The rewards were gratifying

Jackie Corbin reflects on his scientific career

Jackie Corbin

A football game does not air without at least one commercial for an erectile-dysfunction drug. Considering the treatments that were available before them — psychotherapy, implants, vacuum constriction devices, direct injection, surgery — being able to take a pill truly revolutionized the field. The discovery of these drugs, though, is also a success story for basic research.

Viagra, Cialis and Levitra are all inhibitors of phosphodiesterase 5, an enzyme that breaks down cyclic guanosine monophosphate, which is important for increasing blood flow. The idea to use PDE5 inhibitors to promote blood flow came out of the work of Jackie Corbin,  an emeritus professor of molecular physiology and biophysics at Vanderbilt University. Corbin spent his career understanding how cyclic nucleotides control physiological processes, and in his recent “Reflections” article in the Journal of Biological Chemistry, he wrote about how his career demonstrates the importance of basic research in developing new treatments.

Outside the lab, Jackie Corbin enjoys many outdoor activities. Read our conversation about one of his favorites, hunting for arrowheads.

When I chatted with him about his article and his research, I came away with another theme: camaraderie. Corbin’s remarks on going through science as a team and helping the greater good reminded me of an aspect of science that is often forgotten: Science is a group effort, working toward the broader goal of improving people’s health.

Corbin is recognized as a leader in the cyclic nucleotide field. He spent his early career studying cyclic adenosine monophosphate signaling and his later career studying cGMP. Corbin attributes his success with cGMP to his longtime collaborator, Sharron Francis. “Sharron was much more precise than I was,” says Corbin. “I was more general, and she corrected me more than I corrected her. I think to have her involvement and to have all the scientific discussions we had, there’s no question that I never could have achieved anywhere near what I did without her.” He adds, “I like to think I probably helped her a little bit as well.”

Corbin started collaborating with Francis in 1977. He and his postdoctoral fellow had discovered a protein that bound to cGMP, and Francis joined them to elucidate their new protein. Together, they identified the protein as a phosphodiesterase, a member of a class of enzymes that breaks down cyclic nucleotides. They further defined how this phosphodiesterase, which later was named phosphodiesterase 5, interacted with cGMP to regulate and degrade it.

Many health conditions, including erectile dysfunction, result from the arteries not being able to dilate adequately, reducing blood flow and the amount of blood in the region. The diameter of the artery is controlled by smooth muscle cells that make up the walls of blood vessels. When the smooth muscle cells relax, the artery dilates.

Several studies at that time had shown that raising the level of cGMP caused smooth muscle cells to relax, suggesting that cGMP could be important in regulating blood flow. Corbin and Francis established that cGMP caused arterial dilation through the enzyme cGMP-dependent kinase, or PKG. cGMP activates PKG, and PKG proceeds to turn on the cellular machinery that results in the smooth muscle cells relaxing and the artery dilating.

After identifying that pathway, Corbin writes that he and his team came up with the idea that impaired arterial dilation could be treated by elevating cGMP with “a drug such as a PDE5-resistant cGMP analog that would serve as a dual-acting compound to activate PKG and inhibit PDE5.”

Corbin and Francis decided to work toward making cGMP analogs to activate PKG and received a three-year grant in 1989 from the pharmaceutical company Glaxo to pursue their project. In the last year of the grant period, Glaxo recommended that they focus on developing PDE5 inhibitors instead of PKG activators, because PKG activators broke down in the digestive system and could not be used as orally administered drugs.

From what they had learned from creating cGMP analogs, Corbin, Francis and their postdoctoral fellow, Sekhar “Raja” Konjeti, came up with the structure for a PDE5 inhibitor that would be more powerful than what was available commercially. They synthesized and tested several candidate compounds and showed that one “was much better than any known inhibitor of the enzyme at that time,” Corbin recounts.

After reading a study that reported that an elevated cGMP level mediated penile erection in rabbits, Corbin and his team believed that their PDE5 inhibitor could be used to treat erectile dysfunction. They shared their idea with the department of technology transfer at Vanderbilt University. “To our knowledge,” Corbin writes in his Reflections article, “this was the first written mention that PDE5 inhibitors could be used to treat this condition.”

Corbin also told Glaxo their idea. Glaxo encouraged them to submit a new research proposal and detail their experimental design. They did so, received another grant in 1991 and continued working on PDE5 inhibitors, passing along their results and materials to the scientists at Glaxo.

What they did not know, Corbin says, was that at the same time, Glaxo was synthesizing and testing compounds that were similar to the structure he and his team had described. One of these compounds would eventually become tadalafil, which is currently marketed commercially as Cialis.

They did not become aware of Glaxo’s actions until 2003, Corbin says, after the results of tadalafil were published. “We planned to synthesize Cialis to do some research with the compound,” says Corbin. “Raja looked up the structure and came to me and said he noticed the structure was similar to what we had suggested way back. The structure of Cialis is very different from that of Viagra or Levitra; it’s a little bit unique.”

Having actively collaborated with the scientists at Glaxo and having given them their compounds and materials to do the synthesis, Corbin and his team felt that Glaxo was able to develop tadalafil because of their work and assistance. They approached the technology transfer department at Vanderbilt, wondering about their rights. In 2005, Vanderbilt filed a civil action lawsuit against the company, seeking to have Corbin, Francis and Konjeti added to the tadalafil patent as joint inventors.

The litigation lasted five years and went through two courts. Both courts ruled against Corbin and his team. “I guess the major thing the judges ruled was that we did a lot to help and we did provide a lot of information and materials, but that it was not enough,” says Corbin. “In science, we feel that the original ideas and what leads up to the final product is important.” However, Corbin reflects, “the legal system rules that whoever comes up with the final product is most important.” The case was brought to the Supreme Court, but the court declined to hear it, ending their legal quest in 2011.

Although they did not receive the credit they felt they deserved, Corbin would not advise colleagues against collaborating with industry. University technology-transfer offices now are much more aggressive in protecting their researchers’ interests, Corbin says. But he also adds that the broader impacts stemming from university discoveries are fulfilling in themselves. “So what if we don’t get any financial rewards?” he says. “Discoveries move on and are applied. People are better off with the medications, so that works and that’s OK.”

Corbin is semiretired now and does very little research. He leaves two pieces of advice for the next generation of scientists. To junior scientists, Corbin strongly recommends they consider working with a partner. “To have around every day someone to talk to about the results and plan the next experiments, talk about the students in the lab, write grants and papers together — no question that is a good way to do it,” he says.

To potential scientists, he writes, “I urge young people to adopt a scientific career. You will be appropriately challenged; you will meet many interesting people from diverse cultures; you will feel the ecstasy of discovery; you will contribute to the improvement of the health and welfare of all living things.”

Maggie Kuo Maggie Kuo is an intern at ASBMB Today and a Ph.D. candidate in biomedical engineering at Johns Hopkins University.