to maintain metabolic fitness. However, accumulation around the intestines and around the stomach area, which you can see in people that have a “beer belly” or an “apple” shaped body, is much more associated with insulin resistance. This is interesting because females have a higher propensity to accumulate fat in the subcutaneous depots than males.

What is a typical day in your life as a scientist and a professor?

That has changed somewhat over the time I’ve been at Berkeley, of course.  It definitely has been a while since I’ve held a pipette in my hand. My life used to be completely dominated by the pursuit of science, and although things have definitely changed, I still have to say what excites me and gets me to work every day most is still formulating hypotheses, seeing new data, finding new and unexpected explanations for phenomena. Obviously, teaching is a huge part of what we’re doing here at Berkeley, and it’s something that I take very seriously and enjoy quite a lot. Coming from Stanford, I had no teaching experience so I was a little hesitant of teaching large undergraduate courses. But by now, I truly enjoy it and see it as a fun activity. 

What course are you teaching right now? 

I teach NST 160, which is a course that is closely related to my research, which obviously helps me to enjoy teaching it as I get to talk about metabolic bases of human diseases on a daily basis. It’s a large course, with somewhere between 140 and 160 enrolled students, which can be demanding. We cover a lot of ground regarding metabolic pathways. The concept of signalling cascades tends to be challenging for students, and a challenge that I encounter is teaching them in a way that they can see their relevance, because I ultimately want to understand how metabolic diseases work and how interventions for metabolic diseases rely heavily on signalling cascades. I think by now I’ve found a formula that manages to engage the students and prompt them to think about the functional outcomes of cascades rather than to just memorize them. 

What was your experience as an undergraduate student like? Did you already have an affinity for research?

Yeah, I think so! I mean, my nickname back in high school was “The Professor.” I always enjoyed learning about the sciences in general, from chemistry to medicine to astrophysics. As an undergraduate, I certainly was already on the path towards a career in chemistry or biomedical sciences. 

What is your advice for aspiring scientists?

That is always a hard question, because I think that our motivations can differ hugely. Some people are driven by altruistic forces and the joy of helping other human beings that may be sick. Others enjoy the chase of a new discovery. Some of us are driven by teaching and mediating knowledge to new generations. Or maybe a combination of those. So in terms of advice I would give for young scientists, this is not an area I would pursue for financial gain or fame. If you are pursuing it, you need to be sure that you can identify an academic topic that brings joy to you and that this occurs in modern science. Another piece of advice is that you have to be very failure-resilient. If you are not, I would not recommend a career in science. We always read about the experiments that have worked, but there are so many that haven’t worked. So to be able to say, “Let’s do it again” and to be able to re-formulate your hypothesis after a failed experiment and still be happy at the end of the day is important. 

Do you have any advice for undergraduate students approaching a PI for a position in their lab? How do you like to be approached?

Hm, that’s a good question. Obviously, we have a lot of very talented students, particularly in the pre-medical field, that hope to find a placement in a lab, but we can’t take them all. My advice would be to take the time to identify the areas that interest you. You will find that there is biomedically relevant research happening in many places on campus, and not just within the obvious choices, such as MCB and Nutritional Sciences and Toxicology, but also in departments like Chemical Biology, Bioengineering, Ophthalmology. So first of all, do your homework in terms of where you could find a mentor. There may be people out there doing things you find exciting that you haven’t thought about. Second, once you’ve identified researchers, don’t just make a list of names and blast a generic email out to twenty different professors; most would ignore you. I think you should take an extra step, then, to customize the email to the professor and say something like, “I read about your research in X subject that really excites me and fits well with my goals of becoming a researcher in X. I would love to join your lab.” And the third piece of advice is to try to complete your lab courses early on, so that you won’t be starting completely from scratch and to have at least some experience working in a lab environment. Highlight the experience you already have. If you don’t have a lot of lab experience, an advantage you could state in that case would be that you are willing to stay in that lab for more than, let’s just say a semester or a year. I think for most PI’s, students’ time commitment mitigates the steep learning curve that they initially have.