George Rathmann and Fu-Kuen Lin
George Rathmann. Photo by Davis Freeman. Courtesy George Rathmann.
The story of recombinant, or genetically engineered, human erythropoietin (Epogen®) shows how entrepreneurial and scientific intelligence combined to produce one of the great successes of biotechnology. Erythropoietin, a hormone manufactured in tiny quantities in the kidneys, travels through the bloodstream to the bone marrow, where it stimulates the production of red blood cells, or erythrocytes. When the kidneys fail to produce sufficient erythropoietin, debilitating anemia results. Before the development of recombinant erythropoietin, patients suffering from chronic kidney disease and renal failure had to undergo not only dialysis to filter waste products from their blood but also frequent blood transfusions to correct anemia. The work of George Rathmann (b. 1927), CEO of the biotech company Amgen, and Fu-Kuen Lin (b. 1941), a researcher at Amgen, spared hundreds of thousands of anemic patients from expensive treatments that carried the risk for hepatitis and AIDS infections.
Rathmann grew up in Milwaukee, Wisconsin, and graduated from Northwestern University with a bachelor’s degree in physical chemistry. He went on to get his Ph.D. in that field from Princeton University in 1952. Returning to the Midwest to start his career, Rathmann took a position with the 3M Company in St. Paul, Minnesota, where he continued to pursue research he had begun in graduate school: the scattering of light by polymers.
Fu-Kuen Lin. Courtesy Amgen, Inc.
He moved quickly through the ranks at 3M, from research to managerial positions. After two decades with the company he went on to join the Diagnostics Division of Abbott Laboratories in 1975, a well-established pharmaceutical company in Chicago.
While at Abbott, Rathmann worked on diagnostics and vaccines for hepatitis B, which at that time relied on a weakened form of the virus. He believed that a synthetic antigen—one created through recombinant DNA techniques (see Paul Berg, Herbert Boyer, and Stanley Cohen)—had great potential as a substitute for the weakened virus. This early biotechnology project never got under way at Abbott, but in trying, Rathmann did make an important contact that ultimately led him to the expanding world of biotech. Winston Salser, a professor of molecular biology at the University of California at Los Angeles, was the founding member of the scientific advisory board behind a nascent Southern California biotech company, Applied Molecular Genetics, or Amgen. Five major biotech companies already existed at the time, but venture capitalists and university scientists interested in launching Amgen met in the spring of 1980 and decided that the field could support another start-up. Salser recommended bringing Rathmann on board, and shortly after Amgen’s incorporation in April 1980, Rathmann was offered the position of president and CEO at the new company.
Amgen’s first successful drug research project involved finding the genetic code for the human hormone erythropoietin. The existence of erythropoietin was first recognized in 1906 by researchers at the University of Paris. These scientists discovered a substance in the serum of animals that had been recently bled to make them anemic. This substance provoked an overabundance of red blood cells when introduced into healthy animals without anemia. It was not until 1960, however, that erythropoietin was isolated from the blood plasma of anemic sheep, which produced the substance in quantity in order to trigger the production of the needed red blood cells. Almost two decades later, human erythropoietin was isolated from the urine of anemic patients. Researchers at Amgen, who had obtained a small amount of pure erythropoietin, set out to find the genetic code for the hormone—that is, the information necessary for synthesizing it. With a blueprint of the genetic code, producing a genetically engineered version using recombinant DNA techniques would be possible. In August 1981 the company hired Fu-Kuen Lin to head up the research.
Born and educated in Taiwan, Lin came to the United States in 1967 to pursue a doctoral degree in plant pathology at the University of Illinois at Urbana-Champaign. He then held a number of positions in academia in Taiwan and the United States, including a postdoctoral fellowship at the Medical University of South Carolina, where he became familiar with recombinant DNA techniques.
After approximately two years of grueling, meticulous work, Lin and his colleagues found the human gene responsible for the production of erythropoietin. This feat has been likened to finding a needle in a whole field of haystacks. Human chromosomes contain some hundred thousand genes, each made up of about three to five thousand nucleotides, the four small building blocks (adenine, thymine, cytosine, and guanine) that make up DNA and—in combinations of any three—code for specific amino acids. Even with Lin’s strategies for homing in on the objective, which were critical to the success of the project, there remained thousands of experiments to conduct. Some scientists at Amgen came to view the search as an impossible mission, although it was known that other biotechnology companies were seeking the same objective.
Fortunately for the success of the project, Lin was extremely persistent. Through it all Rathmann remained supportive—only once threatening to end the project. When more resources were needed, he allocated them. Beginning with a workforce of only two or three people, the project grew to engage the labors of 20 or so people—about half the total number of workers at Amgen at that time—by the end of 1983, when they were isolating the human gene.
With the gene isolated, it could be sequenced and analyzed further. The human erythropoietin gene was subsequently cloned and, so that it would produce erythropoietin itself, inserted into mammalian cells—Chinese hamster ovarian cells, which possess a very stable chromosome content in culture.
Other scientists at Amgen handled the first scaling up of genetically engineered erythropoietin, designing the processes by which enough of the hormone could be cultured so that tests for safety and efficacy could be run. Clinical trials were begun in December 1985, and FDA approval was granted in June 1989. Since 1989 the uses of Amgen’s genetically engineered erythropoietin, called Epogen, have widened to include treatment of the anemias caused by the HIV-fighting drug azidothymidine (AZT) and by cancer chemotherapy. Epogen can also be administered to individuals scheduled to undergo an operation who want to use their own banked blood instead of transfusions from other sources. By speeding up the formation of red blood cells, Epogen shortens the time needed to bank enough blood. When the same drug is manufactured by licensee Centocor Ortho Biotech, it is called Procrit.