By Saphia Suarez
For Andrew Wang, MD/PhD, AB, his interest in inflammation biology started at home. “My mom has lupus, which is an autoimmune disease that causes the immune system to attack its own organs,” said Wang, assistant professor of medicine (rheumatology) and immunobiology. “So I spent a lot of my childhood accompanying her to the doctor. Then in high school biology, I learned the immune system is the one example where the one gene to RNA to protein rule does not hold. Out of a set of finite genes, our immune system can make an infinite number of proteins to protect us from things we've never seen. And that was just so intellectually addictive. So in high school I started researching inflammation biology, which I continued at Harvard through my undergraduate and PhD. And then I became a rheumatologist, so now I treat patients with the same condition as my mom.”
Wang came to Yale in 2011 to complete his internship, residency, fellowship, and post-doctoral training under the mentorship of Ruslan Medzhitov, PhD, Sterling Professor of Immunobiology, one of the foremost thinkers in inflammation biology. “I came to Yale for him,” said Wang. “I met him here when I was interviewing for the Physician Scientist Training Programs, and we really hit it off. Then I did my postdoc in his lab, and he continues to be the major mentor and father figure in my life now. He is the living definition of a true mentor.”
It was in Medzhitov’s lab that Wang became interested in behavioral responses to inflammation. “One of the major projects in his lab was essentially figuring out why my mom always told me to starve a fever and feed a cold,” said Wang. “I think many people have similar conventional wisdom given to them. And so we made the astonishing observation that it wasn't only that animals didn't eat when sick, but that what you fed them made a big difference depending on what type of infection they had.”
Wang discovered that in mice, sugar-containing foods offered protection from viral infections, but were deadly for mice with bacterial infections. “We identified that metabolic programs in an animal are tied to the type of inflammation that they need to defend against certain types of infection,” said Wang. “I spent about three years trying to decode those programs. This has a lot of clinical implications, because right now we don't adjust feeding based on type of infection.”
Wang now has his own lab, and is currently working on identifying host environment interactions that impact inflammation response. The first paper out of his lab was published in Cell in 2020. “We found a mechanistic explanation for why increased psychosocial stress is a good thing when you're trying to run away from a lion, which is how we evolved to have this stress response. But there's a cost for this, which is that if you experience inflammation, you may not tolerate that well. Which makes sense—there’s usually a cost for most things that we have to do.”
Wang is now exploring the experimental oddity called lethal dose 50. “Lethal dose 50 occurs when you give genetically identical mice living in the same conditions the same dose of something and half of them die. And it turns out that this is a related phenomenon to diseases like lupus, where if you have genetically identical twins and they live in the same conditions with the same characteristics, only about 40% of the time at best will both twins develop the same disease. This goes back to nature versus nurture, and how much of biology is truly random. We don't respond to stress in the same way. Those are not things that are entirely genetically encoded, they're encoded within social structures. So we normalized all these different micro-environmental changes and found a big effect size in psychosocial stress. The lethal dose 50 effect went away, and mortality increased to 100%. In other words, stress kills.”
Wang is looking at the connection between preceding stress and autoimmune flareups. “We are interested in the mind-body connection,” said Wang. “So, how does preceding stress lead to actual physiological changes, like a lupus flare?” Wang knows it starts in the environment. For patients with autoimmune diseases, flares in the disease correlate to environmental stressors, such as major life events. “We don't know what in the environment matters,” said Wang. “There are a lot of diseases that are much more common now in the modern environment than even 50 years ago. So we are essentially trying to sort out the dark matter within this new modern environment.”
Looking forward, Wang is hoping to explore placebo and nocebo effects. “In most clinical trials, there's always a placebo group and there's always a response in that group, often around 20 or 30%. So how does that work? Because if we could figure that out, we could boost drug responses across the board and leverage placebo biology to improve the effect size of therapy. And likewise, can we use nocebo biology—which is when you perceive that something will make you worse and it does—to prevent the failure of certain treatment responses? This could have large implications for inflammation biology, because the observation we made that stress makes inflammation worse is essentially one version of nocebo.”
The Section of Rheumatology, Allergy and Immunology is dedicated to providing care for patients with rheumatic, allergic and immunologic disorders; educating future generations of thought leaders in the field; and conducting research into fundamental questions of autoimmunity and immunology. To learn more about their work, visit Rheumatology, Allergy & Immunology.