Earl W. Davie

Mailing address:

Department of Biochemistry

Box 357350

University of Washington

Seattle, WA 98195- 7350

Email: [email protected]

Brief interview:

Dr. Earl W. Davie, professor and former chair of the School of Medicine’s Department of Biochemistry, has won the ninth annual Bristol-Myers Squibb Award for Distinguished Achievement in Cardiovascular/Metabolic Research. He received the award and the $50,000 prize in New York last week.

Davie is being honored for proposing and then substantiating the complex chain of biochemical events that result in fibrin clotting, the central process of blood coagulation.

During his long research career, he has cloned and sequenced many genes that code for proteins involved in blood coagulation. This work led directly to the development of safer clotting factors that hemophiliacs can self-administer at home to control their bleeding —a development that has changed the total management of the disease.

“It is Dr. Davie who must be credited with the prediction, definition, resolution and elucidation of the blood clotting system, its chemistry, genetics and impact on medicine,” said Dr. Bert Vallee, Edgar M. Bronfman distinguished senior professor at Harvard Medical School. “The totality of his work makes him unique.”

“When people talk about standing on the shoulders of giants, they are referring to scientists such as Dr. Davie,” said Richard Gregg, vice president for cardiovascular and metabolic diseases at Bristol-Myers Squibb Pharmaceutical Research Institute. “At Bristol-Myers Squibb, we are proud to recognize the enormous contributions made by him in the field of cardiovascular medicine.”

Davie earned both his undergraduate degree in chemistry (1950) and his Ph.D. in biochemistry (1954) at the UW.

As a young researcher at Case Western Reserve in the late 1950s, Davie, with Dr. Oscar Ratnoff, studied the blood of John Hageman, Rufus Stuart and other patients who became famous in the medical literature for their various clotting disorders. In some of these cases, the patient’s plasma failed to clot on its own, but did clot when combined in a test tube with plasma from a normal person. From such crude assays, the researchers hypothesized that non-clotting blood was deficient in certain factors that acted as catalysts for coagulation. But what these factors were and how the coagulation process actually worked were largely unknown.

In 1962, Davie returned to the UW and, with Ratnoff, proposed that blood coagulation results from a series of stepwise reactions in which proteins, or “factors,” found in blood plasma are converted from a precursor state to an active form. In this “waterfall cascade,” as it became known, the conversion of each protein triggers the activation of the next one in the chain, culminating in projection of a fibrin clot at the site of injury.

In later years, Davie and colleagues isolated and purified nearly all the plasma proteins in the cascade and identified the way they were activated. After the advent of recombinant DNA technology, Davie and Dr. Dominic Chung, research professor of biochemistry, began cloning and sequencing the genes for each factor.

By cloning and sequencing the genes for more than a dozen other proteins involved in clotting, Davie paved the way for the mass production of these proteins in mammalian cells. Today, these proteins are used as clotting factors to treat hemophilia, in much the way that insulin is produced and used to control diabetes.

More recently, Davie has focused his work on understanding the mechanisms that trigger, regulate and undo blood clots.

Davie is a member of the National Academy of Sciences and the American Academy of Arts and Sciences, and has received several international awards. Since 1980 he has been associate editor of the journal Biochemistry.

Major Publications:

1. Kulman JD, Harris JE, Xie L, Davie EW. Identification of two novel transmembrane gamma-carboxyglutamic acid proteins expressed broadly in fetal and adult tissues. Proc Natl Acad Sci U S A. 2001 Feb 13;98(4):1370-5.

2. Andersen H, Greenberg DL, Fujikawa K, Xu W, Chung DW, Davie EW. Protease-activated receptor 1 is the primary mediator of thrombin-stimulated platelet procoagulant activity. Proc Natl Acad Sci U S A. 1999 Sep 28;96(20):11189-93.

3. Xie Z, Xu W, Davie EW, Chung DW. Molecular cloning of human ABPL, an actin-binding protein homologue. Biochem Biophys Res Commun. 1998 Oct 29;251(3):914-9.

4. Xu W, Xie Z, Chung DW, Davie EW. A novel human actin-binding protein homologue that binds to platelet glycoprotein Ibalpha.
Blood. 1998 Aug 15;92(4):1268-76.

5. Xu WF, Andersen H, Whitmore TE, Presnell SR, Yee DP, Ching A, Gilbert T, Davie EW, Foster DC. Cloning and characterization of human protease-activated receptor 4.
Proc Natl Acad Sci U S A. 1998 Jun 9;95(12):6642-6.

6. Fischer EH, Davie EW. Recent excitement regarding metallothionein. Proc Natl Acad Sci U S A. 1998 Mar 31;95(7):3333-4.

7. Cote HC, Pratt KP, Davie EW, Chung DW. The polymerization pocket "a" within the carboxyl-terminal region of the gamma chain of human fibrinogen is adjacent to but independent from the calcium-binding site. J Biol Chem. 1997 Sep 19;272(38):23792-8.