HomeOur ScientistsDavid Ginsburg

Our Scientists

David Ginsburg, MD
Investigator / 1985–Present

Scientific Discipline

Genetics, Medicine and Translational Research

Host Institution

University of Michigan

Current Position

Dr. Ginsburg is also James V. Neel Distinguished University Professor of Internal Medicine and Human Genetics, Warner-Lambert/Parke-Davis Professor of Medicine, and a member of the Life Sciences Institute at the University of Michigan Medical School.

Current Research

Molecular Genetics of Blood Clotting

David Ginsburg is interested in understanding the components of the blood-clotting system and how disturbances in their function lead to human bleeding and blood-clotting disorders.

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A blood clot formed in vitro...

Biography

If it weren't for the 20 or so clotting factors in your blood and certain cells called platelets, a paper cut would kill you. When vertebrates evolved to have a heart and a circulatory system, they also developed a way to plug blood vessel…

If it weren't for the 20 or so clotting factors in your blood and certain cells called platelets, a paper cut would kill you. When vertebrates evolved to have a heart and a circulatory system, they also developed a way to plug blood vessel damage. The body, though, must carefully control how it stops leaks. Big blockages could also end blood flow.

For the past 25 years, David Ginsburg has dedicated his career to understanding the clotting system and how it maintains its delicate balance. He has identified several genes in the clotting pathway and characterized the causes of a variety of inherited versions of coagulation diseases, which together afflict millions of people.

Ginsburg first became excited about research as a Yale undergraduate, working in the laboratory of Joan Steitz (now an HHMI investigator). He entered Duke's M.D./Ph.D. program, thinking he would immediately do research upon finishing. But he loved medicine, gave up his Ph.D., and pursued clinical training. He became board certified in internal medicine, oncology, hematology, and, later, in genetics.

Ginsburg specialized in hematology because of its close connection to clinical genetics in adults, which had not yet been defined as a distinct medical specialty. Clotting disorders were particularly appealing to him because scientists and clinicians understood a lot about the conditions from genetic analysis of families with factor deficiencies. They knew hemophiliacs needed factor VIII; and people with von Willebrand disease, the most common bleeding disorder, had low levels of von Willebrand factor (VWF), a blood-clotting protein.

Precisely how abnormalities in VWF caused the many different subtypes of von Willebrand disease was still a mystery, however. To better understand its pathology, Ginsburg, a hematology fellow working in the laboratory of Stuart Orkin, (now an HHMI investigator), cloned the VWF gene in 1985 (as did three other laboratories). Back then, cloning was difficult, and his work garnered attention, enabling him to start a lab at the University of Michigan, where he has remained.

With the polymerase chain reaction's introduction, Ginsburg then characterized subtypes of von Willebrand disease and other clotting conditions over the next several years. Different mutations in a causative gene often would explain variations in the severity of a disease.

By 1998, DNA-sequencing advances made it easy for Ginsburg to clone LMAN1 (ERGIC-53), mutations in which were responsible for a rare bleeding disease in some Middle Eastern Jewish families. Patients with the disease, known as combined factor V and VIII deficiency, have levels of both factors that are only about 10 percent of normal and a tendency to bleed. The gene codes for a protein that chaperones other proteins, such as factors V and VIII, in their path out of a cell. When LMAN1 is defective, less V and VIII enter the bloodstream and bleeding occurs.

But 25 percent of people with the combined deficiency did not have LMAN1 mutations. In 2005, Ginsburg found another gene, MCFD2, which when mutated also causes the combined deficiency. LMAN1 and MCFD2 proteins form a complex that shepherds secretory proteins within the cell. Ginsburg believes problems with the complex affect proteins released from cells besides clotting factors, which could cause other previously unappreciated problems in these patients. He is looking for these other proteins.

As a physician-scientist focused on bleeding disorders, Ginsburg also found his attention captured by thrombotic thrombocytopenic purpura (TTP). This disease can be familial (early onset) or sporadic (late onset). Patients with either can become very sick, experiencing severe clotting throughout the body and needing hospitalization. Patients can die within 48 hours of an episode if not treated with plasma exchange, which provides donor plasma (the liquid part of the blood without red blood cells) to a TTP patient.

Why plasma exchange worked and what caused TTP was unknown, though. In 2001, Ginsburg cloned the gene implicated in familial TTP (also identified by nongenetic means by HHMI investigator Evan Sadler, and others). The gene, ADAMTS13, codes for an enzyme that normally trims VWF, a huge molecule. People with familial TTP lack the enzyme and their VWF protein becomes too big and clogs blood vessels. Patients with sporadic disease make antibodies against the enzyme, preventing it from pruning VWF. Plasma exchange replaces the absent enzyme.

While single genes play an important role in inherited disease, they cannot always explain the clinical course of an illness. Some people may have the same mutation but have different disease manifestations. So Ginsburg is looking for other genes, called modifiers, that might explain disparities in clotting factor diseases. To find modifiers, Ginsburg uses mice and zebrafish, whose breeding and genetics can be carefully controlled.

Additionally, he is performing genome-wide studies in people to search for common clotting factor gene variations. He also is interested in whether certain factor gene alterations protect carriers from infection and provide a survival advantage.

Although Ginsburg still sees some patients in the university hospital's genetics clinic, research and directing his laboratory take up most of his time. He remains, nevertheless, indebted to his clinical experience. Study of a human disease allowed him to uncover biological processes that might not otherwise have been discovered, and it gave him an opportunity to try to alleviate human suffering.

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Education

  • BA, Molecular Biophysics and Biochemistry, Yale University
  • MD, medicine, Duke University

Awards

  • Pasarow Cardiovascular Research Award, Robert J. and Claire Pasarow Foundation
  • Distinguished Scientist Award & Basic Research Prize, American Heart Association
  • Stanley J. Korsmeyer Award, American Society for Clinical Investigation
  • E. Donnall Thomas Lecture and Prize, American Society of Hematology
  • International Society for Fibrinolysis and Proteolysis Prize
  • Distinguished Research in the Biomedical Sciences Award, Association of American Medical Colleges
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Memberships

  • Institute of Medicine of the National Academies
  • National Academy of Sciences
  • Association of American Physicians
  • American Society for Clinical Investigation
  • American Academy of Arts and Sciences
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