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Frederick  Alt, PhD

Department: Medicine
Research Centers: Molecular Medicine Research Center
Hospital Title: Director, Program in Cellular and Molecular Medicine/Immune Disease Institute
Academic Title: Charles A. Janeway Professorof Pediatrics
Research Area: Genomic instability

Research Overview

The broad focus of the Alt lab is the elucidation of mechanisms that maintain genomic stability in mammalian cells. More specifically, the lab studies V(D)J recombination in developing B and T lymphocytes and IgH heavy chain class switch recombination (CSR) and somatic hypermutation in mature B lymphocytes.

Studies of these processes employ biochemical approaches to elucidate molecular mechanisms by which the RAG endonuclease and Activation Induced Cytidine Deaminase function on DNA to initiate, respectively, VDJ recombination and CSR. As one example, our recent studies showed a role for the RNA exosome in targeting AID to both strands of duplex DNA. 

Other studies focus on the elucidation of genetic and epigenetic chromosomal processes that regulate how RAG and AID are targeted to their specific chromosomal DNA substrates. In this regard, our recent work defined a control region, termed IGCR1, in the IgH locus that regulates proximal versus distal VH usage, lineage-specificity, ordered assembly of VH, D, and JH segments and feedback regulation/allelic exclusion. Functionally, we showed IGCR1 to employ CTCF binding elements and to be involved in the formation of large IgH loops that contain distant enhancer elements. 

Other studies employ genetic and cytogenetic approaches to study roles of general DNA double strand break (DSB) repair and response pathways in VDJ recombination and CSR, and the interplay of DSB repair and response pathways in suppressing genomic instability and cancer. For such studies, the lab developed several new models for B and T cell lymphomas and brain tumors. A major new lab research area focuses on how organization of the genome in the nucleus influences programmed gene rearrangements and chromosomal translocations. 

For this purpose, we have developed a high throughput genomic translocation sequencing strategies to identify the universe of translocations (e.g., the translocatome) that arise from a fixed DSB. This approach is also useful for defining genomic DSBs. Our goal is to establish the contribution of mechanistic elements (three dimensional genome organization, DSBs, transcription, epigenetic modifications, repair pathways, etc.) that contribute to the formation of translocations in mouse and human cells. 

About Fred Alt

Dr. Alt received his Ph.D. in Biology from Stanford University in 1977 with Robert Schimke and he did his postdoctoral work at MIT with David Baltimore. He was a Professor at Columbia University in New York City from 1982-1991, where he became an HHMI Investigator in 1987. In 1991, Dr. Alt moved to back to Boston as an HHMI Investigator at Children's Hospital Boston; a Professor of Genetics and Pediatrics at Harvard Medical School, and a Senior Investigator at the Immune Disease Institute. 

He was appointed Charles A. Janeway Professor of Pediatrics in 1993 and Scientific Director of the Immune Disease Institute in 2005. He became Director of the Immune Disease Institute and Program in Cellular and Molecular Medicine of Children's Hospital in 2009 and President of the Immune Disease Institute in 2010. Dr. Alt has been elected to the U.S. National Academy of Sciences, the American Academy of Arts and Sciences, the American Academy of Microbiology, and the European Molecular Biology Organization and the American Association for the Advancement of Science. 

He has received the Clowes Memorial Award from the American Association of Cancer Research; the Rabbi Shai Shacknai Prize from The Hebrew University, the Pasarow Foundation Prize for Extraordinary Achievement in Cancer Research, the Leukemia & Lymphoma Society de Villiers International Achievement Award, the Irvington Institute Immunology Award, the National Cancer Institute Alfred K. Knudson Award for pioneering contributions that have revolutionized the field of Cancer Genetics, the American Association of Immunologists AAI-Huang Meritorious Career Award, the William B. Coley Award from the Cancer Research Institute, and the Novartis Basic Immunology Prize for his discoveries on B cell development and antigen responses. 

Dr. Alt has mentored over 100 students and research fellows, many of whom have become leaders in immunology, genetics, or cancer biology and has received the American Association of Immunologists Excellence in Mentoring Award. The Cancer Research Institute (New York) annually presents the Frederick W. Alt Award for New Discoveries in Immunology. Please see the electronic album of Alt Lab alumni, compiled by HHMI in 2010, entitled "Frederick W. Alt: A Supportive Mentor and Hard-Driving Scientist."

The future of pediatrics will be forged by thinking differently, breaking paradigms and joining together in a shared vision of tackling the toughest challenges before us.”
- Sandra L. Fenwick, President and CEO
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