Le Dr. Andrew Wang He develops an approach to inflammatory diseases based on a thorough understanding of the mechanisms of immunity and their adaptive role. Trained between the United States and Europe, he is interested in the links between genetics, environment, and physiology to shed light on how normal immune responses can, in certain contexts, lead to disease.

Dr. Andrew Wang He is a physician-researcher in immunology, trained at Harvard and the University of Texas Southwestern, with additional experience in Paris. A specialist in inflammatory and autoimmune diseases, he has contributed to a better understanding of lupus by identifying key mechanisms involved in organ targeting.

After a postdoctoral fellowship at Yale, his work highlighted a fundamental link between inflammation and metabolismshowing that each inflammatory state corresponds to specific physiological responses.

Now an assistant professor at Yale, he heads a laboratory that studies how The environment influences the immune system and the progression of diseases, with the aim of advancing a personalized medicine.

Urban vs. rural environment: impact on the immune system, allergies, and inflammatory diseases

How has your journey from Harvard to Yale, via Texas and Paris, shaped your approach to research and your perspective on diseases? inflammatory?

Andrew Wang (AW) I started studying immunity and inflammation because my mother suffers from a lupusI remember being quite dissatisfied with how little we knew about this disease, which I thought explained the lack of better treatments. So, when I entered Harvard, I decided to work with Michael Carroll and I began to realize that we also lacked a comprehensive understanding of how the immune system generally functions. After graduating with my undergraduate degree, Mike suggested I pursue further studies in MD/PhD near Ward Wakeland at UT Southwestern.

In Ward's lab, I learned a great deal about the genetics of inflammation and immunity, and I developed a deep appreciation for evolutionary perspectives in biomedical research. It was there that I met Frédéric BatteuxOur collaboration led to my atypical internship at Paris Descartes University During my training, I maximized the synergies between our groups. This led to exciting discoveries and a two-way medical and scientific exchange between Paris and UT Southwestern that continues to this day.

After my MD/PhD, I chose to complete my medical and research training at Yale, under the mentorship of Ruslan MedzhitovRuslan instilled in me a profound rigor for developing and refining conceptual frameworks based on fundamental principles for addressing biomedical problems. My collective training within these diverse and enriching environments across two continents has indelibly shaped our approach to the study of inflammatory diseases: a deep understanding of the adaptive physiology of inflammation, shaped by evolution, in order to use it as a lens through which to grasp the pathophysiologyMy conviction that one must remain intellectually curious and intentionally expose oneself to different paradigms of thought is what led me to undertake my current sabbatical year in the Pasteur Institute of Lille.

Your early work highlighted how certain mechanisms of the immune system can cause specific damage in lupus. What did this discovery teach you about the functioning of the immune system and inflammatory diseases?

AW My early work with Ward attempted to answer a question that remains crucial and unresolved for diseases in general: why do some organs, and not others, become dysfunctional during a pathology? This question remains a focus of research and experimentation in my laboratory. We generally seek to understand which organ functions are critical for enabling animals to adapt to stressors, the underlying mechanisms that determine the prioritization of these organ functions during these challenges, and the logic and mechanisms underlying organs whose functions are interconnected. Some of our recent work on the gut-brain and skin-immune system axes attempts to answer these fundamental and still unresolved questions.

During your postdoctoral research, you demonstrated that different inflammatory states are accompanied by specific metabolic responses in the body. How has this idea influenced your approach to studying complex diseases?

AW My subsequent work with Ruslan aimed to address fundamental questions about how organisms modify their physiology and their behavior in the face of aggression. For example, when animals are deprived of food, they activate both a specific adaptive physiology (fasting) and specific behaviors (the search for food) essential to their survival. When exposed to cold, they trigger thermogenesis with and without shivering, as well as the search for warmth.

These highly conserved and stereotyped physiologies and behaviors are clearly essential for survival. What, then, are the adaptive physiologies and behaviors induced by the multiple inflammatory programs that evolution has shaped to defend us against a wide range of infections and injuries? Understanding this could shed light on the pathophysiologies and pathological behaviors that arise from the activation of these protective evolutionary responses, which remain incompletely understood.

What aspects of the environment do you consider most promising to study in order to better understand how the immune system works?

AW Some of our recent work attempts to address the nature of the evolutionary lag (evolutionary mismatchThe fact is that our The scalable architecture has been optimized. for an environment that no longer exists in much of the modern world. This would be like taking a fish that has been evolutionarily shaped and genetically optimized to thrive in a low-salinity aquatic environment and placing it in a high-salinity environment. Although it has programs designed to adapt to variations in salt content, the physiological trade-offs (trade-offs) related to the activation of these programs, particularly in a chronic manner, lead to pathophysiology.

Our scalable architecture was optimized for an environment that no longer exists in much of today's modern world. This mismatch causes chronic physiological compromises that lead to disease.

Andrew Wang

MD, PhD, AB – Associate Professor of Internal Medicine (Rheumatology)

In this simple example, many elements will differ apart from the salt concentration, and it took time to identify that this difference was the environmental divergence the most critical for this fish. What specific aspects of the modern environment affect which physiological compromises leading to pathophysiologies in which specific diseases? This is what we are trying to decipher. We pay particular attention to "experiments in nature" and spend a lot of time reflecting on studies of monozygotic twins, in whom identical genetic material placed in similar environments nevertheless leads, unexpectedly, to very different phenotypic expressions of the disease. In the laboratory, this phenomenon is frequently observed in genetically identical preclinical models housed in the same cages. Why is the expression of the disease so different? If we could understand the biological aspects that govern these very distinct trajectories, we could better understand and predict the clinical evolution of diseases.

Certain environments, such as urban or rural areas, expose the immune system to different factors. In your opinion, how might these differences help us better understand inflammatory diseases and, potentially, common immune reactions like allergies?

AW Epidemiological studies clearly demonstrate that autoimmune diseases et allergy are modern, urban diseases. As an aside, the reason my laboratory began studying allergies is that my eldest son suffers from a severe allergic condition; we have since radically changed our lifestyle and now live on a working farm. Historically, this observation has been attributed to the "hygiene hypothesis," according to which the absence of frequent exposure to pathogens leads to the expression of the disease in individuals carrying genetic variants maintained within the population because they conferred a survival advantage in the ancestral environment.

We wonder if there are others environmental factors specific to modern urban environments that foster this expression. To achieve real progress, a community effort will be essential, requiring the contribution of basic scientists from multiple disciplines (immunology, genetics, chemical biology, microbiology, neuroscience, etc.), epidemiologists, public health professionals, and clinical researchers. I am extremely pleased to see the current efforts to build these research coalitions.

Between basic research and clinical practice, you are confronted with patients with very diverse profiles. How can your discoveries in the laboratory today help to better prevent or manage inflammatory diseases, and, more broadly, certain immune reactions such as allergies, depending on the patients' living environment?

AW My approach to patient care and research is fully unified. Our efforts to elucidate the mechanisms of interindividual differences in basic laboratory work align with my approach to patients. "Personalized medicine"Although the term has become overused today, it has always been and always will be the goal of medicine for those who practice it with excellence. Doctors do not treat diseases; they treat people, and, obviously, every individual (even identical twins) is biologically unique. Understanding the key biological differences in each patient, how their unique genetics et their specific environmental exposures produce their own expression of the disease, will be key to identifying the unique treatments and lifestyle modifications that will benefit them most.

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