Professor Alex Shalek (Massachusetts Institute of Technology)

E. Bright Wilson Prize Lecture

Title: IDENTIFYING & COUNTERACTING THE IMPACT OF ENVIRONMENT STRESSES ON TISSUE DYSFUNCTION

Abstract:

During chronic stress, cells must support both tissue function and their own survival. Hepatocytes perform metabolic, synthetic, and detoxification roles; with chronic nutrient imbalances, metabolic stress can precipitate metabolic dysfunction-associated steatotic liver disease (MASLD, formerly NAFLD/NASH). Despite prior work on stress-induced drivers of hepatocyte death, the functional impact of chronic stress on surviving cells remains unclear. In my talk, I will discuss how we used cross-species longitudinal single-cell multi-omic profiling to show that ongoing stress drives developmental and cancer-associated programs in non-transformed hepatocytes while reducing mature functional identity – significantly before transformation and predicting worsened human survival. Further, I will outline how we developed and applied integrative computational methods and experimental validations to uncover master regulators perturbing hepatocyte functional balance, increasing proliferation under stress, and directly priming future tumorigenesis. I will also explain how we utilized human tissue microarray spatial transcriptomics and geographic regression to reveal spatially-structured multicellular communities and signaling interactions shaping stress responses. Finally, toward counteracting these core mechanisms driving tissue dysfunction and instability, I will present our development of a new information-rich, high-throughput phenotypic screening platform, with reduced required sample, labor and cost requirements, that can be leveraged to help discover strategies to improve tissue health and resilience. 

Biography:

Alex K. Shalek, PhD, is the Director of the Institute for Medical Engineering & Science (IMES), the J. W. Kieckhefer Professor in the Department of Chemistry, and an Extramural Member of The Koch Institute for Integrative Cancer Research at MIT.  He is also an Institute Member of the Broad Institute, a Member of the Ragon Institute, an Assistant in Immunology at MGB, and an Instructor in Health Sciences & Technology at HMS. Dr. Shalek received his bachelor's degree summa cum laude from Columbia University and his Ph.D. from Harvard University in chemical physics under the guidance of Hongkun Park, and performed postdoctoral training under Hongkun Park and Aviv Regev (Broad/MIT). His lab’s research is directed towards the development and application of new approaches to elucidate cellular and molecular features that inform tissue-level function and dysfunction across the spectrum of human health and disease. Dr. Shalek and his work have received numerous honors including a NIH New Innovator Award, a Beckman Young Investigator Award, a Searle Scholar Award, a Pew-Stewart Scholar Award, the Avant-Garde (DP1 Pioneer) Award from the National Institute for Drug Abuse (NIDA), and an Alfred P. Sloan Research Fellowship in Chemistry, as well as the 2019-2020 Harold E. Edgerton Faculty Achievement Award at MIT and the 2020 HMS Young Mentor Award.