Advances in Immunology, Volume 138

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 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, and the discovery of ”N” regions, which represent 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, he established the role of Ig chains in regulating B cell development and discovered that antigen receptor genes are assembled by a common V(D)J recombinase. He then elucidated a role for non-coding gene transcription and "chromatin accessibility" as means to target the lineage, stage, and allele specific activity of the V(D)J recombinase. He extended that work to show that IgH class switch recombination (CSR) is B cells to particular IgH classes is directed by activation of non-coding transcription units that contain the CSR target sequences. At Columbia, he also discovered N-myc, based on its amplification in human neuroblastomas and he characterized 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 Children's Hospital 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 CHB and IDI, Dr. Alt's group confirmed his earlier proposal with 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 multi-component general cellular non-homologous DNA end joining (NHEJ) pathway. Subsequently, Dr. Alt was involved in the discovery of a number of the NHEJ factors and he then went on to discover the key role of NHEJ proteins in maintenance of genomic stability. Dr. Alt continues to elucidate many new aspects of the mechanism and control of V(D)J recombination and IgH CSR and also continues to elucidate mechanisms that generate and suppress genomic instability, most recently through development of high through-put methods to study DSBs and chromosomal translocations.

In 1994, Dr. Alt was elected to the U.S. National Academy of Sciences, the American Academy of Arts and Sciences, and the American Academy of Microbiology; in 1999 he was elected to the European Molecular Biology Organization; in 2010 he was elected a Fellow of the American Association for Advancement of Sciences; and in 2011 he was elected to the Institute of Medicine. In 2004, Alt received the Clowes Memorial Award from AACR; in 2005 he received the Rabbi Shai Shacknai Prize from Hebrew University, the Pasarow Foundation Prize for Extraordinary Achievement in Cancer Research, the Leukemia & Lymphoma Society de Villiers International Achievement Award, and the Irvington Institute Award. In 2007, Alt received the NCI Alfred K. Knudson Award for pioneering contributions that have revolutionized Cancer Genetics, the AAI-Huang Meritorious Career Award, and the Novartis Basic Immunology Prize for his discoveries on B cell development and antigen responses. In 2009, he received the Cancer Research Institute William B. Coley Award for Distinguished Research in Basic Immunology for fundamental contributions to understanding of B-cell development and B cell lymphomagenesis. For his overall contributions, he most recently received the 2012 Arthur Kornberg and Paul Berg Award for Lifetime Achievement in Biomedical Sciences from Stanford University Medical School. Dr. Alt serves on numerous editorial boards and is Editor in Chief of Advances in Immunology. He also has served on various national and international advisory boards and is currently Chair, of the SAC 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 2003 American Association of Immunologists Excellence in Mentoring Award. The Cancer Research Institute of New York annually presents the Frederick W. Alt Award for New Discoveries in Immunology.