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JOHN C. REED, M.D., PH.D.
President and CEO
Professor and Donald Bren Presidential Chair
Apoptosis and Cell Death Research, Inflammatory Diseases
858.795.5301 (phone)
858.646.3184 (fax)
jreed@burnham.org
Research Assistant Professor
Shu-ichi Matsuzawa, Ph.D.
Research Focus
Apoptosis & Cell Death
Cell
death is a natural part of life. Every day in the human body, 50-70
billion cells die, making room for the equivalent number of new cells
produced daily through cell division. So massive is the flux of cell
birth and death in our bodies, that in the course of single year, each
of us will produce and in parallel eradicate a mass of cells equal to
our entire body weight.
Our cells are endowed with a suicide mechanism that instructs cells when it is time to die. Unfortunately, defects in the regulation of this cell suicide program can occur, leading to diseases characterized by either too much cell death [cell loss] (stroke; heart failure; Alzheimer’s; Parkinson’s; AIDS) or too little cell death [cell accumulation] (cancer; auto-immunity; coronary artery restenosis). In fact, it is estimated that over half of the major medical illnesses for which effective treatments or preventions are currently lacking can be attributed directly or indirectly to defective regulation of programmed cell death mechanisms.
Our laboratory studies fundamental mechanisms of cell life-span regulation, and analyzes how those mechanisms go awry in disease states. We use tools of genomics, proteomics, and bioinformatics to discover genes involved in the causation or suppression of cell death. Characterization of the molecular mechanisms by which the proteins encoded by those genes control cell life and death then provides insights that set the stage for drug discovery. Advances from our laboratory have thus far resulted in a new therapy for cancer, which is in final Phase III clinical trials, and numerous drug-discovery programs at earlier stages of development for cancer, stroke, inflammation, and auto-immunity. Discoveries from our laboratory have also revealed potential new diagnostic tests that can predict whether cancer patients will or will not relapse after receiving therapy, thus providing much need information in planning optimal medical management.
Inflammatory Diseases
Dr. Reed has been engaged in research on immunity, inflammation and infectious diseases for nearly 25 years. He obtained his doctoral degree in Immunology in 1986, initially studying signaling mechanisms of lymphokine receptors, then progressing to investigations of cytopathic mechanisms of Human Immunodeficiency Virus (HIV) and other topics in immunobiology. Dr. Reed’s current interests focus on innate immunity, including studies of NLR-family proteins (intracellular analogs of the Toll-Like Receptors [TLRs], PYRIN domain (PYD)-containing proteins, and the role of TRAF-family adapter proteins in signaling by members of the Tumor Necrosis Factor (TNF) Receptor family. Dr. Reed is the co-discoverer of several NLR-family proteins, several PYD-containing proteins, TRAF3, and several proteins involved in regulation of pro-inflammatory Caspase-family proteases and NF-κB. The Reed laboratory is also engaged in research on pathogens, with a focus on virulence factors encoded in the genomes of bacterial and viruses that impinge on signaling transduction pathways regulating inflammatory Caspases, NF-κB, and apoptosis in infected host cells. Translational applications of the basic discovery research conducted in the Reed laboratory include high throughput screens for novel immunoadjuvants that stimulate NLR-family proteins, and chemical inhibitors of NLRs and TRAF-associated proteins with potential utility for treatment of inflammatory and autoimmune diseases, sepsis, and other conditions.
Biography
John C. Reed, MD, Ph.D., is President & Chief Executive Officer of Burnham Institute for Medical Research, where he has worked as scientist and leader for over 15 years. Dr. Reed is also Professor and Donald Bren Presidential Chair at Burnham, with adjunct Professor appointments at several universities. Dr. Reed’s scientific accomplishments include authorship of over 800 research publications and more than 51 book chapters. He was recently recognized as the world’s most highly cited scientist for his research publications during the decade 1995-2005 in the broad field of “cell biology” and also in the field of “general biomedicine” by the Institute for Scientific Information. Dr. Reed is the recipient of numerous awards and honors, and has been awarded over 76 research grants for his work. He is a named inventor for over 99 patents and the founder or co-founder of four biotechnology companies. Dr. Reed has served as an advisor to numerous biotechnology and pharmaceutical companies, and has also served on the Boards of Directors of several public and private biotechnology companies and life-sciences organizations.
Selected Publications
Deveraux QL, Takahashi R, Salvesen GS, Reed JC. X-linked IAP is a direct inhibitor of cell-death proteases. Nature. 1997 Jul 17;388:300-4.
Takayama S, Bimston DN, Matsuzawa S, Freeman BC, Aime-Sempe C, Xie Z, et al. BAG-1 modulates the chaperone activity of Hsp70/Hsc70. EMBO J. 1997;16:4887-96.
Xu Q, Reed JC. BAX inhibitor-1, a mammalian apoptosis suppressor identified by functional screening in yeast. Mol Cell. 1998;1:337-46.
Wang HG, Pathan N, Ethell IM, Krajewski S, Yamaguchi Y, Shibasaki F, et al. Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD. Science. 1999;284:339-43.
Reed JC. Apoptosis-regulating proteins as targets for drug discovery. Trends Mol Med. 2001;7:314-9.
Reed JC. Apoptosis-based therapies. Nature Reviews Drug Disc. 2002;1:111-21.
Reed JC. Apoptosis-targeted therapies for cancer. Cancer Cell. 2003;3:17-22.
Reed JC, Doctor KS, Godzik A. The domains of apoptosis: a genomics perspective. Science STKE. 2004 Jun 29;2004:RE9.
Chae HJ, Kim HR, Xu C, Bailly-Maitre B, Krajewska M, Krajewski S, et al. BI-1 regulates an apoptosis pathway linked to endoplasmic reticulum stress. Mol Cell. 2004 Aug 13;15:355-66.
Reed JC, Pellecchia M. Apoptosis-based Therapies for Hematological Malignancies. Blood 2005;106 408-18.
Reed JC. Proapoptotic multidomain Bcl-2/Bax-family proteins: mechanisms, physiological roles, and therapeutic opportunities. Cell Death Differ. 2006;13:1378-86.
Reed JC. Drug Insight: cancer therapy strategies based on restoration of endogenous cell death mechanisms. Nat Clin Pract Oncol. 2006;3:388-98.
Bruey JM, Bruey-Sedano N, Luciano F, Zhai D, Balpai R, Xu C, et al. Bcl-2 and Bcl-XL regulate proinflammatory caspase-1 activation by interaction with NALP1. Cell. 2007 Apr 6;129:45-56.
Faustin B, Lartigue L, Bruey JM, Luciano F, Sergienko E, Bailly-Maitre B, et al. Reconstituted NALP1 inflammasome reveals two-step mechanism of Caspase-1 activation. Molecular Cell. 2007;25:713-24.
Reed JC. Bcl-2-family proteins and hematologic malignancies: history and future prospects. Blood. 2008 Apr 1;111:3322-30.
Puto LA, Reed JC. Daxx represses RelB target promoters via DNA methyltransferase recruitment and DNA hypermethylation. Genes Dev. 2008 Apr 15;22:998-1010.
Yip KW, Reed JC. Bcl-2 family proteins and cancer. Oncogene. 2008 Nov 13;27:6398-406.
Krieg A, Correa RG, Garrison JB, Le Negrate G, Welsh K, Huang Z, et al. XIAP mediates NOD signaling via interaction with RIP2. Proc Natl Acad Sci U S A. 2009 Aug 25;106:14524-9.
List of Publications via PubMed
(NIH National Library of Medicine)
Research Report
Programmed Cell Death in Malignancy
Defects
in the regulation of apoptosis (programmed cell death) make important
contributions to the pathogenesis or severity of many diseases,
including cancer, autoimmunity, inflammation, neurodegeneration, and
ischemic diseases (heart attack; stroke). Indeed, it is estimated that
over half of the major medical illnesses for which effective treatments
or preventions are currently lacking can be attributed directly or
indirectly to defective regulation of programmed cell death mechanisms.
Apoptosis is caused by activation of intracellular proteases,
known as "caspases," which are responsible directly or indirectly for
the morphological and biochemical events that characterize the
apoptotic cell. Numerous proteins that regulate these cell death
proteases have been discovered, including proteins belonging to the
Bcl-2, IAP, CARD, Death Domain (DD), Death Effector Domain (DED)
families. These caspase-regulating proteins provide mechanisms for
linking environmental stimuli to cell death responses (e.g. DNA damage,
microtubule disruption; cytokine stimulation) or to maintenance of cell
survival (e.g., growth factors; cell adhesion receptors; oncoproteins).
Knowledge of the molecular details of apoptosis regulation and the
3-dimensional structures of apoptosis proteins have revealed new
strategies for identifying small-molecule drugs that may one day yield
more effective treatments for several diseases. Apoptosis-regulating
genes are also beginning to find utility as targets for antisense
oligonucleotides or for use in gene therapy applications. Moreover,
knowledge about the signal transduction pathways that control the
expression of apoptosis gene or that modulate the functions of
apoptosis-proteins can be exploited for altering the balance of pro-
and anti-apoptotic gene expression and function, using protein kinase
inhibitors, regulators of steroid/retinoid-family transcription
factors, and other approaches.
Our laboratory studies
fundamental mechanisms of apoptosis regulation, and analyzes how those
mechanisms go awry in disease states. The experimental approaches
employed include genomics, proteomics, bioinformatics, structural
biology, and chemistry. Some of the discoveries made by the laboratory
include (a) establishing the role of Bcl-2 in cancer chemoresistance
and use of antisense methods to reduce Bcl-2 expression for sensitizing
tumor cells to anti-cancer drugs (now in Phase III clinical trials);
(b) demonstration of a critical role for mitochondria in apoptosis
mechanisms using a cell-free system; (c) discovery that p53 induces
transcription of death-gene Bax, representing the first p53–inducible
pro-apoptotic gene; (d) discovery of the mechanism of IAP-family
proteins, as endogenous suppressors of Caspase-family proteases; (e)
discovery of BAG-family proteins and their role in cellular stress
resistance; and (f) development of prognostic biomarkers that predict
clinical outcome in patients with cancer.
