Mark C. Fishman’s laboratory seeks (1) to understand the genetic and neuronal structure of social behavior in vertebrates, and (2) to unravel the heart-brain axis, using the larval zebrafish to define the circuitry and function of autonomic control of cardiac function.
1. Social behavior. Social behavior is key to evolution, and its failure the major impediment evident in many psychiatric disorders. The time is ripe for its investigation because of the availability of computational and genetic tools. With quantitative and automated video tracking and imaging, and algorithms which train computers to recognize specific activities, we have captured and analyzed robust social behaviors, such as courtship, shoaling, aggression, and leadership, and discovered the precursors to such complex functions even in the larval fish. This makes this emergent behavior accessible to single cell and circuit analysis of neuronal activity.
We use the zebrafish because we have found previously, based on our large-scale genetic screen, that this species provides access to key genetic nodes, entrance points to complex biological processes. For example, complemented by physiological analyses, we were able to begin to understand the fashioning of vertebrate organ systems and the onset of their function.We compare the behaviors and circuitry of fish with defined genetic changes, introduced by CRISPR-based genetic modification of specific loci, including those putatively related to human disease.
2. Cardiac nervous system. The heart and brain are intimately linked, with second-by-second neural feedback to cardiac physiology from internal baro- and chemoreceptors. In addition, the heart has its own intrinsic set of nerves, today of poorly understood function. We are exploring the development and precise cell fate and connectivity of intrinsic neurons of the heart, and those that connect heart and brain, in order to understand how homeostatic control develops.
In the 1990s, by harnessing the first large-scale genetic screens in zebrafish (performed in collaboration with W. Driever and contemporaneously with C. Nuesslein-Volhard), and by providing much of the early genomic infrastructure, Fishman’s lab helped to make the zebrafish a cornerstone of developmental biology, and led to revelation of many of the pathways that guide vertebrate organ development, particularly the heart and vessels.
From 2002 to 2016, Fishman was the founding President of the Novartis Institutes for BioMedical Research (NIBR). During his tenure, NIBR discovered and brought through successful clinical trials 90 new medicines in more than 120 indications. Fishman brought a particular focus on regenerative medicines as treatments for disorders of aging. He has continued his interest in therapeutics, with Professor Melton inaugurating a new Harvard Masters program in Biotechnology of Life Sciences, combined with a Harvard MBA. He serves on the Board of Directors of Beam Therapeutics and Geneception Therapeutics, is a founder and SAB Chair of Aditum Bio, and SAB member of Tenaya Therapeutics.
Fishman graduated from Yale College and Harvard Medical School, and was a resident and Chief Resident in Medicine, and fellow in Cardiology, at the MGH and later Chief of the Cardiology Division and Director of the Cardiovascular Research Center at Harvard Medical School and MGH. In addition to his publications in developmental biology and drug discovery, Fishman is the author of the medical textbook, Medicine, and of the book Lab: Building a Home for Scientists, on the history and architectural design of buildings for scientists. Fishman is a member of the National Academy of Medicine, where he recently served two terms on the Executive Committee and Council, and is a Fellow of the American Academy of Arts and Sciences.
Frontiers in Therapeutics
How realistic are promises to “eliminate” diseases and to “personalize” medicine? This course looks at biological principles underlying therapeutics, ranging from those described first in Egyptian papyri to those under development today (using chemicals, proteins, cells, and genetic manipulations) and based on traditional philosophies and on science. As part of the class, students will have the opportunity to design novel approaches to diseases today without cure.