A Groundbreaking Discovery for Hemophilia Research

Biochemist Gordon Vehar, PhD, vice president of external innovation at BioMarin Pharmaceutical Inc., has been at the forefront of a scientific revolution.

Gordon Vehar was happily headed toward a career as a science teacher when something happened in his senior year of college that changed his life. He had been inspired by a high school biology teacher who was “mesmerizing,”  Vehar recalls. “He had fun with biology, he could explain things, and he’s the one who really got me focused on science when I got into college.”

Following in his footsteps seemed natural—until Vehar actually spent time in a classroom as a student teacher guiding high schoolers through chemistry experiments. It was not a good fit, recalls the 72-year-old biochemist, former vice president of research and current vice president of external innovation at BioMarin Pharmaceutical Inc. “I realized I had made a mistake—but what do you do with a science degree?”

It turns out, education’s loss would lead to a breakthrough in the treatment of hemophilia that would be hailed as a scientific tour de force. In 1984, Vehar, whose early research was funded in part by a National Hemophilia Foundation (NHF) grant, led the scientific team that cloned the gene for factor VIII, which enabled the production of an artificial, genetically engineered clotting factor that transformed the lives of people with hemophilia A.

But at the time of his student teaching experience, this stellar achievement was more than a decade in the future for the flummoxed college student, who suddenly chose a radical course correction. All through high school, Vehar had grasped scientific concepts easily. “I could sit down and read chemistry and biology, and it would just sink in,” Vehar says. So he decided to stick with the biological sciences as a career after finishing college.

Complicated Search

The summer after graduating from Bowling Green State University, the native of Euclid, Ohio, scrambled to take three prerequisite science classes that allowed him to enter a doctoral program in biochemistry at the University of Cincinnati College of Medicine that fall. Afterward, his academic adviser encouraged him to do his postdoctoral research at the University of Washington, in a laboratory focused on deciphering the chemical makeup of blood proteins involved in coagulation. But at the time, no one in the laboratory was working on the hemophilia protein FVIII. “I was surprised,” he recalls. “Here’s a genetic defect that has a disease associated with it, and everyone was avoiding it.”

He was told it was a career killer—and once he started working on FVIII, he discovered why. Isolating the elusive protein turned out to be extraordinarily difficult, like finding a needle in a haystack, because there were just trace amounts in the blood. “No one who ever worked on it was successful in figuring out what it is,” Vehar recalls. “It was just this magical activity. Hemophiliac plasma won’t clot. But if you put (a regular) person’s plasma into that and mix them (together), it will now clot.” Obviously, there was something lacking in the hemophiliac plasma that was present in regular blood.

Because the protein was scarce, and highly unstable, fragile and easily degraded when isolated, he couldn’t get the volume of human blood required to adequately study it. But Vehar hit upon the idea of using cow blood from a slaughterhouse, giving him enough blood to do his research.

Collaborative Effort

In 1977, he was awarded NHF’s Judith Graham Pool Postdoctoral Research Fellowship, which funds research into bleeding disorders and which paid his salary and reinforced his interest in coagulation. “It was my first and only grant,” says Vehar, who still remembers writing the grant application and was grateful that NHF was willing to take a chance on “some newbie in Seattle who was studying cow blood.”

In an arduous process of trial and error over nearly five years, he separated out proteins in the blood to see which ones caused the plasma to clot, and he was ultimately able to purify a few milligrams of FVIII from tests of 25,000 liters of bovine blood. His research led to his recruitment in 1980 by Genentech, the South San Francisco biotech startup that was a leader in recombinant DNA technology. Its scientists had successfully cloned genes for human insulin and human growth hormone.

The company’s next target was cloning the gene for FVIII. But it was in a race against time. The AIDS epidemic was exploding, and blood products contaminated with HIV posed a grave threat to people with hemophilia, thousands of whom became infected and died of the immune disorder. It was a period of great intellectual ferment, and Vehar was excited to work with scientists who were doing pioneering research on the frontiers of medicine.

But cloning the gene proved tricky because of its immense size. Unknown at the time, the FVIII protein coded—or had instructions—for the manufacture of 2,351 amino acids, which are the building blocks of the cells. In contrast, earlier proteins that had been cloned for human insulin and human growth hormone contain 51 and 191 amino acids, respectively. The protein-sequencing technology was not sensitive enough to map out this gene’s structure. Plus, the rudimentary recombinant DNA technology, which relied on splicing (joining together) genes into bacteria to produce proteins, wasn’t suitable for the unstable FVIII protein that could swiftly become inactivated.

So Vehar and his colleagues had to build new techniques from the ground up and spent three years devising an amino acid sequencer that was 10 times as sensitive as the ones commercially available at the time. And instead of using bacteria to make the proteins, they had to figure out how to coax the larger hamster cells to churn out the huge FVIII protein. “Because it was so big, we had to get four cloning groups all collaborating closely to get the full protein,” Vehar recalls.

Triumphant Discovery

In November 1984, when the Genentech team’s papers about the successful cloning of FVIII were published in Nature, the esteemed journal’s editor, John Maddox, called the research “a technical triumph without parallel.”

“That was three back-to-back papers. It was the first time Nature had ever done that,” Vehar says of the breakthrough that saved countless lives. “Now you were no longer dependent on plasma, which may have had HIV—and the hemophilia community was horribly hit with HIV.”

In the years since, Vehar spent more than two decades as a staff scientist at Genentech, where he helped research tissue plasminogen activator for the treatment of heart attacks and strokes. He is also an inventor with 44 patents and 36 publications. He has received numerous scientific awards, including the Murray Thelin Award for outstanding research from NHF and two Distinguished Inventor of the Year awards from the Intellectual Property Owners Association.

Vehar joined BioMarin in January 2008, and he has helped develop the company pipeline and continued in hemophilia research. But he’ll never forget the exhilaration he felt when those initial papers were published in Nature, a triumph that he was eager to share with NHF, which had supported his early research.

“We had a press release coming out when we were ready to publish, but we didn’t want the NHF to hear about it through the rumor mill,” remembers Vehar, who invited NHF’s president and two of his senior people for an update on the program, timing it so they were on the Genentech campus on the day of the press release. “They were onsite when it came out, and we had a big party and a celebration cake that was blood-red. They got to cut it, and they were so appreciative to feel a part of it.”

Source: National Hemophilia Foundation, HEMAWARExpress