Research Expertise

Research Interests:
Our lab aims to understand cellular host responses to virus infection, and the environment encountered and manipulated by viruses. We study multiple viruses in an integrated experimental approach that combines biochemistry, molecular biology, genetics and cell biology. We have chosen viral models that provide tractable systems to investigate the dynamic interplay between viral genetic material and host defense strategies. The pathways illuminated are key to fighting diseases of both viral infection and genome instability, and our studies have significant implications for the development of efficient viral vectors for gene therapy.

Description of Research:
Viruses try to hijack cellular machinery to aid their own replication, but the host cell often responds with defense systems that can create obstacles for the virus. Watching these battles unfold has contributed significantly to our understanding of fundamental cellular mechanisms and has established viruses as powerful model systems to study cell biology. We have a particular interest in the interactions between viruses and the DNA repair pathways of the host cell. The work in my lab addresses the fundamental question of how the human genome maintains integrity in the face of viral genetic assault. Viral genomes pose a direct threat to the host genome. During infection a battle ensues in which both host and viral genomes must each be protected to maintain their genetic integrity. We study the dynamic interactions between viruses and host cells when their genomes are in conflict. My lab discovered that the cellular apparatus that resolves DNA damage also acts as a defense against viral assault. The sophisticated surveillance network for sensing and repairing DNA prevents an array of human diseases. When compromised it results in genomic instability that ultimately leads to cancer. We are studying how the cellular damage sensing machinery as an intrinsic defense to virus infection, and ways in which viruses mount a counterattack by dismantling the cellular DNA repair machinery or even exploiting it to aid their own replication. In addition to understanding virus-host interactions, studying DNA repair together with the natural process of virus infection provides a platform for interrogating cellular pathways involved in recognition and processing of DNA damage.

We study Adenovirus (Ad), Herpes Simplex Virus (HSV-1), and Adeno-Associated Virus (AAV). These viruses each have different types of DNA genomes and have developed distinct ways of manipulating host defenses. Unraveling the complex host cell response to invading viral genomes has broad implications for fighting diseases of both viral infection and genome instability. Our studies on repair and silencing of viral genomes have significant implications for the development of efficient viral vectors for gene therapy. Viral complexes that manipulate host pathways reveal novel ways in which protein modifications regulate diverse processes. The conflicts between virus and host also impact and inform us about the evolution of our genome.

Keywords:
Virology, Virus Replication, DNA Damage and Repair, Genome Instability, Viral Vectors

Current projects:
We have created an interactive and collaborative lab environment where students and postdocs are encouraged to explore multiple projects and challenge each other intellectually.

- Impact of DNA damage responses on virus infection and gene delivery
- Identifying targets for viral encoded ubiquitin ligases
- Roles for post-translational modifications in regulating viruses
- Epigenetic changes during virus infection
- Identifying host restriction factors during virus infection
- Defining functions for the cellular APOBEC proteins
- Exploiting viral manipulation of cellular pathways to improve gene targeting and gene therapy

Lab Personnel

 

Graduate Groups

Cell and Molecular Biology

Education

B.Sc. (Honours degree in Genetics), University of Leeds, UK, 1987
Ph.D. (Molecular Virology), Oxford Polytechnic and the Institute of Virology and Environmental Microbiology of the Natural Environment Research Council (NERC), Oxford, UK, 1991

Specialty Certification

Postgraduate Training

Fogarty Postdoctoral Fellow, Laboratory of Molecular and Cellular Biology, NIDDK, NIH, 1991-1993
Postdoctoral Fellow, Cystic Fibrosis Foundation Fellow, University of Pennsylvania Medical Center, 1993-1994

Awards and Honors

Natural Environment Research Council (NERC) Graduate Student Scholarship, 1984-1987
Prize Winner in the Daily Telegraph Young Science Writer Awards, "Kamikaze Caterpillar Killers", 1989
Fogarty Visiting Fellowship at NIH, 1991-1993
Cystic Fibrosis Foundation Postdoctoral Fellowship, 1994-1995
Innovation Grant recipient, Presidents' Club of the Salk Institute, 1998
Innovation Grant recipient, Presidents' Club of the Salk Institute, 1999
Young Investigator Award, American Society for Gene Therapy, 2004
Pioneer Developmental Chair, Salk Institute, 2008-2011
Innovation Grant recipient, the Salk Institute Innovation Fund, 2008
Harold S Ginsberg Lecture, America Society for Virology Annual Meeting, 2010
Foerderer Award, The Children’s Hospital of Philadelphia, 2013
CHOP Faculty Mentor Award, The Children's Hospital of Philadelphia, 2016
CHOP Award for Excellence in Mentoring Research Trainees, The Children's Hospital of Philadelphia, 2017
Arthur K. Asbury Outstanding Faculty Mentor Award, University of Pennsylvania Perelman School of Medicine, 2020
Arthur Vincent Meigs Endowed Chair in Pediatrics, The Children’s Hospital of Philadelphia, 2022-Present
Elected Fellow of the American Academy of Microbiology (AAM), 2024

Memberships and Professional Organizations

American Society for Gene and Cell Therapy (ASGCT), 1990 - Present
American Society for Virology (ASV), 1990 - Present
American Society for Microbiology (ASM), 1990 - Present
University of Pennsylvania, 1997 - Present
National Gene Vector Labs (NGVL), 1999 - 2006
United States-Israel Binational Science Foundation, 2000 - 2000
Wellcome Trust Foundation, UK, 2001 - Present
Italian Telephon Foundation, 2002 - 2002
American Society for Gene and Cell Therapy (ASGCT), 2002 - Present
NIH Molecular Therapy Core Centers, 2003 - 2003
NIH Special Emphasis Panel on Gene Delivery, 2003 - 2003
Philip Morris External Research Program, 2004 - 2004
International Centre for Genetic Engineering and Biotechnology
(ICGEB), Trieste, Italy, 2004 - 2004
NIH Virology A Study Section, 2004 - 2004
Medical Research Council (MRC), UK, 2005 - Present
NIH Special Emphasis Panel for SBIR grant, 2005 - 2005
Alliance for Cancer Gene Therapy, 2005 - 2005
NIH Special Emphasis Panel for Gene Therapy PO1 Grants, 2005 - 2005
Human Frontiers Science Program, 2006 - Present
NIH Atherosclerosis & Inflammation Study Section, 2006 - 2006
University of Washington, Molecular Therapy Core Center, 2006 - 2006
NIH Virology A Study Section, 2006 - 2008
Loyola University, Microbiology & Immunology, Chicago, 2008 - 2008
Northwest Genome Engineering Consortium, Seattle, 2009 - 2009
Control of Infectious Diseases Research Fund, Hong Kong, 2009 - 2009
Association Française contre les Myopathies, France, 2009 - Present
NIH Special Emphasis Panel for Virology, 2009 - 2009
Israel Science Foundation (ISF), 2009 - Present
Swiss National Science Foundation, 2010 - Present
NIH Virology B Study Section, 2010 - 2010
The National Medical Research Council of Singapore, 2010 - 2010
Cancer Prevention and Research Institute of Texas (CPRIT), 2010 - Present
Italian Association for Cancer Research (AIRC), 2011 - Present
University of Kansas Medical Center (KUMC) Grant Program, 2012 - 2012
Health and Medical Research Fund (HMRF), Hong Kong, 2012 - Present
National Science Center, Poland, 2013 - 2013
“Fondation pour la Recherche Médicale” (FRM), 2013 - 2013
National Institutes of Health, National Institute of Dental and Craniofacial Research, Special Grants Review Panel, 2013 - 2013
National Institutes of Health, National Cancer Institute, 2013 - Present
The Children's Hospital of Philadelphia, 2014 - Present
German-Israel Foundation for Scientific Research and Development, 2015 - Present
National Institutes of Health, Cancer Etiology (CE) Study Section, 2015 - 2015
Program Committee, American Society of Virology, 2015 - 2017
National Institutes of Health, Cancer Etiology (CE) Study Section, 2016 - Present
National Institutes of Health, Virology B (VIRB) Study Section, 2016 - 2016
Austrian Science Foundation, 2016 - 2016
Fight for Sight Foundation, United Kingdom, 2016 - 2016
Israel Cancer Research Fund (ICRF), 2017 - 2020
Yale Cancer Center, New Haven, CT., 2018 - Present
Natural Sciences and Engineering Research Council of Canada (NSERC), 2018 - Present
National institutes of Health, 2019 - 2019
Research Foundation Flanders (FWO), European Science Foundation, 2019 - Present
US-Israel Binational Science Foundation (BSF), 2021 - Present
Israel Cancer Research Fund (ICRF), 2021 - Present
Deutsche Forschungsgemeinschaft (German Research Foundation), 2021 - Present
National Institute of Environmental Health Sciences (NIEHS), 2022 - 2022

Web Links

Selected Publications

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