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  • Updated 10.25.2022
  • Released 07.28.2022
  • Expires For CME 10.25.2025

Perspectives: Dr. Christopher Walsh and genetic mechanisms underlying the developing and aging brain

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).

References

All contributors‘ financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

01
Bae BI, Tietjen I, Atabay KD, et al. Evolutionarily dynamic alternative splicing of GPR56 regulates regional cerebral cortical patterning. Science 2014;343(6172):764-8. PMID 24531968
02
Bizzotto S, Dou Y, Ganz J, et al. Landmarks of human embryonic development inscribed in somatic mutations. Science 2021;371(6535):1249-53. PMID 33737485
03
Chenn A, Walsh CA. Regulation of cerebral cortical size by control of cell cycle exit in neural precursors. Science 2002;297(5580):365-9. PMID 12130776
04
Doan RN, Bae BI, Cubelos B, et al. Mutations in human accelerated regions disrupt cognition and social behavior. Cell 2016;167(2):341-54.e12. PMID 27667684
05
Evrony GD, Cai X, Lee E, et al. Single-neuron sequencing analysis of L1 retrotransposition and somatic mutation in the human brain. Cell 2012;151(3):483-96. PMID 23101622
06
Ferland RJ, Eyaid W, Collura RV, et al. Abnormal cerebellar development and axonal decussation due to mutations in AHI1 in Joubert syndrome. Nat Genet 2004;36(9):1008-13. PMID 15322546
07
Fox JW, Lamperti ED, Ekşioğlu YZ, et al. Mutations in filamin 1 prevent migration of cerebral cortical neurons in human periventricular heterotopia. Neuron 1998;21(6):1315-25. PMID 9883725
08
Gleeson JG, Allen KM, Fox JW, et al. Doublecortin, a brain-specific gene mutated in human X-linked lissencephaly and double cortex syndrome, encodes a putative signaling protein. Cell 1998;92(1):63-72. PMID 9489700
09
Gleeson JG, Lin PT, Flanagan LA, Walsh CA. Doublecortin is a microtubule-associated protein and is expressed widely by migrating neurons. Neuron 1999;23(2):257-71. PMID 10399933
10
Guillery RW, Walsh C. Changing glial organization relates to changing fiber order in the developing optic nerve of ferrets. J Comp Neurol 1987;265(2):203-17. PMID 3693606
11
Hill RS, Walsh CA. Molecular insights into human brain evolution. Nature 2005;437(7055):64-7. PMID 16136130
12
Huang AY, Li P, Rodin RE, et al. Parallel RNA and DNA analysis after deep sequencing (PRDD-seq) reveals cell type-specific lineage patterns in human brain. Proc Natl Acad Sci U S A 2020;117(25):13886-95. PMID 32522880
13
Jamuar SS, Lam AT, Kircher M, et al. Somatic mutations in cerebral cortical malformations. N Engl J Med 2014;371(8):733-43. PMID 25140959
14
Johnson MB, Sun X, Kodani A, et al. Aspm knockout ferret reveals an evolutionary mechanism governing cerebral cortical size. Nature 2018;556(7701):370-375. PMID 29643508
15
Lehtinen MK, Zappaterra MW, Chen X, et al. The cerebrospinal fluid provides a proliferative niche for neural progenitor cells. Neuron 2011;69(5):893-905. PMID 21382550
16
Lim ET, Uddin M, De Rubeis S, et al. Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder. Nat Neurosci 2017;20(9):1217-24. PMID 28714951
17
Lodato MA, Rodin RE, Bohrson CL, et al. Aging and neurodegeneration are associated with increased mutations in single human neurons. Science 2018;359(6375):555-9. PMID 29217584
18
Lodato MA, Woodworth MB, Lee S, et al. Somatic mutation in single human neurons tracks developmental and transcriptional history. Science 2015;350(6256):94-8. PMID 26430121
19
Miller MB, Huang AY, Kim J, et al. Somatic genomic changes in single Alzheimer's disease neurons. Nature 2022;604(7907):714-22. PMID 35444284
20
Morrow EM, Yoo SY, Flavell SW, et al. Identifying autism loci and genes by tracing recent shared ancestry. Science 2008;321(5886):218-23. PMID 18621663
21
Poduri A, Evrony GD, Cai X, et al. Somatic activation of AKT3 causes hemispheric developmental brain malformations. Neuron 2012;74(1):41-8. PMID 22500628
22
Reid CB, Tavazoie SF, Walsh CA. Clonal dispersion and evidence for asymmetric cell division in ferret cortex. Development 1997;124(12):2441-50. PMID 9199370
23
Rodin RE, Dou Y, Kwon M, et al. The landscape of somatic mutation in cerebral cortex of autistic and neurotypical individuals revealed by ultra-deep whole-genome sequencing. Nat Neurosci 2021;24(2):176-85. PMID 33432195
24
Walsh C, Cepko CL. Clonally related cortical cells show several migration patterns. Science 1988;241(4871):1342-5. PMID 3137660
25
Walsh C, Cepko CL. Widespread dispersion of neuronal clones across functional regions of the cerebral cortex. Science 1992;255(5043):434-40. PMID 1734520
26
Walsh C, Cepko CL. Clonal dispersion in proliferative layers of developing cerebral cortex. Nature 1993;362(6421):632-5. PMID 8464513
27
Walsh C, Polley EH, Hickey TL, Guillery RW. Generation of cat retinal ganglion cells in relation to central pathways. Nature 1983;302(5909):611-4. PMID 6835394
28
Walsh C, Polley EH. The topography of ganglion cell production in the cat's retina. J Neurosci 1985;5(3):741-50. PMID 3973694
29
References especially recommended by the author or editor for general reading.

Contributors

All contributors‘ financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

  • Walsh Christopher 325 X325

    Christopher A Walsh MD PhD

    Dr. Walsh of Harvard Medical School has no relevant financial relationships to disclose.

    See Profile

Editor

  • Aprr

    Raymond P Roos MD

    Dr. Roos is a shareholder in Amgen, Ionis, Merck, and Pfizer.

    See Profile

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