In 1924, the German physiologist Otto Warburg discovered that cancer cells consume an unusually enormous amount of glucose, pointing to the role of cell metabolism in tumor growth. Then, in the 2000s, a resurgence of interest in the metabolic pathways of malignant cells led to a renaissance in metabolism research.
Cancer is also where Jing Fan, the Arthur Nielsen chair in metabolism at the Morgridge Institute, built her early academic track record. But shortly after her arrival at Morgridge in 2016, Fan, who once wanted to study Chinese literature, made one more pivot — this time into a younger field called immunometabolism. The Fan Lab focuses on the way innate immune cells rewire their metabolism to support their functions. As the body’s first line of defense against any intruder or injury, these cells patrol the body and must be ready to take on a remarkably wide and dynamic set of functions to keep us healthy.
Fan discussed why she is so fascinated by the relationship between immunity and metabolism and what can go wrong when that relationship frays. The interview has been edited for length and clarity.
What should we know about immunometabolism — a relatively new field in the world of metabolism research?
- I think immunometabolism is so cool for the same reason that anything metabolism is so cool. It’s such a fundamental process that it is in the very definition of life. Once metabolism stops, life stops. But also, because it’s a fundamental chemistry of life, it’s very flexible. All cells have to do it, but they do it differently. That’s where innate immune cells become very interesting to me because immune cells are very functionally flexible. They have to defend. They have to regulate. They have to go all the way from killing to healing. Let’s say you have a cut and you want to make sure you fight against the pathogens, but then later you want to heal the wound. That involves very dynamic functional changes, and I think one important question in immunometabolism — and probably what I’m most excited about — is how this two-way interaction between the fundamental biochemistry reactions in metabolism and different immune functions works.
You’ve described Morgridge as a place where researchers can be like stem cells, where you can take your research into new directions. What has that meant for you over the ten years you’ve been here, coming in with an initial track record in cancer metabolism?
Earlier in my career I had an opportunity to work on cancer metabolism, and really loved that experience. That’s where we had a renaissance in metabolism; that’s where it started. But there can also be a tendency of chasing the wave — where the most papers and funding seem to be, like the wave of cancer metabolism. So initially, I came here and had some small projects still on cancer, for good reason. And yet my heart was really saying: this is a new thing. There were a lot more knowledge gaps that had not been addressed in other fields, including immune cells. So there was a feeling of wanting to go to where the frontier in the field is, and go after the questions that most interest me. With cancer, there was one major dimension: cells grow, don’t grow, grow fast, grow slow, and so on. Innate immune cells are fascinating. They don’t grow, but they have a lot of functional dimensions and nuances, for example even many different kinds of pro-inflammatory macrophages.
In addition to advice from Brad (Schwartz) and Dave (Pagliarini) who encouraged me to do what is meaningful and important to me, I really depended on a lot of collaborations and new mentorship. This is a very collaborative place, both here at Morgridge and at UW. I have a lot of people in my department on campus that are really good immunologists, and they’re very collaborative. That’s the beauty of being a scientist, being a lifelong learner.
What happens when innate immune cell metabolism goes wrong? And how does innate immunity interact with the metabolic diseases we hear about frequently in the news?
A lot of those factors are very interconnected and are hard to isolate one at a time. That’s why the more straightforward examples are inborn errors of metabolism, where one gene’s not functioning and causing a pathway to have some dysfunction.
More broadly, immune cell metabolism is often found altered in inflammatory conditions and autoimmune disorders, like rheumatoid arthritis. And on the other hand, metabolic disorders like diabetes often have comorbidities with defects and dysregulation in immunity. Things like diet can change metabolism directly and then change immunity, as can more complex things like aging. So there is a correlation, and the causal factors are an active area of research.
How does that interconnectedness affect the way we develop new therapeutic interventions based on immune cell metabolism?
With immune cells, you want them to do the right thing at the right time to the right amount — that makes for a highly complicated and interesting challenge in these cells. Whenever I see commercials about boosting your immunity, I think, “Why do you want to simply boost your immunity?” You could get into serious trouble if your immune cells overreact. As a field we want to learn ways to modulate, or to steer the different ways innate immune cells can do the right thing in the right amount, by learning how these things are regulated and modulated.