Our goal is to discover the genetic, cellular, and neural pathways that govern social behaviors.
Animals live in conspecific groups, as schools of fish, flocks of birds, or tribes of humans. This behavior provides evolutionary advantages in foraging for food, avoidance of predators, and choice of migratory routes, but also requires sacrifices on the part of individuals. What are the forces that direct individuals to participate in and lead such groups? How are they communicated? Are these behaviors encoded In the nervous system and how are they translated into action? How and when do these behaviors develop?
The medical implications of this work are profound. Many psychiatric disorders, including autism and schizophrenia, are manifest primarily as deficits in certain social abilities. Are the genes associated with psychiatric illness among those dedicated to social interactions? Are their roles conserved from fish to man?
Mark C. Fishman, M.D.
- Professor of Stem Cell and Regenerative Biology
- Principal Faculty
Harvard Stem Cell Institute
- Board of Directors
- Board of Directors
- Co-Founder and Chair of the Scientific Advisory Board
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.
Genetics of Adult Collective Behavior
Collective behavior is an “emergent” group property, with complexities not readily predicted by behaviors of the individuals, but rather dependent upon their interactions. Thus, one might question whether genetic changes in individuals can lead to interpretable changes in the collective. We know that other complex emergent systems can be amenable to genetic dissection. We discovered this more than 25 years ago as we helped to pioneer the use of zebrafish genetic screens, in our case to explore the fashioning of vertebrate organ form and function, where we found that single gene mutations can delete a specific part of a tissue, or change its function in an interpretable manner.
We have developed computer vision tools to track individual zebrafish in shoals while swimming in open arenas, and have generated algorithms to quantify and describe the activity of individual fish and to surmise the forces between them (for example, attraction or alignment). By CRISPR-Cas9 we have systematically deleted individual genes. Several distinctive shoal patterns emerge, driven by individual mutations. We have modelled the patterns and forces and can describe the mutations’ effects upon individual fish that would drive the novel emergent behaviors of the group. Some mutations cause fish to scatter, essentially ignoring one another; others to huddle in small relatively immobile clusters; and others to enhance coordinated aligned swimming of the whole group.
Relationship to Psychiatric Disease
The genes we have knocked out, and which affect the social interactions of the fish, are those believed to be related to psychiatric disease in humans particularly autism and schizophrenia. In one case, we have been able completely to reverse the behavioral changes using Clozapine, the anti-psychotic medicine used for patients with schizophrenia. This suggests that some genes may have conserved roles in social behavior from fish to man.
Development of Social Behavior
Larvae do not exhibit profound social behaviors, but the neuronal circuity are more readily assayed in the smaller and transparent larvae. Indeed, in collaboration with the laboratory of Florian Engert, using a variety of assays including virtual reality, we have shown specific behavioral deficits caused by their mutations. Our models can predict how and where in the brain such perturbations are based, theories now being explored with single cell calcium imaging.
We have defined a genetic structure to collective behavior. Many questions remain, for example: (i) are the single genes part of “social behavior pathways”? If so, we should be able to elicit similar phenotypes by mutating other genes in the same pathway or cellular function. (ii) Can we discover “social behavior” neurons and circuits? We are currently modeling the larvae behavior, an approach which can suggest responsible brain regions, which we are exploring with GCaMP imaging. We will also avail ourselves of new techniques to image the brain of head-fixed adult zebrafish exposed to virtual reality environments. (iii) Are “group behavior genes” conserved and, if so, are their mutations related to psychiatric disease and potential therapies? Recent research suggests that autism and other psychiatric illnesses may perturb the “social brain”, many elements of which are conserved from fish to man. Thus, given our current success, as new candidate genes emerge, we will continue to explore their roles in social behaviors of zebrafish.