PCMM Research | Overview
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
Getting a grip on genetic loops
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.”
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
PCMM 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!
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.
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 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."
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!
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.
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!
Sun Hur named 2021 HHMI Investigator
We are delighted to announce that Sun Hur has been named a Howard Hughes Medical Institute Investigator!
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!
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!
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 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!
Here at PCMM, Hao has done outstanding work in structural biology and mechanistic immunology that has fundamentally revised our understanding of the molecular mechanisms of innate immune signaling.
David Oxtoby, President of the American Academy of Arts and Sciences, noted of the 2021 class of newly elected members, “The past year has been replete with evidence of how things can get worse; this is an opportunity to illuminate the importance of art, ideas, knowledge, and leadership that can make a better world.”
Congratulations to Hao and Akiko for this wonderful achievement!
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.
He was cited “for the discovery of gene amplification in mammalian cancer cells, discoveries that contributed to establishing oncogene amplification as a tumor progression mechanism, elucidating non-homologous end-joining, and revolutionizing the understanding of how genomic rearrangements form and how they contribute to cancer.” The chief executive officer of the AACR, Margaret Foti, PhD, MD (hc), added, “Dr. Alt is a pioneer in the fields of genetics and immunology whose landmark discoveries have had a defining impact on the study of cancer biology. We thank him for his immeasurable contributions to cancer research and are proud to honor his ongoing dedication to progress against cancer with this award.”
In addition to his groundbreaking work on cancer, recognized with this award, his pioneering research in immunology helped define the processes that generate the immense diversity of antibodies that can be produced to ward off infection.
The PCMM community extends its warmest congratulations to Fred for this well-deserved honor!
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!
This honor follows her election to the National Academy of Sciences in April, so this has been an exceptional year indeed for Judy. It is a fitting tribute to how her life's work of outstanding discoveries in immunology and inflammation have influenced the fields of health and medicine. Judy's achievements bolster the entire PCMM community, and we look forward to her many more successes and contributions to come.
Please join us in extending our heartfelt congratulations to Judy!
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.
Dornase alfa, also called DNase 1, is FDA-approved for patients with cystic fibrosis, to break up thick mucus secretions and prevent lung infections. The trial is supported by the Massachusetts Consortium on Pathogen Readiness, and the drug is being provided by Genentech, a member of the Roche Group, which is also providing supplementary financial support.
“We hope this drug, which is known to be safe, will help reduce the inflammation that contributes to worsening respiratory distress in COVID-19,” says Benjamin Raby, MD, MPH, chief of the Division of Pulmonary Medicine at Boston Children’s Hospital and principal investigator on the study.
The 18-month study will randomize patients to twice-daily nebulized dornase alfa or placebo (a saline solution) within 48 hours after intubation and placement on a ventilator. Treatments will be given via the ventilator tubing, twice a day for up to 28 days. Researchers will then monitor both groups for up to 28 days, or until patients are no longer receiving mechanical ventilation, whichever is sooner. Neither the researchers nor the patients (and families) will know which treatment is being given.
The main outcome of interest is the number of patients in each group who are alive and ventilator-free 28 days after treatment. Other measures will include airway resistance to breathing, lung compliance (the lungs’ ability to stretch and expand), blood oxygenation, and length of stay in the ICU and hospital.
Why dornase alfa for COVID-19 pneumonia?
Some patients with COVID-19 pneumonia produce large amounts of thick mucus that can make effective delivery of oxygen by mechanical ventilation more challenging. Dornase alfa is an effective mucolytic — able to soften mucus and promote its clearance from the airways. In addition, dornase alfa may be able to reduce lung inflammation promoted by neutrophil extracellular traps, or NETs. NETs are webs of DNA and toxic protein released by neutrophils, first responders in the immune system, in an excessive effort to entrap invading microbes. NETs are also known to produce dangerous blood clots such as those that form in COVID-19 patients, and are known, in general, to contribute to blood clots in the lung capillaries, inflammation, and lung injury.
Denisa Wagner, PhD, of the Program in Cellular and Molecular Medicine at Boston Children’s Hospital, who helped to initiate the new trial, has been studying NETs and their role in unwanted clot formation and fibrosis (thickening and scarring of tissue) for more than a decade.
“Preclinical studies by several groups, including ours at Boston Children’s Hospital, have found that DNase 1 improved outcome in lung injury models and thrombotic models mimicking events that occur frequently in COVID-19, such as deep vein thrombosis, stroke and microvascular thrombosis,” Wagner says. “This suggests to us that treatment with DNase could be beneficial in severe lung injury observed in COVID-19.”
Although this study is limited to the lung, it’s hypothesized that NETs contribute to coagulopathies seen with COVID-19 elsewhere in the body.
Other study principals include Rebecca Baron, MD, and Laura Fredenburgh, MD, of Brigham and Women’s Hospital and Meera Subramaniam, MD, and Gregory Sawicki, MD, of Boston Children’s Hospital.
Boston Children’s Hospital is ranked the #1 children’s hospital in the nation by U.S. News & World Report and is the primary pediatric teaching affiliate of Harvard Medical School. Home to the world’s largest research enterprise based at a pediatric medical center, its discoveries have benefited both children and adults since 1869. Today, 3,000 researchers and scientific staff, including 9 members of the National Academy of Sciences, 21 members of the National Academy of Medicine and 12 Howard Hughes Medical Investigators comprise Boston Children’s research community. Founded as a 20-bed hospital for children, Boston Children’s is now a 415-bed comprehensive center for pediatric and adolescent health care. For more, visit our Answers blog and follow us on social media @BostonChildrens, @BCH_Innovation, Facebook and YouTube.
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!
NAS membership is one of the highest honors that a scientist can receive, recognizing distinguished and continuing achievements in original research across all disciplines, from mathematics to biomedical sciences to social sciences.
This distinguished honor is a tribute to Judy's lifetime of truly outstanding work in immunology and inflammation. Her ongoing science and her broad contributions continue to be amazing. Please join us in extending our heartfelt congratulations to Judy!
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.
Selection as a Distinguished Fellow is one of the highest honors bestowed by AAI, presented to members who have been active 25 or more years and have made outstanding contributions to science, demonstrating such qualities as “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.”
PCMM congratulates Fred, Hidde, and Richard on this achievement!
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.
The award honors members who have supported the society, demonstrated scientific excellence, and expanded the field of biophysics. Hao was honored “for fundamentally revising how we view intracellular signaling and cellular organization, through discovering supramolecular ‘signalosomes’ formed by innate immune signaling proteins, mechanisms that govern cooperative assembly, and proximity-driven enzyme activation.” TJ was honored “for his contributions to single molecule biophysics approaches which have furthered our understanding of complex interacting biological systems.” All six newly elected Society Fellows were honored at Biophysical Society’s 64th Annual Meeting on February 17 at the San Diego Convention Center in California.
PCMM congratulates Hao and TJ for achieving this honor!
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.
Her work has revealed the importance of filament formation of nucleic acid sensors in self vs. non-self discrimination and transmission of innate immune signaling, as well as the molecular mechanisms of RNA-receptor interactions. A picture has emerged from this work in which each receptor multimerization step in the RNA sensing signaling pathway provides a specificity checkpoint that insures correct initiation of the antiviral response, and the efficiency of RNA-receptor interactions fine tunes the balance between immunity and tolerance.
Sun was named a Massachusetts Life Sciences Center New Investigator in 2009 and a Pew Biomedical Scholar in 2010. In 2015, she received the prestigious Vilcek Prize for Creative Promise in Biomedical Science and was named a Burroughs Wellcome Investigator in the Pathogenesis of Infectious Disease. Earlier this year, she received an NIH Director’s Pioneer Award. Sun will be nominated to become the first incumbent of the endowed Oscar M. Schloss MD Professorship at Harvard Medical School, based in PCMM and the BCH Department of Pediatrics. There will be more news in the near future.
We are thrilled to have Sun Hur as a PCMM colleague!
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