Frederick Alt

Frederick Alt received his PhD in Biology from Stanford University in 1977 where he worked with Robert Schimke on the mechanism by which cancer cells become resistant to the methotrexate chemotherapy drug. He moved to MIT for postdoctoral work with David Baltimore, where he helped elucidate basic principles of recombination in the immune system. He became an Assistant Professor of Biochemistry and Molecular Biophysics of Columbia University College of Physicians and Surgeons (CUCPS) in 1982 and subsequently became Professor of Biochemistry and Molecular Biophysics in 1985, Professor of Microbiology in 1986 and a Howard Hughes Medical Institute (HHMI) Investigator at CUCPS in 1987. In 1991, Dr. Alt moved to Boston Children's Hospital (BCH), and the Harvard Medical School (HMS) affiliated Center for Blood Research (CBR), as a Professor of Genetics and Pediatrics at HMS, HHMI Investigator at BCH and a Senior Investigator at the CBR. He was appointed Charles A. Janeway Professor of Pediatrics in 1993 and Scientific Director of the CBR in 2005. He continued as Director in 2007 when the name of the CBR was changed to Immune Disease Institute (IDI). Dr. Alt went on to serve as President of IDI and led the merger of IDI with Boston Children's Hospital where it was named the Program in Cellular and Molecular Medicine (PCMM) in 2012. Dr Alt was the Director of the PCMM until January of 2025 and continues as Director Emeritus and Co-Director.

Research Accomplishments

As a PhD student with Robert Schimke, Alt discovered mammalian gene amplification and genomic instability in the context of methotrexate-resistant cancer cells. Studies from his own lab, including discovery of the N-Myc oncogene, contributed to establishing gene amplification, beyond being a major mechanism of anti-cancer drug resistance, as a major mechanism of oncogenesis. His lab made discoveries that were foundational for elucidation of the non-homologous end joining (NHEJ) pathway of DNA double-strand break repair. They discovered the critical role of NHEJ in lymphocyte-specific V(D)J recombination and in preserving genome stability more generally. The Alt lab discovered multiple basic mechanisms underlying antigen receptor gene rearrangement, diversification, and the regulation of these processes and the mechanisms by whic they are integrated into lymphocyte development. His lab developed and applied new high- throughput genomic technologies to make groundbreaking discoveries on how DNA breaks are joined within the three-dimensional genome. They further developed and applied these technologies to discover that the cohesin-mediated chromatin loop extrusion plays fundamental roles in both V(D)J recombination and IgH class switch recombination. Their studies revealed that both lymphocyte-specific recombination processes use chromatin loop extrusion to reel long loops of chromatin past recombination centers to juxtapose cis-regulatory elements, substrate DNA sequences, and initiating enzymes. The Alt lab has exploited these basic findings to develop new humanized mouse models for testing vaccine approaches for eliciting HIV-1 broadly neutralizing antibodies and for discovering humanized antibodies against emerging pathogens.

Service and Mentoring

Dr. Alt serves on several editorial boards and is Co-Editor in Chief of Advances in Immunology. He also serves on several national and international advisory boards. He has Chaired the Scientific Advisory Committee of the Cold Spring Harbor Laboratory since 2008 and has served as Chair of the National Academy of Sciences Class IV (Biomedical Sciences). Dr. Alt has mentored over 150 students and research fellows, many of whom have become leaders in immunology, genetics, or cancer biology. In recognition of his training and mentoring accomplishments, he received the American Association of Immunologists Excellence in Mentoring Award and the William 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.

Honorific Memberships

• 2024: Elected Fellow of the American Association of Cancer Research Academy
• 2020: Elected Distiguished Fellow of American Association of Immunologists 2011--Elected Member of the National Academy of Medicine
• 2011: Elected Fellow of the American Association for the Advancement of Science
• 1999: Elected Member of the European Molecular Biology Organization
• 1994: Elected Fellow of the American Academy of Microbiology
• 1994: Elected Fellow of the American Academy of Arts and Sciences
• 1994: Elected Member of the National Academy of Sciences

Awards and Prizes

• 2023: Foundation for Primary Immunodeficiency Diseases William E. Paul Memorial Award for Excellence in Immunology and Cell Biology
• 2023: Alumni Achievement Award, Brandeis University
• 2023-: Paul Ehrlich and Ludwig Darmstaedter Prize (with David Schatz "for the discovery of essential molecular components and mechanisms by which somatic diversification of antigen receptors is achieved in the vertebrate adaptive immune system"
• 2021: American Association for Cancer Research Award for Lifetime Achievement in Cancer Research
• 2019: NIH Merit Award
• 2019: American Association of Immunologists AAI-BioLegend Herzenberg Award for outstanding contributions to the field of immunology in the area of B cell biology.
• 2017: Honorary Professor, Peking Union Medical College and Chinese Academy of Medical Sciences
• 2016: The William Silen Lifetime Achievement Excellence in Mentoring Award from Harvard Medical School
• 2016: The Lewis S. Rosenstiel Award for Distinguished Work in Basic Medical Science
• 2015: The American-Italian Cancer Foundation Prize for Scientific Excellence in Medicine, New York, NY
• 2015: The Katharine Berkan Judd Award for Distinguished Achievement in Biomedical Research from the Memorial Sloan Kettering Cancer Center, New York, NY
• 2015: National Foundation for Cancer Research Szent-György Prize for Progress in Cancer Research "for pioneering work in the area of cancer genetics"
• 2013: The Elmezzi Graduate School of Molecular Medicine, Manhasset, NY Honorary degree: Doctor of Science honoris causa.
• 2012: The Stanford University Medical Center Arthur Kornberg and Paul Berg Lifetime Achievement Award in Biomedical Science.
• 2009: Cancer Research Institute William B Coley Award for Distinguished Research in Basic Immunology
• 2007: Novartis Prize for Basic Immunology for “Discoveries on B cell Development and Antigen Responses”
• 2007: American Association of Immunologists AAI-Huang Foundation Meritorious Career Award
• 2007: Alfred G. Knudson Award, from the National Cancer Institute, for “Pioneering Contributions that have revolutionized the field of Cancer Genetics”
• 2005: Establishment of the Frederick W. Alt Award for New Discoveries in Immunology
• 2005: Pasarow Foundation Prize for Extraordinary Achievement in Cancer Research
• 2005: Leukemia and Lymphoma Society de Villiers International Achievement Award
• 2005: Rabbi Shai Shacknai Memorial Prize in Immunology and Cancer Research, Hebrew University, Jerusalem, Israel
• 2005: Irvington Institute Scientific Leadership Award in Immunology
• 2004: American Association for Cancer Research-G.H.A.Clowes Memorial Award " for outstanding basic cancer research"
• 2003: American Association of Immunologists Excellence in Mentoring Award 1991--NIH Health Merit Award
• 1983: Irma T. Hirschl Career Scientist Award
• 1983: Searle Scholars Award
• 1984: Mallinckrodt Award
• 1973: Stephen J. Fox Memorial Award in Biological Sciences, Stanford University

Selected Publications

1. Zhang, Y., Li, X., Ba, Z., Lou, J., Gaertner, K.E., Zhu, T., Lin, X., Ye, A.Y. *Alt, F.W. and *Hu, H. (2024) Molecular basis for differential Igk versus Igh V(D)J joining mechanisms. Nature, 630(8015):189-97. doi:10.1038/s41586-024-07477-y. PMC11153149. (co-corresponding authors)
2. Luo, S., Jing, C., Ye, A.Y., Kratochvil, S., Cottrell, C.A.,, Koo, J-H., Williams, A.C., Francisco, L.V., Batra, H., Lamperti, E., Kalyuzhniy, O., Zhang, Y., Barbieri, A., Manis, J.P., Haynes, B.F., Schief, W.R., Batista, F.D., Tian, M. and Alt, F.W. (2023) Humanized V(D)J-rearranging and TdT-expressing mouse vaccine models with physiological HIV-1 broadly neutralizing antibody precursors. Proc. Natl. Acad. Sci. USA, 120(1), e 2217883120. PMC9910454.
3. Liang, Z., Zhao, L., Yongxin, Ye A., Lin, S.G., Zhang, Y., Guo, C., Dai, H.Q., Ba, Z and Alt, F.W. (2023) Contribution of the IGCR1 regulatory element and the 3‘Igh CTCF-binding elements to regulation of Igh V(D)J recombination. Proc. Natl. Acad. Sci. USA, 120(26):e2306564120. PMC10293834.
4. Zhang, Y., Zhang, X., Dai, H-Q., Hu, H. and Alt, F.W. (2022) The role of chromatin loop extrusion in antibody diversification. Nat. Rev. Immunol., 22(9):550-566. Review
5. Zhang, X., Yoon, H-S., Chapdelaine-Williams, A.M., Kyritsis, N. and Alt, F.W. (2021) Physiological role of the 3'IgH CBEs super-anchor in antibody class switching. Proc. Natl. Acad. Sci. USA, 118(3), e2024392118. PMC7826415
6. Dai, H-Q., Hu, H., Lou, J., Ye, A.Y., Ba, Z., Zhang, X., Zhang, Y., Zhao, L., Yoon, H.S., Chapdelaine-Williams, A.M., Kyritsis, N., Chen, H., Johnson, K., Lin, S., Conte, A., Casellas, R., Lee, C-S. and Alt, F.W. (2021) Loop extrusion mediates physiological IgH locus contraction for RAG scanning. Nature. 590(7845), 338-343. PMC7685531
7. Ba, Z., Lou, J., Ye, A.Y., Dai, H-Q., Dring, E.W., Lin, S.G., Jain, S., Kyritsis, N., Kieffer-Kwon, K-R., Casellas, R. and Alt, F.W. (2020) CTCF orchestrates long-range cohesin-driven V(D)J recombinational scanning. Nature. 586(7828), 305-310. PMC7554077.
8. Tena, A., Zhang, Y., Kyritsis, N., Devorak, A., Zurita, J., Wei, P-C. and Alt, F.W. (2020) Induction of recurrent break cluster genes in neural progenitor cells differentiated from embryonic stem cells in culture. Proc. Natl. Acad. Sci. USA, 117(19), 10541-10546. . PMC7229678.
9. Zhang, X., Zhang, Y., Ba, Z., Kyritsis, N., Casellas, R. and Alt, F.W. (2019) Fundamental roles of chromatin loop extrusion in antibody class switching. Nature. 575(7782), 385-389. PMC6856444.
10. Zhang, Y., Zhang, X., Ba, Z., Liang, Z., Dring, E.W., Hu, H., Lou, J., Kyritsis, N., Zurita, J., Shamim, M.S., Presser Aiden, A., Lieberman Aiden E. and Alt, F.W. (2019) The fundamental role of chromatin loop extrusion in physiological V(D)J recombination. Nature. 573(7775), 600-604. PMC6867615
11. Chang, A.N., Liang, Z., Dai, H-Q., Chapdelaine-Williams, A.M., Andrews, N., Bronson, R.T., Schwer, B. and Alt, F.W. (2018) Neural blastocyst complementation enables mouse forebrain organogenesis. Nature 563(7729), 126-130. PMC6588192
12. Jain, S., Ba, Z., Zhang, Y., Dai, H-Q and Alt, F.W. (2018) CTCF-binding elements mediate accessibility of RAG substrates during chromatin scanning. Cell 174(1), 102-116, PMC6026039