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PCMM Research | Overview

About PCMM

The Program in Cellular and Molecular Medicine (PCMM), is a research program at Boston Children's Hospital (BCH) recognized worldwide for its discoveries that increase the body's ability to fight disease and to heal. The breakthroughs of PCMM scientists are greatly increasing our understanding of the influence of immune defense and inflammation on medical discovery, healthcare, and disease management. PCMM officially joined seven other interdisciplinary programs at Boston Children's Hospital in October 2012 with the goal of increasing collaborations and scientific synergies. Our investigators are academically affiliated with Harvard Medical School.

We pursue six (at least) primary areas of research:

  • Adhesion molecules and inflammation
  • Autoimmunity and allergy
  • Genetics of immunodeficiency and cancer
  • Immune defenses against infectious diseases, viruses, and tumors
  • Stem Cells
  • Structural Biology

Research Highlights

Illustrated image of protein strings

A Solution That Holds Water

Research from Tim Springer’s lab published in the September 15 issue of Cell presents a general principle by which integrins can be inactivated by inhibitors that stabilize the closed form of these proteins, which also explains why integrin-targeting drugs have failed in clinical trials thus far. His group showed that small-molecule drugs that failed to inhibit integrins actually stabilize the open, high-affinity confirmation, and designed successful inhibitors that stabilize a water molecule at the highly conserved metal-ion-dependent adhesion site (MIDAS) that must be expelled for transition to the open confirmation, and thus successfully stabilize the bent-closed integrin conformation. For more, see the story by Stephanie Dutchen at HMS News

Announcements

Tim Springer Headshot

Tim Springer wins Lasker Award

On September 28, 2022, the Lasker Foundation announced that Tim Springer, along with Richard O. Hynes of MIT and Erkki Ruoslahti of Sanford Burnham Prebys, won the 2022 Albert Lasker Basic Medical Research Award.  Tim and his co-recipients were honored for discoveries concerning integrins, key mediators of cell-matrix and cell-cell adhesion in physiology and disease

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Widely regarded as America’s top biomedical research prize since its creation more than 75 years ago by Mary and Albert Lasker, the Lasker Awards carry an honorarium of $250,000 for each category. Recipients of the Lasker Medical Research Awards are selected by a distinguished international jury chaired by Joseph L. Goldstein, recipient of the 1985 Lasker Award for Basic Medical Research and the Nobel Prize in Physiology or Medicine. Ninety-five Lasker Laureates have received the Nobel Prize, including seven in the last four years. The September 28 award presentation, featuring short videos on this year’s winners and their work, occurred at a celebratory online event, viewable at laskerfoundation.org, where full citations are listed for each award category.

From the Foundation’s official press release: In their respective labs, Richard O. Hynes and Erkki Ruoslahti identified a cell-surface-associated protein that helps affix cells to the surrounding material, called the extracellular matrix; later, they identified a receptor to which this protein binds. Separately, Timothy A. Springer detected transmembrane proteins that underlie the ability of immune cells to interact with their targets. These initially disparate discoveries converged and their significance mushroomed after the investigators realized that these proteins—later dubbed “integrins”—belong to the same molecular family.

The work of Springer, Ruoslahti, and Hynes launched the field of integrin research, which explores the essential roles these proteins play in physiology and health. They provided a greater understanding of the diseases that can result when integrin function is perturbed. Their discoveries laid the foundation for novel therapeutic strategies to treat a variety of autoimmune disorders, such as ulcerative colitis, Crohn’s disease, and certain clotting conditions.

The PCMM family salutes Tim on this truly outstanding honor!

 

Judy Lieberman and Hao Wu win the William B. Coley Award

Headshot of Judy LeibermanHeadshot of Hao WuOn September 27, 2022, the Cancer Research Institute presented the William B. Coley Award for Distinguished Research in Basic and Tumor Immunology to Judy Lieberman and Hao Wu at its annual awards ceremony at The University Club in New York City.

Established in 1975 in honor of Dr. William B. Coley, a pioneer of cancer immunotherapy, whose daughter, Helen Coley Nauts, founded CRI, the award is given to one or more scientists for seminal discoveries in the field of basic immunology and cancer immunology.  Over the years, its distinguished recipients have deepened our knowledge of the immune response to cancer and other diseases and advanced the development of effective immunotherapies.

Judy and Hao share the 2022 William B. Coley Award with Vishva Dixit of Genentech and Feng Shao of the National Institute of Biological Sciences, Beijing, for their collective work that revealed the role of the pore-forming gasdermins in pyroptosis and promotion of antitumor immunity that set the stage for targeting gasdermins in cancer therapeutics.
 
In addition to the Coley Award, CRI presented the Frederick W. Alt Award for New Discoveries in Immunology, named after PCMM Director Fred Alt,  which is given to a former winner of the CRI Irvington Postdoctoral Fellowship in recognition of outstanding success in academia or industry for research that has a major impact in the field of immunology. This year’s recipient is David Masopust of the University of Minnesota.

Congratulations to Judy and Hao for this prestigious honor!

Fred Alt and David Schatz win 2023 Paul Ehrlich and Ludwig Darmstaedter Prize

Headshot of Fred Alt, an older male scientist who recieved the Darmstaedter prize.Headshot of an older man, David Schatz.PCMM’s Director Fred Alt and David Schatz of Yale’s Department of Immunobiology and Department of Molecular Biophysics and Biochemistry, have been named co-recipients of the 2023 Paul Ehrlich and Ludwig Darmstaedter Prize, which is considered to be Germany’s most prestigious award for medical research. The Scientific Council of the Paul Ehrlich Foundation awarded the prize to Alt and 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."

Warmest congratulations from PCMM to Fred for this outstanding achievement!

Four Wu Lab postdocs win fellowships

 

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Four postdoctoral researchers in Hao Wu’s laboratory at PCMM recently received prestigious fellowships.

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Yumei Zheng won a fellowship from the Jane Coffin Childs Memorial Fund for Medical Research. Dr. Zheng will capitalise on the striking new mechanism identified recently to effectively activate Death Receptor 5 (DR5) on cancer cells for anticancer therapy. She will determine the molecular requirements for both the autoinhibition and activation of DR5, and to screen for agonistic anti-DR5 antibodies that specifically disrupt the autoinhibitory state of DR5 to consequently boost apoptosis in tumor cells for therapeutic potentials..

Le Xiao was named winner of the Jared J. Grantham Research Fellowship from the Ben J. Lipps Research Fellowship Program. Dr. Xiao will explore the relationship of protein folding and transport to disease, as well as on drug development. Compelling evidence strongly supports the hypothesis that accumulation of misfolded proteins leads to many human diseases including synaptic dysfunction, neuronal apoptosis, brain damage, and kidney diseases. However, the mechanism by which protein misfolding and aggregation trigger these diseases is still unclear. He will work on mucin 1 kidney disease (MKD), which is caused by defects in protein folding and trafficking, and seek to elucidate the pathogenic mechanism of MKD and contribute to the development of drugs for MKD.

Mohammad Kawsar Manik won a Cancer Research Institute Irvington Postdoctoral Fellowship. Dr. Manik will elucidate the molecular mechanism of the TIR-domain-containing adapter-inducing interferon-β (TRIF, also known as TICAM-1). TRIF is a member of TIR adaptors that engage ligand-bound TLRs at the center of MyD88-independent signaling by forming signalosomes on the endosome upon dimerization of TLR3 or TLR4, which is critical for the viral immunity. Elucidation of the molecular mechanism of the TRIF signalosome would provide better understanding about the TLR-mediated antiviral responses.

Ying Dong won a Charles A. King Trust Postdoctoral Research Fellowship. Dr. Dong will pursue the structural assembly and regulatory mechanism of B Cell antigen Receptor (BCR) complex. BCR has been known as a complex composed of transmembrane-bound immunoglobulin (mIg) for antigen recognition and Igα and Igβ heterodimer for signal transduction. Her study would reveal the how BCR fulfil its function as a signaling entity and provide a structural platform for designing rational therapies against BCR-mediated diseases.

Congratulations to all, PCMM is proud of you!

 

PCMM researchers win Career Development Awards

 

PCMM researchers win Career Development Awards

Three PCMM researchers recently received prestigious awards supporting advanced and independent career development.

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Venkat Magupalli, Ph.D., Assistant Professor of Pediatrics in the laboratory of Hao Wu, received both a 2021 Office of Faculty Development (OFD) Basic/Translational Research Executive Committee (BTREC) Clinical and Translational Research Executive Committee (CTREC) fellowship and an R21 award from the National Institutes of Health. His research projects will determine the molecular mechanisms and players underlying sustained inflammatory signaling. Elucidation of these pathways would provide finer insights about inflammasome-mediated inflammatory responses.

Jing Li, Ph.D., an instructor in the laboratory of Timothy Springer, was named a winner of a 2022 OFD/BTREC/CTREC fellowship. She will study how integrins αVβ6 and αVβ8 activate latent TGF-β1, which is important in development, wound-healing, immune regulation, and tumor biology. The mechanism of activation of TGF-β1, and whether tensile force is required, has important implications in therapeutic interventions. Jing hypothesizes that the tensile force exerted by the actin cytoskeleton through integrins plays an important role in αVβ6-mediated TGF-β1 activation but possibly not in αVβ8-mediated activation. To test this, Jing is going to measure single-molecule force exertion by TGF-β1-binding integrins with tension gauge tethers. She will also measure tensile force-dependent activation of TGF-β1 by integrins.

Tiffany Hsu, M.D., Ph.D. a Brigham & Women’s Hospital Rheumatology Fellow and a postdoctoral fellow in the laboratory of Sun Hur, received a Rheumatology Research Foundation Scientist Development Award. She will investigate the regulation of MDA5 signaling, which triggers the antiviral immune response upon detection of cytoplasmic double-stranded RNAs. Aberrant activation of MDA5 in the absence of infection is associated with increased risk of systemic lupus erythematosus and drives lupus-like autoinflammatory diseases. Her studies seek to identify novel biomarkers and therapeutic targets for identifying and treating lupus patients with activated MDA5.

Congratulations and best wishes for your continued success!

 

Sun Hur headshot

Sun Hur wins Dorothy Crowfoot Hodgkin Award

We are very happy to announce that Sun Hur is the 2022 recipient of the Protein Society’s Dorothy Crowfoot Hodgkin Award. From The Protein Society’s web site: “The Dorothy Crowfoot Hodgkin Award, sponsored by Genentech, is granted in recognition of exceptional contributions in protein science which profoundly influence our understanding of biology.”

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The citation states, “Professor Hur’s structural and biochemical work on a family of vertebrate innate immune receptors, RIG-I-like receptors (RLRs), led to the discovery of receptor polymerization and clustering in response to detection of foreign RNA. Her laboratory elucidated how RLR filament formation enables detection of various types of viral and host RNA signatures, such as secondary structure and modification, and integration of such disparate information for discrimination between foreign and self nucleic acids. By reconstituting the signaling complex with purified components for the first time, Hur determined long sought-after structures of an activated RLR in complex with its co-factor and signaling adaptor. These studies revealed how receptor oligomerization activates the downstream signaling pathway. Her group also showed that certain mutations in the receptor and regulators can shift the immunological “threshold” for self-tolerance, leading to constitutive activation of RLRs by self-RNAs in lupus-like inflammatory disorders. Finally, the findings by Professor Hur’s laboratory that RLRs remodel protein-RNA complexes demonstrated an unanticipated signaling-independent, effector-like function of RLRs, challenging the conventional view of immune receptors as simple signaling molecules. In summary, her investigations have provided a molecular framework for understanding the RLR pathway, which sets the paradigm for how other nucleic acid sensors play roles in innate immunity.” Congratulations to Sun for this prestigious honor!

 

Michael Carroll and Arlene Sharpe elected Distinguished Fellows of AAI

Michael Carroll headshotArlene Sharpe headshotPCMM Senior Investigator Michael Carroll and PCMM Scientific Advisory Board member Arlene Sharpe were elected as members of the Class of 2022 of the Distinguished Fellows of the American Association of Immunologists!

This is among the highest honors bestowed by AAI, annually recognizing long-term (25 or more years) members for distinguished careers and outstanding scientific contributions, as well as their service to AAI and the immunology community; fellows bear the designation “DFAAI.” Distinguished Fellows of the AAI have “demonstrated one or more of the following: excellence in research accomplishment in the field of immunology; exceptional leadership to the immunology community in academia, foundations, nonprofits, industry, or government at a national or international level; notable distinction as an educator.”

Please join us in congratulating Mike and Arlene for this milestone accomplishment!

PCMM Irvington Fellows from left to right: Ryan Alexander, Hongli Hu, Rui Miao and Sherry Zhang

 

Four PCMM researchers win Irvington Fellowships in banner year

Four PCMM postdoctoral researchers were honored in 2021 by the Cancer Research Institute. Ryan Alexander of the Ploegh Lab was an inaugural recipient of the CRI Irvington Postdoctoral Fellowship to Promote Racial Diversity, and Hongli Hu of the Alt Lab, Rui Miao of the Lieberman Lab, and Qianxia (Sherry) Zhang of the Hur Lab were winners of the CRI Irvington Postdoctoral Fellowship.

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Ryan Alexander, a postdoctoral fellow in the laboratory of Hidde Ploegh, will explore a modular strategy of utilizing a combination of nanobody-based chimeric antigen receptor (nano-CAR) T cells and macrophages to target and overcome normally resistant pancreatic tumors in mice; these cells bear alpaca antibody-derived nanobodies, which are smaller and displayed more efficiently on the cell surface than antibodies and are designed to target proteins that are highly and selectively expressed by pancreatic tumors compared to healthy tissue, and are thus less likely to be recognized as “foreign” and attacked by the immune system.

Hongli Hu, an instructor in the laboratory of Fred Alt, will compare and contrast the long-range mechanisms in the context of higher-order chromatin structure used by antibody heavy and light chain loci to incorporate Vs into the V(D)J recombination reaction, which will provide major new insights into fundamental mechanisms that establish highly diverse primary antibody repertoires and how this process can go awry to generate genomic rearrangements in cancers of developing B cells, as well as inform new approaches to generate therapeutic human antibodies against cancer and other diseases.

Rui Miao, a postdoctoral fellow in the laboratory of Judy Lieberman, will investigate the role of granzyme M (GzmM), one of the most abundant and important granzymes in innate killer lymphocytes, in killer lymphocyte-driven pyroptotic killing of tumor cells and anti-tumor immunity mediated by gasdermin E (GSDME), a member of the pore-forming gasdermin protein family, aiming to uncover the molecular basis for tumor cell evasion and provide insights into how to harness the GzmM-GSDME-pyroptosis axis in the tumor microenvironment to ignite an effective immune response to immunologically cold tumors.

Sherry Zhang, a postdoctoral fellow in the laboratory of Sun Hur, will elucidate the molecular mechanism of transcription mediated by autoimmune regular (Aire), which drives autoreactive T cells to undergo clonal deletion or regulatory T cell differentiation and has been linked to impairment of antitumor immunity, mutations in which lead to multi-organ autoim;mune diseases, through functional analysis of its interactions with the co-activator CBP/P300 and genetic screen-based identification of its key downstream factors, with the aim of identifying potential therapeutic targets for manipulating self-tolerance, autoimmune syndromes, and antitumor immunity.

Congratulations to all, PCMM is proud of you!

 

Sun Hur headshot

Sun Hur wins Paul Marks Prize

We are very happy to announce that Sun Hur is a 2021 recipient of the Memorial Sloan Kettering Cancer Center’s Paul Marks Prize for Cancer Research! From MSKCC’s web site: "The prize, named in honor of MSK's past President Emeritus, the late Paul Marks, MD, recognizes a new generation of leaders in cancer research who are making significant contributions to the understanding of cancer or are improving the treatment of the disease through basic or clinical research."

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The citation states, "Dr. Hur studies the innate immune system — in particular, how host cells distinguish between self and non-self nucleic acids. She has used her expertise in chemistry and structural biology to address vital questions in this field. Her research has led to the discovery of mechanisms for key signaling pathways that play a role in both the immune response and pathogenesis of a wide range of immune disorders. It also can be applied to the development of new kinds of cancer immunotherapy." Congratulations to Sun!

 

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Tim Springer wins the Biophysical Society’s Founders Award

We are very pleased to announce that Tim Springer has been named the 2022 winner of the Founders Award by the Biophysical Society! The Founders Award is given annually for outstanding achievement in any area of biophysics.

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To quote his award citation, Tim was lauded “for pioneering contributions to biophysical studies of immune cell rolling, activation, and adhesion and for revealing the force-based activation of integrins through an innovative combination of structural biology, single-molecule mechanical measurements, and thermodynamic analysis.” He will be honored at the 66th Biophysical Society Annual Meeting in San Francisco this coming February. The PCMM community offers its warmest congratulations to Tim!

 

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Sun Hur named 2021 HHMI Investigator

We are delighted to announce that Sun Hur has been named a Howard Hughes Medical Institute Investigator!

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To quote her HHMI citation, her focus is “solving the immune system’s most perplexing mysteries.” Her work has contributed fundamental new insights into the mechanisms by which the immune system responds to viral versus host RNA, in turn providing major implications for therapy of viral infections, inflammatory diseases, and cancers. Sun’s accomplishment not only highlights her own outstanding research achievements, but also elevates the profile of our program as a whole. The PCMM community sends her its warmest congratulations!

 

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Denisa Wagner wins the American Society of Hematology’s Henry M. Stratton Medal

It with great pleasure that we announce that Denisa Wagner has been awarded the American Society of Hematology’s Henry M. Stratton Medal!

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As described by ASH: “The Henry M. Stratton Medal is named after the late Henry Maurice Stratton, co-founder of Grune and Stratton, the medical publishing house that first published ASH’s journal Blood. The prize honors two senior investigators whose contributions to hematology both basic and clinical/translational research are well recognized and have taken place over a period of several years.”

As the 2021 basic science awardee of the Henry M. Stratton Medal, Denisa was cited “for her contributions to the fields of vascular biology, inflammation, and thrombosis. Her discovery that von Willebrand factor (VWF) is contained in a reservoir within endothelial cells ready to coat the inside of blood vessels to aid platelet and leukocyte recruitment, was important to the understanding of vascular response to injury. The regulated release of VWF guided subsequent studies on the molecular basis of von Willebrand disease. Her recent study of neutrophil extracellular traps (NETs), chromatin actively ejected from neutrophils, has led to the discovery of a link between neutrophil activation and thrombosis. This link revealed a significant pathological contribution of ‘immuno-thrombosis’ to ischemic organ injury and cancer.”

Congratulations to Denisa for this well-deserved honor!

 

Hao Wu headshotAkiko Iwasaki headshot

Hao Wu and Akiko Iwasaki elected to American Academy of Arts and Sciences

We are delighted to announce that Hao Wu, Associate Director of PCMM, and Akiko Iwasaki of the Yale School of Medicine, PCMM Scientific Advisory Board member, have been elected to the American Academy of Arts & Sciences!

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Frederick Alt, PhD

PCMM Director Fred Alt receives 2021 AACR Award for Lifetime Achievement in Cancer Research

The American Association for Cancer Research (AACR) has honored Fred Alt, Director of PCMM, with the 18th AACR Award for Lifetime Achievement in Cancer Research. The award, established in 2004, is presented to individuals who have made fundamental contributions to cancer research through a single discovery or a body of work.

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Judy Lieberman elected to National Academy of Medicine

We are delighted to announce that Judy Liberman has been elected as a member of the National Academy of Medicine!

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Randomized study for treatment of COVID pneumonia in children and adults uses cystic fibrosis drug, dornase alfa (Pulmozyme)

Drug may break up 'neutrophil extracellular traps' or NETS, which contribute to lung inflammation and thicken mucus.

BOSTON — Researchers at Boston Children's Hospital and Brigham and Women's Hospital have launched a randomized, placebo-controlled clinical trial of dornase alfa (Pulmozyme) in patients with severe COVID-19 pneumonia and respiratory failure requiring mechanical ventilation. The study aims to enroll 60 adults and children (over age 3) admitted to intensive care units.

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Judy Lieberman elected to National Academy of Sciences

It is our great pleasure to announce that PCMM's Judy Lieberman has been elected as a member of the U.S. National Academy of Sciences!

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Fred Alt, Hidde Ploegh, and Richard Flavell named Distinguished Fellows of the American Association of Immunologists

The American Association of Immunologists has named PCMM Director and Senior Investigator Fred Alt, Charles A. Janeway Professor of Pediatrics and Professor of Genetics at Harvard Medical School and Howard Hughes Medical Institute Investigator at BCH, and PCMM Senior Investigator Hidde Ploegh as members of the Distinguished Fellows of American Association of Immunologists, Class of 2020. Also among the latest class of AAI Distinguished Fellows is PCMM Scientific Advisory Board member Richard Flavell, Sterling Professor of Immunobiology at Yale School of Medicine and Investigator of the Howard Hughes Medical Institute.

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TJ Ha headshotHao Wu Headshot

Hao Wu and TJ Ha honored as 2020 Biophysical Society Fellows

The Biophysical Society has named Hao Wu, PCMM Senior Investigator and Asa and Patricia Springer Professor Biological Chemistry and Molecular Pharmacology and Professor of Pediatrics at Harvard Medical School, and Taekjip (TJ) Ha, the newest member of the PCMM Scientific Advisory Board and Bloomberg Distinguished Professor, Professor of Biophysics and Biophysical Chemistry, Professor of Biomedical Engineering, and Howard Hughes Medical Institute Investigator at Johns Hopkins School of Medicine, as 2020 Society Fellows.

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Sun Hur promoted to Professor

The PCMM is most pleased to congratulate PCMM Investigator Dr. Sun Hur on her promotion to Professor of Biological Chemistry and Molecular Pharmacology at Harvard Medical School. She is also being proposed for an appointment as Professor of Pediatrics. Sun came to PCMM as a theoretical chemist and X-ray crystallographer, and here focused her lab upon a key question in immunology and biology more generally: how self vs. non-self nucleic acids are distinguished in the host cell to lead to appropriate innate immune responses.

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Chromatin loops unlock antibody class switching

Researchers in the laboratory of Frederick Alt of the Howard Hughes Medical Institute and Program in Cellular and Molecular Medicine (PCMM) at Children's Hospital Boston continue their groundbreaking work at the nexus of genetics and immunology, specifically the response of antigen-activated B cells to the enormous variety of possible threats, including bacteria, viruses, and parasites.

Two reports from the Alt Lab in Nature (the first in September 2019 and a second online on October 30, 2019, with a Nature “News and Views” covering both) present major advances in chromatin regulation, showing that two distinct types of antibody gene recombination, occurring at different developmental stages, both depend upon reeling long loops of chromatin past recombination centers to align substrate gene segments in the processes known as V(D)J recombination and class switch recombination (CSR).

Fred Alt Received AAI-BioLegend Herzenberg Award

Congratulations to Dr. Frederick W. Alt for receiving the BioLegend Herzenberg Award from the American Association for Immunologists (AAI). Established to honor the memory of AAI member Leonard A. Herzenberg Ph.D., this award recognizes investigator who has made outstanding for outstanding contributions to the field of Immunology in the area of B cell biology. This award is generously supported by BioLegend

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Fred Alt, a blond man wearing a blue polo shirt, smiles at the camera.