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Sandy Chang, MD, PhD, BS

Professor of Laboratory Medicine, of Pathology and of Molecular Biophysics and Biochemistry
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Additional Titles

Associate Director, Molecular Diagnostics Laboratory

About

Titles

Professor of Laboratory Medicine, of Pathology and of Molecular Biophysics and Biochemistry

Associate Director, Molecular Diagnostics Laboratory

Biography

Dr. Chang graduated with a BS from Yale College in 1988, and obtained his MD from Cornell University Medical College and his PhD from Rockefeller University in 1997. He completed residency in Clinical Pathology at the Brigham and Women's Hospital, and did his postdoctoral fellowship with Dr. Ronald DePinho at the Dana Farber Cancer Institute, Harvard Medical School. He was an Assistant and then Associate Professor in the Department of Genetics, MD Anderson Cancer Center, before joining the faculty at Yale Medical School as a tenured Associate Professor in 2010. Dr. Chang's research interests focuses on how telomeres, protein/DNA structures at the ends of chromosomes, are properly maintained to protect chromosome ends from engaging a DNA damage response.

Dr. Chang is the recipient of numerous awards, including those from the Howard Hughes Medical Institute, the Ellsion Medical Foundation, the Sidney Kimmel Foundation for Cancer Research, and the Ellis Benson Award from the Academy of Clinical Laboratory Physicians and Scientists. He was elected into the American Society of Clinical Investigation in 2009.

Beginning in 2017, Dr. Chang is also the Associate Dean of Science Education and Quantitative Reasoning and Undergraduate Research at Yale College.


Appointments

Education & Training

Resident
Brigham & Women's Hospital (2000)
Resident
Brigham & Women's Hospital (1998)
MD
Cornell University Medical College (1997)
PhD
Rockefeller University (1996)
BS
Yale University (1988)

Research

Overview

Dr. Chang’s research program focuses on telomeres,repetitive DNA sequences at the ends of chromosomes critically important for the maintenance of genome stability. Perturbation of telomere length results in telomere dysfunction, leading to increased genomic instability that can promote early aging and cancer development. Dr. Chang’s laboratory was the first togenerate a faithful mouse model of Werner Syndrome (WS). This rare disease strikes individuals in their 30s and is marked by the development of aging phenotypes and early onset of cancer.

Dr. Chang found that when WRN deficiency is coupled withtelomere dysfunction, the combination increases genomic instability, pre-matureaging and increased tumorigenesis. In addition, his findings conclusively demonstrate that telomere status plays an important role in the development of premature aging pathologies observed in WS patients. With this mouse model, Dr. Chang's laboratory has also identified common genetic pathways that unify aging and cancer development. His laboratory was the first to show that WRN plays a critical role in preventing telomeres from undergoing aberrant homologous recombination. In the absence of both telomerase and WRN, telomeres readily undergo homologous recombination to generate long telomeres, activating an Alternative lengthening of Telomeres (ALT) phenotype that contributes to tumor formation. Dr. Chang’s findings thus shed light on the important link between aging and cancer by suggesting that WRN plays an important role in both of these processes.

Dr. Chang then went on to decipher the molecular mechanisms of how telomere dysfunction initiates premature aging phenotypes in the laboratory mouse. Dr. Chang's laboratory recently discovered that the POT1 (Protection of Telomere 1) protein is an integral member of a protein complex that binds to telomeres and is essential for the maintenance of telomere stability. Using homologous recombination, hislaboratory conditionally deleted POT 1 from the mouse genome and discovered that chromosomes became highly unstable. These results indicate that POT1 is normally required to suppress genomic instability by preventing the formation of dysfunctional telomeres. Importantly, loss of POT1 potently activates a DNA damage pathway that results in rapid onset of cellular senescence. In p53 null cells, this elevated genomic instability promotes malignant transformation and rapid onset of cancer. These important results suggest that dysfunctional telomeres could either suppress tumorigenesis by initiating cellular senescence (in the setting of an intact p53 pathway), or promote cancer through elevated genomic instability (in the setting of p53 deficiency). Dr. Chang is currently using this novel mouse model to explore the roles that cellular senescence play in initiating premature aging phenotypes in highly proliferative organs, including the intestine and hematopoietic systems.

Dr. Chang then proceeded to address a long standing question in the telomere field-is cellular senescence capable of suppress tumorigenesis in vivo? While apoptosis clearly has a tumor suppressive role in vivo, until recently it was not clear whether p53-dependent cellular senescence plays anyrole in tumor suppression in vivo. Usingclever mouse genetics, Dr. Chang’s laboratory generated mouse models with dysfunctional telomeres and a knock-in p53 allele that is able to activatecellular senescence but not apoptosis. His laboratory demonstrated for the first time that activation of cellular senescence by dysfunctional telomeres in mice potently suppressed tumorinitiation. Interestingly, while these mice did not succumb to cancer, many dieearly from cellular defects resembling advanced aging. These results suggest that initiation of telomere dysfunction in vivo compromises cellular renewal, resulting in the onset of premature aging phenotypes.

Dr. Chang is currently focusing on how dysfunctional telomeres activate the DNA damage pathway, and the mechanisms that repair them.He continues to use novel molecular and biochemical approaches, as well as the generation of new mouse models of telomere dysfunction, to address thesequestions.

Medical Subject Headings (MeSH)

Diseases; DNA Damage; Early Detection of Cancer; Molecular Biology; Pathology; Telomere-Binding Proteins; Werner Syndrome

Research at a Glance

Yale Co-Authors

Frequent collaborators of Sandy Chang's published research.

Publications

2024

2023

2021

2020

2019

Academic Achievements & Community Involvement

  • honor

    Election into the American Society of Clinical Investigation

  • honor

    Ellis Benson Award

  • honor

    Sidney Kimmel Foundation for Cancer Research Scholar Award

  • honor

    New Scholar in Aging Award

Clinical Care

Overview

Clinical Specialties

Pathology; Laboratory Medicine

Fact Sheets

Board Certifications

  • Clinical Pathology

    Certification Organization
    AB of Pathology
    Original Certification Date
    2003

Get In Touch

Contacts

Academic Office Number
Lab Number
Mailing Address

Laboratory Medicine

PO Box 208035

New Haven, CT 06520-8035

United States

Locations

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