Interview questions

[00:35] Can you tell us about your early life--your family, mentors, and other people or circumstances that inspired or influenced you toward a scientific or medical career?

[02:50] How did your mother and father influence your career?

[04:30] What were some of the pivotal moments in the development of your career?

[07:11] Why did you end up in neurology with a strong focus on genetics?

[11:17] Who else has inspired you in your career?

[14:00] Tell us what got you involved in studying brain development.

[16:30] Tell us about your studies of brain development--tracking cell lineage and barcoding.

[21:10] How about the use of barcoding in the human central nervous system?

[23:36] You seem focused on DNA and somatic mutations. How about RNA?

[29:00] What’s on the horizon? What do you see as the next challenge?

[31:16] Is travel still important in your studies?

[35:00] As an MD investigator. How important is the role of physician scientist going forward?

[38:00] You have Norweigan heritage, and the Kavli is a Norweigan award. Have you been to Norway--explored your roots there?

[40:20] What advice would you give to medical students, residents, and fellows who are interested in research?

Introduction

Education and training

Institution and Location	Degree	Completion Date	Field of Study
Bucknell University	BS	06/1978	Chemistry
The University of Chicago	PhD	12/1983	Neurobiology
The University of Chicago	MD	06/1985	Medicine
Massachusetts General Hospital	Resident	06/1986	Internal Medicine
Massachusetts General Hospital	Resident and Chief Resident	06/1989	Neurology
Harvard Medical School	Postdoctoral Fellow	12/1992	Genetics

Personal statement

Our lab is well suited to mentor trainees in the Neuroscience T32 Training program because of our longstanding interest in (1) genetics of human brain disorders, (2) cell lineage in human brain, and (3) single-cell genomic technologies. Previous and ongoing work from our lab studies genetic disorders of human cerebral cortical development that are associated with epilepsy, intellectual disability, and other learning disorders. Mutations in these essential genes disrupt the normal development and function of the human brain and cause pediatric brain diseases, manifesting as autism and epilepsy, as well as intellectual disability and other learning disorders. We have identified more than three dozen human disease genes over the course of 20 years. Recent work from our lab has pioneered the analysis of clonal somatic mutations as causes of disease, and we have revealed roles for somatic mutations in focal epilepsy, autism spectrum disorders, and schizophrenia. We have also analyzed rates of occurrence of somatic mutations in normal neural cells and revealed the ongoing accumulation of somatic mutations with age in single human neurons, even though these cells do not divide in adulthood. Our work on single-cell genomics has resulted in an expansion of our research into brain aging and degenerative diseases.

Before becoming Chief of the Division of Genetics and Genomics at Boston Children’s Hospital, I served as Director of the Harvard-MIT MD-PhD training program for 3 years and have been active on many committees and as an advisor for this program for 20 years; I have also served on the steering committee of the Program in Neuroscience. I have been involved in postdoctoral training of over 40 MDs, PhDs, and MD PhDs and more than 20 successful predoctoral PhD students. Most of these trainees continued to be involved in medical research after leaving my lab, many starting their own labs. I am enthusiastic to continue in my role as a mentor to graduate trainees.

Ongoing projects

Howard Hughes Medical Institute	Walsh (PI)	10/01/02 to 08/31/24 HHMI
HHMI Investigator in patient-oriented research The major goals of this project are to describe syndromes in which the development of the human brain is abnormal and determine the genetic basis of these syndromes. Role: PI
R01 NS035129	Walsh) (PI)	07/01/20 to 07/31/24 NIH/NINDS
Human epilepsy genetics: neuronal migration disorders The major goals of this project are to map and clone autosomal recessive neuronal migration disorders. Role: PI
R01NS032457	Walsh (PI)	07/01/20 to 06/30/25 NIH/NINDS
Cell identity determination in human brain: somatic mutation and cell lineage The goal of this study is to use somatic mutations to trace normal cell lineage in the human cerebral cortex. Role: PI
R01AG070921	Walsh (PI)	04/01/21 to 03/31/26
NIH/NIA Rates and mechanisms of age-related somatic mutation in normal and Alzheimer brain The major goal of this grant is to determine the rates and signatures of somatic variants across the aging and Alzheimer brain. Role: PI
Tan-Yang Center for Autism Research	Walsh (PI)	04/01/21 to 03/31/26
Harvard Medical School Functional analysis of somatic and de novo mutations in autism spectrum disorder The major goals of this project are to study the functional impact of noncoding mutations on autism spectrum disorder
(16; 17; 23; 19)

Positions, scientific appointments, and honors

Positions and Employment

2017-	Director and Co-PI, Allen Discovery Center for Human Brain Evolution at BCH and HMS
2006-	Professor of Pediatrics, Harvard Medical School
2005-	Chief, Division of Genetics and Genomics, Children’s Hospital Boston
2004-	Associate Member, Broad Institute of MIT and Harvard
2002-	Investigator, Howard Hughes Medical Institute
1999-	Bullard Professor of Neurology, Harvard Medical School
1997-1999	Associate Professor of Neurology, Harvard Medical School
1996-2009	Chief, Division of Neurogenetics, Beth Israel Deaconess Medical Center
1993-1997	Assistant Professor of Neurology, Harvard Medical School

Other Experience and Professional Memberships

2020-	Scientific and Academic Advisory Committee, The Weizmann Institute, Israel
2019-	Editorial Board, neuroDEVELOPMENTS, Lieber Institute for Brain Research
2019-	Clinical and Translational Advisory Board, Maze Therapeutics
2018-	Member, National Academy of Sciences
2017-2021	Multi-Council Working Group for the NIH BRAIN Initiative
2016-2020	National Advisory Mental Health Council, NIMH
2014-2021	Cell Types and Connectivity Advisory Council, Allen Brain Institute, Seattle
2013-	Member, National Academy of Medicine
2012-2021	Associate Editor, Annals of Neurology
2009	NIMH ARRA “Editorial Board”
2003-2007	Director, Harvard-MIT Combined MD-PhD Training Program
2002-2010	Board of Reviewing Editors, Science
1999-	Editorial Board, Neuron

Honors

2022	Kavli Prize in Neuroscience (with Huda Zoghbi, Harry Orr, Jean-Louis Mandel)
2021	Gruber Prize in Neuroscience (with Christine Petit)
2020	Distinguished Alumni Award, University of Chicago Medical and Biological Sciences Alumni Association
2018	The Mary and Joseph Pignolo Award and Lecture for Aging Research, Univ. of Pennsylvania
2018	Elected member, National Academy of Sciences
2018	Elected member, American Academy of Arts and Sciences
2017	Boston Children’s Hospital Postdoctoral Association Award for Outstanding Mentoring
2016	Science/Eppendorf Grand Prize to Gilad Evrony for work done in the Walsh lab
2016	Perl-University of North Carolina Neuroscience Award
2013	Elected member, Institute of Medicine/National Academy of Medicine
2013	Howard Hughes Medical Institute “Holiday Lectures”
2010	Pruzansky Award and Lecture, American College of Medical Genetics
2010	Cortical Discoverer Award, Cajal Club
2010	Wilder Penfield Award, Middle Eastern Medical Assembly
2010	Elected Fellow, American Association for the Advancement of Science
2008	Elected member, Association of American Physicians
2008	Galloway Award, Bucknell University
2007	Jacoby Research Award, American Neurological Association
2002	Science/Eppendorf Grand Prize to Anjen Chenn for work done in the Walsh lab
2002	Epilepsy Research Award, American Epilepsy Society
2001	Jacob Javits Distinguished Investigator Award, NINDS
2001	Dreifuss-Penry Epilepsy Award, American Academy of Neurology
1999	Derek Denny-Brown Award, American Neurological Association
1988	Chief Resident in Neurology, Massachusetts General Hospital
1985	Steven Lukes award for excellence in neurology, The University of Chicago
1978	Phi Beta Kappa, Bucknell University

Contributions to science

Cell lineage and cell migration in the cerebral cortex. Work that I started as a fellow and continued in our lab was the first to analyze patterns of cell lineage and migration in mammalian cerebral cortex using retroviral gene transfer (24), showing for the first time that cortical neurons are generated by symmetric and asymmetric cell divisions of cortical progenitor cells (25; 22). I developed the first retroviral libraries encoding DNA “barcodes” to definitively mark lineage patterns (25; 22), showing that some clones of cortical neurons remain clustered near “sister” neurons derived from a common progenitor, whereas in other clones, daughter neurons take long, roundabout routes, becoming widely separated from their sister cells (24; 25; 22). Further work from our lab and others has elaborated this initial model into an increasingly precise description of cell lineage in the cortex, whereas our most recent work suggests that single-neuron, whole-genome sequencing allows cell lineage analysis of key steps in human embryogenesis as well as in human brain, postmortem (17; 02).

Gene discovery in human brain diseases. Our lab has identified, alone or collaboratively, more than three dozen genes mutated in developmental brain disorders, including malformations of the brain (DCX, RELN, FLNA, POMT1, POMT2, GTDC2, AHI1, GPR56, LRP2, AKT3, CEP85L) (08), microcephaly (ARFGEF2, CENPJ, ASPM, CDK5RAP2, PNKP, NDE1, JAM3, ZNF335, WDR62, QARS, CHMP1A, KATNB1, DONSON), “nonsyndromic” intellectual disability, in which intelligence is low without other obvious signs or symptoms (PAK3, CC2D1A, METTL23, and TRAPPC9), and autism spectrum disorders. Our pioneering contribution was to study consanguineous pedigrees from the Middle East that allow analysis of heterogeneous recessive brain disorders. We were the first to apply this approach systematically to autism spectrum disorders, implicating recessive and noncoding mutation in autism spectrum disorder (20). We were the first to show that somatic mutations cause a significant fraction of brain malformations (21; 13). Identification of these genes has provided (1) new diagnostic tests for patients and parents, (2) novel insights into how the cerebral cortex is constructed during development, and (3) new targets for future therapy.

Molecular mechanisms of cerebral cortical development. By creating animal models to complement our discoveries of genes essential for normal human brain development, we showed that modulation of symmetric and asymmetric cell divisions of cortical progenitor cells (25; 22) dramatically increases (03) or decreases (14) the overall size of the cerebral cortex developmentally and evolutionarily and that the embryonic cerebrospinal fluid represents a proliferative niche for cortical stem cells (15). We identified the DCX gene, essential for neuronal migration, and showed that DCX is expressed transiently in newborn neurons (08). This transient DCX expression in newborn neurons has been used as a marker in thousands of neurogenesis studies of the developing and adult brain (09) and in response to many manipulations and disease states.

Somatic mutation in the developing, aging, and degenerating human brain. Our lab discovered that somatic mutations--present in brain tissue but not in blood--resulting in activation of the PIK3-AKT3- MTOR pathway cause human hemimegalencephaly, a remarkable disorder in which half of the brain is overgrown, disorganized, and highly epileptic (21). We have also shown that somatic mosaic mutations contribute to autism spectrum disorders (16). We pioneered the intensive analysis of the genome of single human neurons in normal and diseased brain in order to understand the prevalence and range of somatic mosaic mutations that distinguish one neuron from another. We showed directly that LINE retrotransposons mobilize in neuronal progenitor cells at a low but consistent rate (05; 02) and that single human neurons frequently show large deletions or duplications that can arise during neurogenesis, as well as hundreds to thousands of single nucleotide mutations that reflect developmental and transcriptional histories (18). Most recently, we have shown that point mutations in mature, nondividing neurons accumulate inexorably with age--with multiple, specific mutagenic signatures--and more rapidly in conditions showing premature neurodegeneration, suggesting a potential general model of age-related neurologic decline (17).

Human brain evolution. Our lab has shown that a few of the genes mutated in human developmental brain disorders were targets of the evolutionary processes that distinguished the human brain from that of our primate ancestors (11). ASPM, which controls cortical size (14), and AHI1 (06), which controls axon targeting patterns and which is mutated in Joubert syndrome, show particularly strong evidence of positive evolutionary selection in the protein sequence in the lineage separating humans from other primates. GPR56 is subject to more than a dozen alternatively spliced forms that also showed dynamic evolution among mammals (01). Most recently, we have shown that some human-accelerated regions, which are considered to be evolutionarily critical for human brain evolution, can be mutated in disorders of human cognitive and social behavior (04), providing a means to systematically identify the genomic sequences underlying human evolution.

See a complete list of published work in MyNCBI (> 61,000 citations on Google scholar, h index=130).