Dr. Brenner was named president and chief executive officer of Sanford Burnham Prebys in September 2022 after serving as vice chancellor for health sciences at UC San Diego and dean of its school of medicine for an unprecedented 15 years, during which he oversaw the launch and expansion of numerous multidisciplinary efforts, including the Institute for Engineering in Medicine, the Institute for Genomic Medicine, the Sanford Consortium for Regenerative Medicine, the UC San Diego Sanford Clinical Stem Cell Program, and the C3 Cancer Center Consortium (comprising UC San Diego, the Salk Institute for Biological Studies and Sanford Burnham Prebys).
Previously, he served as chair of the Department of Medicine and Physician-in-Chief of New York Presbyterian Hospital/Columbia University and, before that, as Chief of Gastroenterology and Hepatology at University of North Carolina at Chapel Hill.
As a distinguished physician-scientist, Brenner is a recognized leader in the field of gastroenterology research, with more than 200 peer-reviewed publications, two patents and ranking among Highly Cited Researchers by Web of Science and Clarivate Analytics.
He is an elected member of the National Academy of Medicine; past president of the Association of American Physicians and former editor of the journal Gastroenterology (2001 to 2006).
He is currently deputy editor of the journal PNAS Nexus.
Education and Training
1988: Fellowship, Gastroenterology, UC San Diego 1986: Fellowship, Genetics & Biochemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 1985: Intern & Residency, Internal Medicine, Yale University 1979: MD, Medicine, Yale University 1975: BS, Biology, Yale University
Awards, Honors and Recognition
2005: Fellow (FACP), American College of Physicians 1986: Bomedical Scholar, Pew Foundation
Other Appointments and Memberships
Alcoholic Beverage Medical Research Foundation American Society for Clinical Investigation Association of American Physicians American College of Physicians American Gastroenterological Association American Clinical and Climatological Association
Mahata B, Cabrera A, Brenner DA, Guerra-Resendez RS, Li J, Goell J, Wang K, Guo Y, Escobar M, Parthasarathy AK, Szadowski H, Bedford G, Reed DR, Kim S, Hilton IB
Douglas Sheffler studies the many facets of addiction, including addiction to the nicotine found in tobacco products. Smoking continues to be the leading cause of preventable deaths in the United States, and the second leading cause of preventable deaths worldwide after hypertension (of which smoking is a risk factor).
With Peter Cosford, PhD, Sheffler, in collaboration with colleagues at UC San Diego and Camino Pharma LLC, a San Diego-based biotechnology company Cosford co-founded, are conducting clinical trials to advance an investigational drug called SBP-9330.
SBP-9330 targets a neuronal signaling pathway that underlies addictive behaviors, including tobacco use. If ultimately approved for market, it would be a first-in-class oral therapeutic to help people quit smoking.
“Our research suggests that SBP-9330’s mechanism of action—how it works—may also be effective for other types of addiction, such as cocaine, opioid and methamphetamine. In the future, we hope to explore and broaden the drug’s therapeutic uses.”
Prior to coming to Sanford Burnham Prebys in 2012 as a research assistant professor, Sheffler served in the same capacity at Vanderbilt University. He earned his PhD in biochemistry from Case Western Reserve University and his Bachelor of Science degree from Saint Vincent College.
2013 NARSAD Young Investigator Award Brain and Behavior Research Foundation
Related Disease
Alzheimer’s Disease, Huntington’s Disease, Neurodegenerative and Neuromuscular Diseases, Neurological and Psychiatric Disorders, Schizophrenia
Dr. Sheffler joined the Sanford Burnham Prebys faculty in September 2012. Prior to this, he was a Research Assistant Professor at Vanderbilt University in the laboratory of P. Jeffrey Conn (2010-2012), where he also performed post-doctoral work (2006-2010). Dr. Sheffler has over 15 years’ experience in the study of G-protein coupled receptor (GPCR) signaling, assay development, high throughput screening for novel GPCR ligands, cell biology, neuroscience, and pharmacology. His interests are in the complex regulation of GPCRs: their signal transduction, ligand binding, receptor desensitization, and the processes of GPCR internalization and down-regulation. In addition, he has also has a specific interest in both the pharmacology of GPCRs, in general mechanisms of signal transduction, and in the pathogenesis of schizophrenia. During his graduate studies at Case Western Reserve University in the laboratory of Bryan L. Roth, MD, PhD, he discovered the regulation of 5-HT2A serotonin receptor signal transduction by p90 ribosomal S6 kinase (RSK2). During his post-doctoral studies and work as a Research Assistant Professor at Vanderbilt University, he focused on the discovery and characterization of orthosteric and allosteric modulators of GPCRs and led pharmacology efforts characterizing novel M1 muscarinic acetylcholine receptor agonists and antagonists, M1 positive allosteric modulators (PAMs), Glycine Transporter Type 1 (GlyT1) inhibitors, and novel Group II metabotropic glutamate receptor (mGlu) PAMs and NAMs. Dr. Sheffler’s research has resulted in more than 45 journal articles and is a listed inventor on five patent applications pertaining to small molecule therapeutics. Dr. Sheffler received a NARSAD Young Investigator Award in 2013 from the Brain and Behavior Research Foundation.
Douglas Sheffler’s Research Report
The metabotropic glutamate receptors (mGlus) are G protein-coupled receptors (GPCRs) that play numerous roles in modulating synaptic transmission and cell excitability. Recent preclinical and clinical studies provide strong evidence that agonists of the group II mGlus, comprised of the mGlu2 and mGlu3 subtypes, may provide a novel approach to treatment of schizophrenia and anxiety disorders. Based on this, there has been a major focus on understanding the roles of these receptors in regulating transmission in forebrain and limbic circuits. However, currently available orthosteric (glutamate site) agonists activate both mGlu2 and mGlu3 and do not provide insight into which subtype is most important for clinical efficacy. Alternatively, recent focus on compounds interacting with less highly conserved allosteric sites has led to advances in subtype selective compound development. Dr. Sheffler and others have discovered and characterized highly selective mGlu2 positive allosteric modulators (PAMs), that have no effect on mGlu3, and these compounds have allowed us to elucidate many of the physiological roles of mGlu2. These PAMs do not activate the receptor directly but act allosterically to potentiate glutamate responses. Dr. Sheffler and collaborators have also discovered group II mGlu negative allosteric modulators (NAMs) and have very recently discovered the first highly selective antagonist of mGlu3. The development of these pharmacological tools provides an opportunity to fully elucidate the roles of these mGlu subtypes. The group II mGlus play important roles in regulating transmission through the hippocampal formation. For example, activation of presynaptic group II mGlus reduces transmission at numerous hippocampal synapses including perforant path-dentate gyrus synapses and the mossy fiber synapse. In contrast, presynaptic group II mGlus are not involved in directly regulating transmission at the Schaffer collateral – CA1 (SC-CA1) synapse. However, we have previously reported extensive studies demonstrating group II mGlu involvement in a novel form of glial-neuronal communication in hippocampal area CA1. When coincidentally activated with β-adrenergic receptors (βARs) in astrocytes, group II mGlus induce a marked potentiation of cAMP responses elicited by activation of βARs. This synergistic increase in glial cAMP accumulation results in the release of adenosine, which activates presynaptic A1 adenosine receptors on neighboring SC terminals and induces a profound depression of transmission at the SC-CA1 synapse. This novel form of glial-neuronal signaling may provide a protective mechanism to reduce the risk of excitotoxicity when there is excessive excitatory drive to the hippocampus, such as during periods of intense or prolonged stress. This potential role has implications relevant for the therapeutic effects of group II mGlu agonists and is consistent with multiple studies suggesting group II mGlu agonists can reduce both acute and long term responses to stress. We have postulated that this effect is mediated by mGlu3 based on heavy expression of mGlu3 in hippocampal astrocytes. However, until now, selective reagents that differentiate between mGlu2 and mGlu3 have not been available to rigorously determine the specific group II mGlu subtype involved. The long term goal of Dr. Sheffler’s research is to establish the relative roles of individual group II mGlu subtypes in mediating glial-neuronal communication and modulating synaptic transmission in the hippocampus using pharmacological, biochemical, and electrophysiological approaches.
Dr. Zhao joins us from University of California San Francisco, where he recently completed his Postdoctoral Training. His lab will focus on understanding how proteins function under different physiological and disease states from a structural biology perspective. Specifically, Dr. Zhao brings significant expertise in visualizing proteins at high resolution using cryogenic electron microscopy (cryo-EM). Dr. Zhao received his Bachelor’s and PhD in Medical Biophysics from the University of Toronto, Canada, where he completed 5 years of graduate training investigating rotary ATPases. He then went on and completed 5 years of postdoctoral training at UCSF studying Transient Receptor Potential ion channels.
Education and Training
2010: Postdoctoral associate, Molecular Biophysics and Biochemistry, Yale University 2009: PhD, Computer Science, Yale University 2003: M.Phil., Computer Science, The University of Hong Kong 1999: B.Eng., Computer Engineering, The University of Hong Kong
Related Disease
Biliary Atresia, Cancer, Diabetes – General, Hirschsprung Disease, Liver Cancer, Nasopharyngeal Carcinoma, Type 2 Diabetes
Phenomena or Processes
Cancer Epigenetics, Gene Regulation, Oncogenes, Posttranslational Modification, Transcriptional Regulation, Tumor Microenvironment
Anatomical Systems and Sites
Endocrine System, General Cell Biology, Immune System and Inflammation, Liver
Research Models
Computational Modeling
Techniques and Technologies
Bioinformatics, Comparative Genomics, Genomics, Machine Learning, Protein-Protein Interactions, Systems Biology
We study gene regulatory mechanisms by means of computational modeling. To facilitate our data-centric approach, we develop novel methods for analyzing large amounts of biological data, including those produced by cutting-edge high-throughput experiments. Our computational models provide a systematic way to investigate the functional effects of different types of perturbations to regulatory mechanisms, which creates testable hypotheses for studying human diseases and facilitates translational research.
Yu Yamaguchi earned his MD from Tohoku University in Japan in 1981, followed by a PhD in 1985, and training in obstetrics and gynecology at the same institute. Dr. Yamaguchi came to Sanford Burnham Prebys for his postdoctoral training. He was appointed to the staff in 1991.
Honors and Recognition
The Humanitarian Scientific Achievement Award, The MHE Research Foundation The Kushima Prize, The Alumni Association, Tohoku University School of Medicine
Related Disease
Alzheimer’s Disease, Arthritis, Autism Spectrum Disorders, Bone Mineralization Disorders, Epilepsy, Multiple Hereditary Exostoses
The goal of research in the Yamaguchi laboratory is to understand the role of proteoglycans and glycosaminoglycans in the context of development and human disorders. The general strategy is to define the role of proteoglycans and glycosaminoglycans by characterizing the phenotype of mutant mice lacking the synthesis of individual glycosaminoglycans. Specifically, mutant mice lacking the Ext1 and Has genes have been created to study heparan sulfate and hyaluronan, respectively. Recent progress in genetic studies in humans and mice has begun to reveal that deficiencies in glycosaminoglycans can be the causes and/or confounding factors of human childhood disorders. The Yamaguchi lab is now working to clarify the molecular mechanisms of two such disorders (multiple hereditary exostoses and autism) in order to develop new medical treatments.
For more information on the impact of Dr. Yamaguchi’s work, read letters from the patients with MHE.
Yu Yamaguchi’s Research Report
What Are Proteoglycans and Glycosaminoglycans?
Proteoglycans are a family of glycoproteins consisting of a core protein and a various number of long sugar chains called glycosaminoglycans attached to the core protein (Fig. 1). There are four classes of glycosaminoglycans; heparan sulfate, chondroitin sulfate, keratan sulfate, and hyaluronan (hyaluronic acid). Heparin, the anticoagulant widely used in clinics, is a specialized form of heparan sulfate. Although there is ample circumstantial evidence that these glycosaminoglycans have important biological functions, a complete understanding of their function and their relevance to human diseases requires genetic animal models.
Figure 1. Proteoglycans consist of a protein core and one or more covalently attached glycosaminoglycan chains. From Esko, JD, Kimata, K., and Lindahl, U. Proteoglycans and Sulfated Glycosaminoglycans, In: Essentials of Glycobiology, CSH Press.
Developmental Roles Of Glycosaminoglycans
HEPARAN SULFATE – The Ext1 gene encodes an enzyme essential for the elongation of nascent heparan sulfate chains. As a result of genetic ablation of Ext1 using a ‘conditional knockout’ approach, heparan sulfate is eliminated from specific tissues and cell types. Our previous studies using brain-specific Ext1 conditional knockout have demonstrated critical roles of heparan sulfate in brain patterning, neurogenesis in the cerebral cortex, and pathfinding of various axon tracts (1)(2)(3)(4). More recently, conditional Ext1 knockout in developing limb bones revealed critical roles of heparan sulfate in the growth and patterning of bones and joint formation (5).
Moreover, our conditional Ext1 mutant mouse model has been distributed to more than 20 laboratories worldwide to characterize the role of heparan sulfate in various tissues and cell types, such as colon (6), kidney (7), lymphocytes (8), blood vessels (9), eyes (10), embryonic stem cells (11), and so on.
HYALURONAN – Three Has genes (Has1, Has2, Has3) encode the entire repertoire of hyaluronan synthases in mammalian cells. Genetic ablation of these genes, singly or in combination, results in a reduction or total elimination of hyaluronan, depending on the repertoire of Has expression in the given tissue. We created a conditional null allele of the Has2 gene, which is the predominant Has in many tissues. Our conditional Has2 knockout study targeted to the limb bud mesenchyme has revealed that hyaluronan plays a critical role in the proliferation and maturation of chondrocytes in the developing limb skeleton (12). Like Ext1 mutant mice, these Has2 conditional knockout mice are being used in more than a dozen laboratories worldwide for studies on the role of hyaluronan in various tissue and cell types.
Deficiencies in glycosaminoglycan synthesis can be the causes of childhood disorders
Recent progress in genetic studies in humans and mice has begun to reveal that deficiencies in glycosaminoglycans can be the causes and/or confounding factors of human childhood disorders. The research focus of our lab is to elucidate the molecular mechanisms of such disorders and to develop new medical treatments. We are currently studying two such disorders.
MULTIPLE HEREDITARY EXOSTOSES – One of the major diseases studied in our lab is Multiple Hereditary Exostoses (MHE; also known as Hereditary Multiple Exostoses [HME] or Multiple Osteochondroma [MO]). MHE is caused by a mutation in Ext1 (see above) or its related gene, Ext2. As mentioned above, these genes encode an enzyme necessary to produce heparan sulfate. MHE occurs in children of 0-12 years old. Although no comprehensive survey has been conducted, it is estimated that there are several thousand individuals affected by MHE in the US, which makes MHE one of the more prevalent among ’rare diseases’. Dr. Yamaguchi is a member of the scientific advisory board of the MHE Research Foundation and has been working to promote collaborations between basic scientists, academic physicians, and patient advocates.
Children with MHE suffer from the formation of multiple –– sometimes as many as 100 –– bony tumors (osteochondromas) (Fig. 2). These bony tumors stunt their growth and can cause pain and disfigurement. Fortunately, the chance these tumors becomes cancerous is relatively low, partly because they are surgically removed as they develop. This means, however, children with MHE need to go through multiple surgeries over the course of their lives. There is currently no medical treatment for the disease.
Figure 2. MHE patients, Carol and her 12-year-old son, Bruce. Shown on the right are three-dimensional CT images of Bruce’s right upper leg and knee joint area. Note that there are many bony protrusions (‘exostoses’), as indicated by white arrowheads. These tumors need to be surgically removed to prevent possible malignant transformation. Surgery is also needed to correct bone deformities and bone length inequalities. For example, Bruce and Carol have had 21 and 36 surgeries, respectively.
Our lab is currently working to elucidate the molecular and cellular mechanisms of MHE. One of the major thrusts has been to create a mouse model that mimics the manifestations of human MHE. A long-term issue of MHE research has been the lack of mouse models that faithfully recapitulate the manifestation of human MHE; when Ext genes were inactivated in mice just as they are in human MHE patients, the mice failed to develop the symptoms of MHE. Instead of knocking out the Ext1 gene in the whole mouse, we targeted the gene in only a small fraction of bone cells (Ext1-SKO mice). This minimalistic approach led to a mouse with all the physical manifestations of MHE, such as bony protrusions, short stature, and other skeletal deformities (Fig. 3)(13). The new mouse model answered some long-standing questions about MHE. Scientists had gone back and forth on whether osteochondromas observed in MHE are true tumors or just malformations of the bone. In this study, the tumors were made up of two cell types. A minority were mutant cells lacking Ext1, but, amazingly, most were normal bone cells. Hence, osteochondroma in MHE is not considered a true neoplasm in its strictest sense.
Figure 3. Ext1-SKO mice develop multiple osteochodromas in a pattern almost identical to human MHE. The X-ray images of the knee joint area of an MHE patient and the wrist, knee, and shoulder areas of Ext1-SKO mice. Osteochondromas are indicated by arrows. Ext1-SKO mice also mimic other skeletal deformities frequently seen human MHE, such as bowing of the forearm, the subluxation/dislocation of the radial head, and scoliosis (not shown).
Our lab has been using this and additional mouse models to further dissect the pathogenic mechanism of MHE. Moreover, this mouse model provides new opportunities to test potential drugs to prevent osteochondroma formation and other clinical symptoms of MHE.
AUTISM – Children with MHE sometimes suffer from neurological and mental symptoms, which is not surprising because heparan sulfate is expressed and plays critical roles in the nervous system (1). The MHE community has long noticed the prevalence of autism-like behavioral traits in the patient population, and there are clinical reports describing the association of autism with MHE. Aided by the funds from the Sanford Health and the MHE Research Foundation, we have been studying the behavior of Ext1 mutant mice. Our preliminary data suggest that heparan sulfate has indeed a physiological function in the nervous system, and that its deficiency can cause behavioral deficits relevant to human autism. We are also analyzing DNA samples from individuals with autism for abnormalities in enzymes for heparan sulfate synthesis. Since heparan sulfate is a modulator of a number of neuronal molecules, we hope to identify functional networks of molecules underlying autism and other childhood mental disorders.
A career history of fundamental discovery and translational research in immunology has guided Dr. Ware to identify new drug targets and develop novel therapeutics. Dr. Ware’s career in immunology and virology began in 1982 when he became a Professor at the University of California, Riverside’s Division of Biomedical Sciences. In 1996, he joined the La Jolla Institute for Immunology in San Diego as Head of the Division of Molecular Immunology. Professor Ware joined Sanford Burnham Prebys Medical Discovery Institute in 2010, serving as the Director of the Infectious and Inflammatory Disease Center and Adjunct Professor of Biology at the University of California at San Diego. He is currently the Director of the Laboratory of Molecular Immunology, which focuses on discovering and designing immunotherapeutics.
As an educator, he taught medical students immunology and virology. He trained over 60 postdoctoral fellows and graduate students who chose careers in research in academic and pharmaceutical science, patent law, or teaching.
Dr. Ware advises scientific panels and review boards for the National Institutes of Health and serves on the scientific advisor boards for the Allen Institute for Immunology and the Arthritis National Research Foundation. Scientific advisor with several biotechnology and pharmaceutical companies on immunotherapy for cancer and autoimmune diseases using innovative approaches to target discovery and drug development.
Dr. Ware’s research program is dedicated to unraveling the intricate intercellular communication pathways that govern immune responses. His work, which centers on cytokines in the Tumor Necrosis Factor (TNF) Superfamily, particularly those that regulate cell survival and death in response to viral pathogens, spans the domains of cancer,autoimmune and infectious diseases.
At Sanford Burnham Prebys, Dr. Ware is pivotal in promoting the translation of the faculty’s scientific discoveries. His efforts have led to the Institute’s reputation as a productive and preferred partner in collaborations with Pharma, including multi-year research and drug development projects with Eli Lilly and Avalo Therapeutics. His success translating fundamental knowledge into rational drug design has led to three novel therapeutics targeting inflammatory pathways, currently in clinical trials.
Education
1981-1982: T cell Immunology, Dana-Farber Cancer Institute of Harvard Medical School in Boston, MA. Tim Springer and Jack Strominger, advisors.
1979-1981: Biochemistry of Complement, University of Texas Health Science Center, San Antonio, TX. W Kolb, advisor
1974-1979: PhD in Molecular Biology and Biochemistry from the University of California, Irvine; Gale Granger, PhD mentor.
Honors and Recognition
Distinguished Fellow, American Association of Immunologists
Honorary Lifetime Membership Award International Cytokine and Interferon Society
Hans J. Muller-Eberhardt Memorial Lecture
Biotech All Star, San Diego Padres Award
“Pillars of Immunology” discovery of the Lymphotoxin-b Receptor, published in Science
Outstanding Alumnus, Ayala School of Biological Sciences, University of California, Irvine
National MERIT Award R37 (10 years), National Institute of Allergy and Infectious Disease, NIH
National Research Service Award, NIH Postdoctoral Fellowship
Related Disease
Arthritis, Breast Cancer, Cancer, Crohn’s Disease (Colitis), Infectious Diseases, Inflammatory Bowel Disease, Inflammatory/Autoimmune Disease, Inherited Disorders, Leukemia/Lymphoma, Myeloma, Pathogen Invasion, Psoriasis, Systemic Lupus Erythematosus, Type 1 Diabetes
Research in the Laboratory of Molecular Immunology is directed at defining the intercellular communication pathways controlling immune responses. Our work is focused on the Tumor Necrosis Factor (TNF)-related cytokines in regulating decisions of cell survival and death, especially in responses to viral pathogens. Translational research is redirecting the communication networks of TNF superfamily to alter the course of autoimmune and infectious disease and cancer.
Carl Ware’s Research Report
Discovery of the TNF-LIGHT-LTαβ Network
The molecular elements of this cellular communication network were revealed with our discovery of Lymphotoxin-β and its formation of the trimeric heterocomplex with LTαβ1 and its signaling receptor, Lymphotoxin-β Receptor2. The LTβR revealed a new inter-cellular communication pathway that provides a key mechanism underlying the development and homeostasis of lymphoid organs. A second ligand we discovered, LIGHT (TNFSF14), is a novel ligand for the herpesvirus entry mediator (HVEM; TNFRSF14), and surprisingly, the LTβR3 heralding the concept that TNF, LTαβ, and LIGHT form an integrated signaling network thru distinct receptors controlling inflammation and host defense.4
LTβR Signaling in Host Defense and Immune Evasion
Our investigations into the mechanisms of virus evasion of the immune system revealed an essential role of the LTβR pathway in regulating the type 1 interferon response to cytomegalovirus5 and now recognized as a major defense against other pathogens. LTβR signals differentiate macrophages and stromal cells into IFN-producing cells. LTβR transcriptomics and proteomics datasets we generated revealed a novel constellation of anti-viral host defense mechanisms6. Importantly the role of the LTβR pathway to alter tissue microenvironments by differentiation of specialized stromal cells has implications for promoting effective immune responses to cancer.
Discovery of the HVEM-BTLA Immune Checkpoint
The LTBR-HVEM-BTLA Network in the TNF Superfamilies. Arrows indicate ligand-receptor binding (black), inhibitors (red arrow) and bidirectional signaling (dual arrowheads); HSV, herpes simplex virus; CMV, human cytomegalovirus. BTLA and CD160 are Ig Superfamily proteins. BTLA is an inhibitory checkpoint receptor; DcR3, decoy receptor 3 inhibits LIGHT binding to HVEM and LTBR.
The discovery that HVEM is a coreceptor for the immune checkpoint, B and T lymphocyte attenuator (BTLA), an Ig superfamily member, established a new paradigm in TNF Receptor signaling pathways 7. Additional investigations revealed the importance of the HVEM-BTLA system in limiting immune responses, including T cell help for B cell clonal expansion, antibody maturation, and secretion8. HVEM-BTLA also regulates control of the intestinal microbiome, limiting invasion of pathogenic bacteria and enhancing Treg cell homeostasis 9. The diverse roles of this pathway are seen in the loss of BTLA signaling from mutations in HVEM frequently present in B cell lymphomas10. Additional layers of immune regulators, CD160 and DcR3, control the LIGHT-HVEM-BTLA pathways, revealing this network as a key mechanism controlling immune homeostasis.
Appreciating the fundamental features of the TNF-LIGHT-LTab Network in effector and homeostasis mechanisms presents a target-rich resource for therapeutic intervention in autoimmunity, infection, and cancer11, 12.
Translational research and Immunotherapy
2021-current: Lead Scientific Advisor, Avalo Therapeutics A neutralizing, fully human mAb (quisovalimab) to the proinflammatory cytokine LIGHT (TNFSF14) completed Phase I with an excellent safety profile and a Phase II trial establishing efficacy in COVID-19 pneumonia (NCT0441205)13. We identified elevated serum levels of LIGHT in hospitalized patients with COVID1914 spurring a randomized, double-blind, multicenter, proof-of-concept trial with adults hospitalized with COVID-19-associated pneumonia and mild to moderate ARDS15. The results established efficacy with a significant proportion of patients remaining alive and free of respiratory failure through day 28 after receiving quisovalimab, most pronounced in patients >60 years of age (76.5% vs. 47.1%, respectively; P = 0.042). These results and animal models validated LIGHT as a target for non-COVID inflammatory conditions, clinical trials ongoing in asthma (NCT05288504)12.
2021-current: Principal Investigator, Avalo Therapeutics – Sanford Burnham Prebys collaboration Bioengineered a first-in-class checkpoint agonist targeting BTLA immune checkpoint16 in preclinical development
2019-current: Director and Principal Investigator, Fair Journey Biologics – Sanford Burnham Prebys collaboration Immunotherapy for TNBC and PANC, in preclinical development
2015-2022: Director and Lead Principal Investigator, LILLY-Sanford Burnham Prebys Collaboration in Autoimmunity Collaborative research partnership with Eli Lilly involved target discovery and therapeutic development directed at immune regulators for autoimmune diseases. The collaboration produced three novel biologics currently in Phase I/2 trials (NCT03933943). The collaboration included a target discovery platform for T cell effector memory and NK cell immunomodulators.
2015-2020: Lead Principal Investigator, Sanford Burnham Prebys – Capella Biosciences collaboration Created a fully human mAb specific for membrane LIGHT (CBS001); phase I initiated (NCT05323110).
2016-2020: Lead Scientific Investigator, Boehringer Ingelheim – Sanford Burnham Prebys Collaboration Target discovery collaboration in inflammatory and fibrotic diseases6
2012-2014: Pfizer Innovation Center, Principal Investigator Bioengineering TNFR Superfamily in Autoimmune disease
1. Browning, J.L. et al. Lymphotoxin beta, a novel member of the TNF family that forms a heteromeric complex with lymphotoxin on the cell surface. Cell72,847-856 (1993).
2. Crowe, P.D. et al. A lymphotoxin-beta-specific receptor. Science264,707-710 (1994).
3. Mauri, D.N. et al. LIGHT, a new member of the TNF superfamily, and lymphotoxin alpha are ligands for herpesvirus entry mediator. Immunity8,21-30 (1998).
4. Ward-Kavanagh, L.K., Lin, W.W., Sedy, J.R. & Ware, C.F. The TNF Receptor Superfamily in Co-stimulating and Co-inhibitory Responses. Immunity44,1005-1019 (2016).
5. Schneider, K. et al. Lymphotoxin-mediated crosstalk between B cells and splenic stroma promotes the initial type I interferon response to cytomegalovirus. Cell Host Microbe3,67-76 (2008).
6. Virgen-Slane, R. et al. Cutting Edge: The RNA-Binding Protein Ewing Sarcoma Is a Novel Modulator of Lymphotoxin beta Receptor Signaling. J Immunol204,1085-1090 (2020).
7. Sedy, J.R. et al. B and T lymphocyte attenuator regulates T cell activation through interaction with herpesvirus entry mediator. Nat Immunol6,90-98 (2005).
8. Mintz, M.A. et al. The HVEM-BTLA Axis Restrains T Cell Help to Germinal Center B Cells and Functions as a Cell-Extrinsic Suppressor in Lymphomagenesis. Immunity51,310-323 e317 (2019).
9. Stienne, C. et al. Btla signaling in conventional and regulatory lymphocytes coordinately tempers humoral immunity in the intestinal mucosa. Cell reports38,110553 (2022).
10. Sedy, J.R. & Ramezani-Rad, P. HVEM network signaling in cancer. Adv Cancer Res142,145-186 (2019).
11. Croft, M., Benedict, C.A. & Ware, C.F. Clinical targeting of the TNF and TNFR superfamilies. Nat Rev Drug Discov12,147-168 (2013).
12. Ware, C.F., Croft, M. & Neil, G.A. Realigning the LIGHT signaling network to control dysregulated inflammation. J Exp Med219 (2022).
13. Zhang, M., Perrin, L. & Pardo, P. A Randomized Phase 1 Study to Assess the Safety and Pharmacokinetics of the Subcutaneously Injected Anti-LIGHT Antibody, SAR252067. Clin Pharmacol Drug Dev6,292-301 (2017).
14. Perlin, D.S. et al. Levels of the TNF-Related Cytokine LIGHT Increase in Hospitalized COVID-19 Patients with Cytokine Release Syndrome and ARDS. mSphere5 (2020).
15. Perlin, D.S. et al. Randomized, double-blind, controlled trial of human anti-LIGHT monoclonal antibody in COVID-19 acute respiratory distress syndrome. J Clin Invest132 (2022).
16. Sedy, J.R. et al. A herpesvirus entry mediator mutein with selective agonist action for the inhibitory receptor B and T lymphocyte attenuator. J Biol Chem292,21060-21070 (2017).
Dr. Yu Xin (Will) Wang received his PhD at the University of Ottawa where he identified cellular asymmetry and polarity mechanisms regulating muscle stem cell self-renewal and skeletal muscle regeneration. He then carried out postdoctoral training at Stanford University School of Medicine developing single cell multi-omic approaches to characterize the regenerative process and what goes awry with disease and aging.
“I’ve always had a passion for science and became fascinated with how the body repairs and heals itself when I was introduced to the potential of stem cells in regenerative medicine. I was struck by the ability of a small pool of muscle stem cells that can rebuild and restore the function of muscle. My lab at Sanford Burnham Prebys aims to better understanding the repair process and harness our body’s ability to heal in order to combat chronic diseases and even counteract aging.”
Education and Training
Postdoctoral Fellowship, Stanford University School of Medicine PhD in Cellular Molecular Medicine, University of Ottawa, Canada BS in Biomedical Sciences, University of Ottawa, Canada
Phenomena or Processes
Adult/Multipotent Stem Cells, Aging, Cell Signaling, Development and Differentiation, Epigenetics, Exercise, Extracellular Matrix, Neurogenesis, Organogenesis, Regenerative Biology, Transcriptional Regulation
Anatomical Systems and Sites
Immune System and Inflammation, Musculoskeletal System, Nervous System
Research Models
Clinical and Transitional Research, Computational Modeling, Human Adult/Somatic Stem Cells, Mouse
Techniques and Technologies
3D Image Analysis, Bioinformatics, Cellular and Molecular Imaging, Gene Knockout (Complete and Conditional), Genomics, High Content Imaging, High-Throughput/Robotic Screening, Live Cell Imaging, Machine Learning, Microscopy and Imaging, Proteomics, Transplantation
The Wang lab is interested in elucidating critical cell-cell interactions that mediate the function of tissue-specific stem cells during regeneration and disease, with a focus on
how a coordinated immune response can promote regeneration and
how autoimmunity impacts tissue function and hinder repair.
Specifically, the Wang lab aims to identify cellular and molecular crosstalk between muscle, nerve, and immune systems to develop targeted therapies that overcome autoimmune neuromuscular disorders and autoimmune aspects of “inflammaging.”
Yu Xin (Will) Wang’s Research Report
The lab’s research is translationally oriented and utilizes interdisciplinary molecular, genetic, computational (machine learning and neural networks), and bioengineering approaches to view biology and disease from new perspectives. We combine multi-omics sequencing and imaging methods to resolve how different cell types work together after injury to repair tissues and restore function. We use a data-driven approach to identify targetable disease mechanisms and, through collaborations with other researchers and clinicians, develop therapies that promote regeneration. Visit our lab website to learn more.
Eric has a broad background in chemical biology, with specific training and expertise in kinase inhibitors and targeted protein degradation, an emerging modality in which small molecules recruit E3 ligase complexes to target proteins to induce their ubiquitination and subsequent proteasomal degradation. He also has experience in pharmacological modulation of immune cells to improve anti-tumor immunity.
He received his PhD from the University of California San Francisco and postdoctoral training at the Dana-Farber Cancer Institute.
Education and Training
2021: Postdoctoral Fellow, Dana-Farber Cancer Institute / Harvard Medical School 2015: PhD, University of California San Francisco 2009: BS, Duke University
Fellowship
Damon Runyon Cancer Research Foundation Fellowship
Related Disease
Cancer, Immune Disorders, Molecular Biology
Phenomena or Processes
Adaptive Immunity, Cancer Biology, Cell Biology, Disease Therapies, Tumor Microenvironment
Techniques and Technologies
Chemical Biology, Drug Discovery
Dysregulation of transcriptional circuits is a common hallmark of disease, and in particular is found in both tumor and host immune cells in cancer. Eric’s lab is focusing on developing and using chemical tools to modulate the activity of key transcriptional regulators of both tumor cells and host immune cells, with a long-term goal of identifying new therapeutic approaches.
Kristiina Vuori earned her MD and PhD at University of Oulu, Finland. After completion of internship and residency, she received postdoctoral training at the Institute and was appointed to faculty in 1996. Dr. Vuori was selected as a PEW Scholar in the Biomedical Sciences in 1997. She has been co-Director of the Conrad Prebys Center for Chemical Genomics, housed at Sanford Burnham Prebys, since its inception in 2005. She was appointed Deputy Director of the Institute’s NCI-Designated Cancer Center in 2003, and Director of the Cancer Center in 2006. In 2008, she was appointed Executive Vice President for Scientific Affairs at Sanford Burnham Prebys. She was President of the Institute from 2010 to 2022.
Related Disease
Brain Cancer, Breast Cancer, Cancer, Leukemia/Lymphoma, Lung Cancer, Ovarian Cancer, Prostate Cancer
Dr. Vuori’s research is aimed at unraveling the cell mechanisms of the most life-threatening aspect of cancer, which is cancer metastasis. Metastasis is responsible for nearly all deaths in cancer patients, and understanding of the mechanisms that turn a cancer from a locally growing tumor into highly metastatic cancer cells will provide clues how to prevent this step in cancer progression. All cells in our body stick to one another and to the packaging material, or extracellular matrix, around them. This adhesion is essential for cell survival; if cells become detached from their microenvironment, they will die through a process known as apoptosis. This phenomenon, which is called adhesion dependency of survival, is one of the safeguards that maintain the integrity and normal function of tissues, and prevent cells from becoming cancerous. Normal cells cannot detach from their tissue and establish themselves somewhere else, because they will die on the way. Yet cancer cells somehow get around this requirement; they trespass aggressively into other tissues and metastasize to distant sites in the body without dying. Dr. Vuori’s work is aimed at identifying the molecular mechanisms that in normal cells makes them adhesion-dependent; false action of the very same mechanisms is likely to be the key step in allowing cancer cells to metastasize.
Dr. Xiao Tian participates in the Degenerative Diseases Program and the Cancer Genome and Epigenetics Program at Sanford Burnham Prebys. He started his lab in 2024 to understand the fundamental biology of aging and its contribution to age-related diseases. He joined the Institute after his postdoctoral research in Dr. David Sinclair’s lab at Harvard Medical School where he co-wrote the Information Theory of Aging. He obtained his BS from Shandong University and his PhD from the University of Rochester where he worked with Dr. Vera Gorbunova.
Education
2018-2023: Postdoc, Harvard Medical School 2016-2018: Postdoc, University of Rochester 2010-2016: PhD, Biology of Aging, University of Rochester 2005-2009: BS, Microbial Technology, Shandong University
Honors and Awards
2020-2026: K99/R00 Pathway to Independence Awards, NIH/NIA 2019-2020: NASA Postdoctoral Fellowship, NASA Ames Research Center 2017: Outstanding Dissertation Award for the Natural Sciences, University of Rochester 2015: Messersmith Dissertation Fellowship, University of Rochester 2014: Award for Outstanding Self-Financed Students Abroad, China Scholarship Council 2010-2014: Holtfreter Fellowship, University of Rochester 2007: Weichai Power Scholarship, Shandong University 2006-2008: Excellent Student Scholarship, Shandong University
Related Disease
Aging-Related Diseases, Alzheimer’s Disease, Cancer
Phenomena or Processes
Aging, Epigenetics, Genomic Instability, Neurodegeneration
Research Models
Computational Modeling, Mouse, Naked Mole Rat, Primary Human Cells
Techniques and Technologies
Bioinformatics, Epigenomics, Gene Expression, Gene Knockout (Complete and Conditional), High-Throughput/Robotic Screening, Mouse Behavioral Analysis
The Tian lab studies the fundamental mechanisms of aging and their roles in the onset of age-related diseases. Our recent research in epigenetic reprogramming and aging clocks indicates that the progressive loss of epigenetic information over time is a key driver of aging. The current research of the lab focuses on understanding how the epigenetic landscape is set up and maintained and investigating why the maintenance system fails which leads to aging and related diseases including cancer and neurodegeneration. Building on this, our ultimate goal is to develop safe and effective rejuvenation strategies to counteract aging.
Xiao Tian’s Research Report
Below are my major contributions to the field of aging research during my PhD and postdoc work:
Uncovering the first anti-cancer and longevity mechanism of the naked mole rat
Epigenetic reprogramming as a strategy to counteract aging and age-related diseases
We illustrated that epigenetic information loss as a result of DNA damage repair is a key driver of aging. One interventional strategy is to recover the lost epigenetic information, such as through reprogramming. We revealed that epigenetic reprogramming is an effective strategy to counteract aging and even potentially modify the trajectory of age-related diseases including glaucoma. We are currently testing other disease settings.
Lu Y, Brommer B, Tian X, Krishnan A, Meer M, Wang C, Vera DL, Zeng Q, Yu D, Bonkowski MS, Yang JH, Zhou S, Hoffmann EM, Karg MM, Schultz MB, Kane AE, Davidsohn N, Korobkina E, Chwalek K, Rajman LA, Church GM, Hochedlinger K, Gladyshev VN, Horvath S, Levine ME, Gregory-Ksander MS, Ksander BR, He Z, Sinclair DA
Tian X, Firsanov D, Zhang Z, Cheng Y, Luo L, Tombline G, Tan R, Simon M, Henderson S, Steffan J, Goldfarb A, Tam J, Zheng K, Cornwell A, Johnson A, Yang JN, Mao Z, Manta B, Dang W, Zhang Z, Vijg J, Wolfe A, Moody K, Kennedy BK, Bohmann D, Gladyshev VN, Seluanov A, Gorbunova V
