PCMM | Frederick Alt

Biography and Research Summary

Frederick Alt received his Ph.D. in Biology from Stanford University in 1977 where he worked with Robert Schimke and discovered gene amplification and genomic instability in mammalian cancer cells.  Alt moved to MIT for postdoctoral work with David Baltimore, where he helped elucidate basic principles of recombination in the immune system.  His work with David Baltimore included the discovery that production of membrane versus secreted immunoglobulin is achieved via differential RNA processing and the discovery that allelic exclusion of Immunoglobulin (Ig) gene rearrangements is controlled by feedback from protein products.  With Baltimore, Alt also elucidated major aspects of the V(D)J recombination mechanism, including involvement of site-specific DNA double strand breaks (DSBs) that are end joined, as well as the discovery of ”N” regions added by terminal deoxynucleotydl transferase (TdT) that provide a major source of antigen receptor diversity.  

Dr. Alt moved to Columbia University in 1982 as Assistant Professor of Biochemistry.  He became Professor of Biochemistry and Molecular Biophysics in 1985 and HHMI Investigator in 1987.  At Columbia, his lab established the role of Ig chains in regulating sequential stages of B cell development and discovered that all antigen receptor genes are assembled by a common V(D)J recombinase.  They then elucidated a role for non-coding gene transcription in mediating  "chromatin accessibility" as means to target the lineage, stage, and allele specific activity of the V(D)J recombinase.  His group extended that work to show that, in B cells, IgH class switch recombination (CSR) to particular IgH classes is directed by activation of non-coding transcription units that contain the CSR target sequences.  At Columbia, the Alt lab also co-discovered the  N-myc cellular oncogene, based on its amplification in human neuroblastomas and he went on to characterize the Myc cellular oncogene family. 

In 1991, Dr. Alt moved to Boston Children' Hospital (BCH) and Harvard Medical School as a Professor of Genetics and HHMI Investigator.  He also became a Senior Investigator at the Immune Disease Institute (IDI).  He was appointed Charles A. Janeway Professor of Pediatrics in 1993, Scientific Director of IDI in 2005, and Director of the Program in Cellular and Molecular Medicine (PCMM) at BCH in 2008.  He also became President of IDI in 2010 and continues to serve as director since the merger of IDI with BCH, where it remains the PCMM.  At BCH and IDI, Dr. Alt's group confirmed the proposal of Alt and  Baltimore that N regions are added by terminal dexoynucleotidyl transferase, demonstrating that TdT is a V(D)J recombinase component.  They also discovered that the joining activity of the V(D)J recombinase is carried out by a novel multi-component general cellular non-homologous DNA end joining now known as the major C-NHEJ DSB repair pathway.  Subsequently, the Alt lab was involved in the discovery of a number of the first characterized NHEJ component factors and then went on to discover the key role of NHEJ proteins in maintenance of genomic stability. 

The Alt lab continues to elucidate many new aspects of the mechanism and control of V(D)J recombination including discovering that this reaction is regulating by a process that allows the initiating RAG endonuclease V(D)J recombination factors to explore directionally within chromosomal loop domains for target substrates.  His lab also continues to discover new aspects of the mechanism and regulation IgH CSR and the related process of Ig variable region exon somatic hypermutation.  The lab's recent work, based on their development of high through-put methods to study DSBs and chromosomal translocations, have provided major new insights into the mechanisms that contribute to chromosomal rearrangements within the 3D genome of developing lymphocytes and cancer cells or their progenitors.  The lab also has used their new approaches to identify a set of genes that recurrently break in neuronal stem and progenitor cells and, thereby, which may contribute to brain diversification and neuropsychiatric diseases and cancer.  Most recently, the lab has built on their more basic molecular immunology discoveries on antibody gene assembly to generate innovative new mouse models for testing immunization strategies for eliciting HIV-1 broadly neutralizing antibodies. 

Frederick Alt has been elected to the National Academy of Sciences, the Institute of Medicine (National Academy of Medicine), the American Academy of Arts and Sciences, and the European Molecular Biology Organization.  His cancer biology awards include the American Association of Cancer Research Clowes Award, the Pasarow Foundation Prize for Extraordinary Achievement in Cancer Research, the National Cancer Institute Alfred K. Knudson Award for  "Pioneering Contributions that Revolutionized the Field of Cancer Genetics", the Leukemia and Lymphoma Society de Villiers Award, The Katharine Berkan Judd Award from Memorial Sloan Kettering Cancer Center, the Albert Szent-Gyorgyi Prize for Progress in Cancer Research from the National Foundation for Cancer Research, and the American-Italian Cancer Foundation Prize for Excellence in Medicine.  His immunology awards include the American Association of Immunologists (AAI) Huang Meritorious Career Award, the Cancer Research Institute (CRI) Coley Award, and the Novartis Prize for Basic Immunology.  More generally, he has also received the Arthur Kornberg & Paul Berg Lifetime Achievement Award in Biomedical Science and the Lewis S. Rosensteil Prize for Distinguished work in Biomedical Sciences. Dr. Alt serves on numerous editorial boards and is Editor in Chief of Advances in Immunology.  He also serves on many national and international advisory boards and is currently Chair of the Scientific Advisory Committee of the Cold Spring Harbor Laboratory.  Dr. Alt has mentored over 100 students and research fellows, many of whom have become leaders in immunology, genetics, or cancer biology and he received the American Association of Immunologists Excellence in Mentoring Award and the Willam A. Silen Award for Lifetime Achievement in Mentoring from Harvard Medical School.  The Cancer Research Institute of New York annually presents the Frederick W. Alt Award for New Discoveries in Immunology.