Trailblazer

When little Jim Fisher was growing up in a small South Carolina textile mill town, he didn't hang around the mills or their noisy hydroelectric generators. What he loved most was exploring the lush woods and walking along the riverbanks, looking for wild animals and birds.

"I'd often go into the woods with my friends to look for birds and small animals like squirrels and such," recalls Fisher, now 75. "I was an avid bird watcher-intrigued with all animals, especially wild ones. I just had an intense curiosity about nature when I was young."

Fisher no longer spends his days looking for squirrels in the woods, but his intense curiosity about life sciences and a passion for exploration served him well through his career as a research scientist and academician.

As the first Ph.D. recipient in pharmacology at UofL, James W. Fisher has had a long and illustrious career in pharmacological research and academia.

His pioneering work with the elusive hormone erythropoietin, or Epo, resulted in its approval by the Food and Drug Administration for treatment of anemic patients with end-stage renal failure, anemic AIDS patients and people suffering from anemia associated with cancer chemotherapy. Fisher received the UofL School of Medicine Alumni Fellow Award in 1999 for his lifetime achievements.

Early research on cobalt

Fisher's interest in Epo was preceded by an interest in cobalt, a trace element found in vitamin b12. A deficiency in cobalt may lead to anemia, and its excess leads to an elevated red blood cell count.

The researcher began studying cobalt in 1954 while employed as a junior scientist for the now-defunct Lloyd Brothers Pharmaceutical Inc. in Cincinnati.

"I was working on the compound cobalt, for anemia," Fisher recalls. "It was known to produce polycythemia -- too many red blood cells -- but no one knew how it acted or how it increased production of red cells. Epo was just _coming to the forefront at that time."

Lloyd Brothers marketed cobalt under the brand name Roncovite, which was used for several years during the 1950s for the treatment of anemia. Premature infants with anemia responded very well to the treatment, according to Fisher, but they also developed goiters, or enlarged thyroid glands.

"For that reason, the FDA required Lloyd Brothers to take Roncovite off the market until that problem could be clarified," Fisher says.

It was apparent to Fisher that cobalt did not directly affect the bone marrow, where red blood cells are produced, but rather it initiated the production of some erythropoietic factor that then affected the bone marrow.

"This stimulated me even further to pursue this problem," he says. "I wanted to know how cobalt produced polycythemia, so I went on a trip down to UofL to visit the Division of Hematology.

"I had the idea I might want to go back to school and finish up my Ph.D. work in pharmacology."

While visiting UofL, he spoke to Peter K. Knoefel, chairman of pharmacology, who encouraged Fisher to pursue his doctorate. The National Institutes of Health were just announcing fellowships in the mid-1950s, and Knoefel sponsored him for one of the first NIH predoctoral fellowships.

Fisher and his wife had three young children at the time, and the fellowship enabled him to support his family and return to graduate school to study the mechanism of cobalt polycythemia. However, Fisher's employer was reluctant to see him leave.

"So I talked to the director of research at Lloyd Bros., and he just smiled and said, 'Is there anything we can do?'" recalls Fisher. "And they took me to see the president of the company. Since the company was interested in cobalt research, they offered to help me out financially, with the understanding that I would come back after my Ph.D. work."

Digging into Epo's source

"The best possible mechanism to explain how cobalt produces polycythemia is that it triggers some organ to produce Epo," Fisher says.

When he began his research at UofL in 1956, Fisher thought that organ was the adrenal gland. Preliminary tests using rats injected with hydrocortisone, which is secreted by the adrenal gland, seemed to support Fisher's hypothesis: The rats developed elevated red blood cell counts.

However, further studies in which adrenal glands were surgically removed demonstrated that the adrenal cortex played a "permissive role" in Epo production.

"In other words, it triggered another organ to produce Epo," Fisher says.

That organ, it turned out, was the kidney, but Fisher wouldn't discover Epo's true source for a few more years.

After completing his Ph.D. at UofL in 1958, Fisher obtained a full-time faculty position as an instructor at the University of Tennessee Medical Units in Memphis. It was there that he continued his quest for the mechanism of cobalt polycythemia, and ultimately, the mechanism for Epo production.

With the assistance of three UT medical students, Ben Birdwell, Joanne Sivadon and James Langston, Fisher developed an isolated dog kidney perfusion system in 1960.

"We suspected the kidney could be the site of Epo production, but we weren't sure," he says. "We also thought maybe it was just permissive, like we'd found with the adrenal cortex."

The team perfused a number of dog kidneys with blood containing cobalt, then froze the perfusates for further analysis. Scientists at the Argonne Cancer Research Hospital at the University of Chicago learned of his work during a visit that year, and Fisher was invited to spend a few months with Leon Jacobson and other researchers there who also were studying kidney production of Epo.

He used their lab to analyze the isolated, perfused dog kidney samples and conducted more testing on rats. Eventually, the researchers were able to show that the kidneys were, indeed, the source of Epo production.

"Once I knew cobalt's mechanism, which we proved was the kidney, then I was intrigued. Here was a hormone -- Epo -- that no one had worked with before."

Ghost buster

Fisher likes to tell the story of ghost chasing.

"A colleague of mine said to me, 'Are you sure there is such a thing as Epo? Or are you chasing ghosts?'

"It was a great challenge to say there is such a thing. When you make a new finding, it just triggers you to work even harder to try to elucidate mechanisms that are behind the findings. I think I've always been a person of meticulous detail, intrigued by any new findings such as this."

Fisher had caught his ghost: He had successfully demonstrated that cobalt enhanced production of Epo in the dog kidneys.

When Fisher and his team finished up the analysis of kidney samples at Argonne Cancer Research Hospital, their study was published in the June 1961 edition of "Acta Haematologica."

Other research teams around the world began doing similar studies on the source of Epo production. But Fisher was moving forward. He now was on a quest to determine exactly which cells in the kidney produced Epo.

Fisher began traveling internationally, conducting and sharing his research with other scientists, giving talks and presentations, and writing papers for publication.

In 1963 Dr. Lazlo Lajtha invited Fisher to spend a sabbatical studying Epo in Manchester, England. The decision to accept was a difficult one because it meant moving Fisher's entire family, which by then included six children.

While in England, Fisher joined with doctors at the Christie Hospital and University of Manchester School of Medicine to localize the specific kidney cells that produce Epo.

Using an indirect fluorescent antibody technique, the researchers discovered that epithelial cells in the glomerular tuft of sheep kidneys contained Epo. Further study using recombinant DNA technology revealed that the interstitial cells outside the glomerular tuft were the actual site of Epo production.

As a result of his discovery, Fisher's reputation was rapidly growing in international circles. He was invited to present papers at the European Society of Hematology in Lisbon, Portugal, and at the Second International Pharmacology Congress in Prague in the former Czechoslovakia. He also was invited to consult with a university medical school in Argentina in 1968 and '69.

After that, Fisher's calendar filled up rapidly with invitations to lecture or make presentations. All in all, he appeared at more than 85 conferences and professional gatherings around the globe prior to his retirement.

The Tulane years

Tulane University School of Medicine welcomed Dr. Fisher in 1968 as a professor and chairman of the pharmacology department.

With the help of another medical student, Ronald Busuttil, and an assistant professor, B.L. Roh, Fisher immediately started further analysis of the kidney cells that produce Epo. More importantly to sufferers of kidney disease, Fisher also began work on the mechanism of anemia associated with end-stage renal disease.

Occasionally he had to reduce his research activities, such as during his tenure as president of the Association for Medical School Pharmacology or the periods in which he served as a consultant to high-tech pharmaceutical concerns like Upjohn, Biogen and the Life Sciences Division of McDonnel Douglas.

Ultimately, his research on Epo resulted in FDA approval of the hormone's use for treating anemia in end-stage renal disease. According to Fisher, at least 150,000 patients undergo dialysis at any given time in the United States, and most of them now receive human recombinant Epo to treat anemia.

"Also, patients with HIV infections who are receiving the drug AZT often become more anemic, and Epo is approved by FDA to be used for them too," Fisher notes.

Other Epo recipients include cancer patients undergoing chemotherapy.

Another achievement of which Fisher is quite proud are the 62 pre- and postdoctoral fellows from all over the world with whom he worked side by side on Epo research.

"I am truly proud of the achievements of my research fellows, many of whom have risen to become deans, chairmen of science departments and directors of research in drug companies," he says.

Dr. Krishna Agrawal, chairman of the pharmacology department at Tulane, speaks highly of Fisher's efforts on behalf of his colleagues.

"He made a point, in terms of people he hired, to see to it that their careers were advanced," said Agrawal, who was hired by Fisher as an associate professor in 1976. "We all admire him because he worked so hard for everyone, including his post-doc students and faculty.

"He had a strong determination to see that each one of those people would be successful in their careers."

Fisher officially retired as chairman of the pharmacology department at Tulane in 1996, yet he still continues his research on the elusive hormone Epo. He also spends time with genealogy research and still enjoys the occasional invitation to speak or consult.

Fisher has received more than a dozen high-level honors and awards over his career. One of the greatest, according to Fisher, was the Experimental Therapeutics Award from the American Society for Pharmacology and Experimental Therapeutics in 1992.

"He deserved that award, because all scientists look forward to their work becoming a widely-used drug," Agrawal says. "Epo is now a billion dollar market. That is a great achievement."

Fisher also received the Purkinje Medal from the Czech Medical Society in 1975 for his work on the kidney as the site of Epo production. And recently, Fisher added another honor to his list when he was selected as the University of Louisville School of Medicine's 1999 Alumni Fellow.

"That was so important to me, and I feel very rewarded being honored that way," Fisher says. "I will always have a warm spot in my heart for UofL."