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From Saphia Suarez
Andrew Wang, MD / PhD, AB, became interested in inflammation biology at home. “My mother has lupus, an autoimmune disease in which the immune system attacks its own organs,” said Wang, assistant professor of medicine (rheumatology) and immunobiology. “So I spent a large part of my childhood accompanying her to the doctor. Then I learned in high school biology that the only example where the one gene-to-RNA-to-protein rule doesn’t apply is the immune system. From a series of finite genes, our immune system can make an infinite number of proteins that protect us from things we have never seen before. And that was just so intellectually addicting. So, in high school, I began research into inflammation biology, which I continued at Harvard through my bachelor’s and doctorate degrees. And then I became a rheumatologist and now treat patients with the same ailments as my mother. “
Wang came to Yale in 2011 to complete his internship, residency, fellowship, and postdoctoral training under the direction of Ruslan Medzhitov, PhD, Sterling Professor of Immunobiology, one of the leading thinkers in inflammatory biology. “I came to Yale because of him,” said Wang. “I met him here at interviews for the Physician Scientist Training Program and we got along really well. Then I did my postdoc in his laboratory, and he is still the most important mentor and father figure in my life. He is the living definition of a true mentor. “
In Medzhitov’s laboratory, Wang became interested in behavioral responses to inflammation. “One of the big projects in his lab was basically trying to figure out why my mother used to tell me to starve to death and feed a cold,” said Wang. “I think a lot of people have similar conventional wisdom. And so we made the amazing observation that animals not only do not eat when they are sick, but that what you feed them makes a big difference, depending on what type of infection they have. “
Wang discovered that sugary foods offered protection from viral infections in mice, but were fatal to mice with bacterial infections. “We found that an animal’s metabolic programs are tied to the type of inflammation it needs to fight off certain types of infections,” Wang said. “I spent about three years deciphering these programs. This has a lot of clinical implications because at the moment we are not adapting the diet to the type of infection. “
Wang now has his own laboratory and is currently working on identifying interactions with the host environment that affect the inflammatory response. The first work from his laboratory was published in Cell in 2020. “We found a mechanistic explanation for why increased psychosocial stress is a good thing when trying to run away from a lion, and that’s how we evolved into that stress.” However, there is a cost to this, namely that if you have inflammation, you may not tolerate it as well. That makes sense – most of the things we have to do usually come at a cost. “
Wang is now exploring the experimental oddity known as the 50 fatal dose. “The fatal dose of 50 occurs when you give genetically identical mice that live under the same conditions the same dose of something and half of them die. And it turns out that this is a phenomenon related to diseases like lupus, in which if you have genetically identical twins and they live in the same conditions with the same traits, only about 40% of the time at best both twins develop the same disease. This goes back to nature versus care and how much of the biology is really random. We don’t react the same way to stress. These are not things that are completely genetically coded, but coded within social structures. So we normalized all of these various micro-environmental changes and found a large effect size on psychosocial stress. The lethal dose-50 effect disappeared and the mortality rose to 100%. In other words, stress kills. “
Wang examines the relationship between previous stress and autoimmune attacks. “We are interested in the mind-body connection,” said Wang. “So how does previous stress lead to actual physiological changes, like a lupus flare?” Wang knows that it starts in the area. In patients with autoimmune diseases, disease flare-ups correlate with environmental stressors, such as major life events. “We don’t know what’s important in the environment,” said Wang. “There are many diseases that are much more common in the modern environment than they were 50 years ago. So we are essentially trying to sort out the dark matter in this new modern environment. “
Looking ahead, Wang hopes to explore placebo and nocebo effects. “In most clinical trials there is always a placebo group and there is always a response in that group, often around 20 or 30%. How does this work? Because if we could figure that out, we could increase drug response across the board and use placebo biology to improve the effectiveness of therapy. And can we also use nocebo biology – that is, when you notice that you are making something worse and it is – to prevent certain treatment responses from failing? This could have a major impact on inflammation biology, because our observation that stress exacerbates inflammation is essentially a version of nocebo. ”
The Rheumatology, Allergy and Immunology Section is dedicated to the care of patients with rheumatic, allergic and immunological diseases; Training future generations of thought leaders in this field; and research on basic autoimmunity and immunology issues. To learn more about their work, visit Rheumatology, Allergy & Immunology.