August 25, 2016

New fund honors spirit of Cohen’s innovative research

When Tom Daniel, M.D., joined the Vanderbilt University faculty in December 1986, Stanley Cohen, Ph.D., had just been awarded the Nobel Prize in Physiology or Medicine for his discovery of epidermal growth factor (EGF).

Legendary Vanderbilt scientist Stanley Cohen, Ph.D., talks to students during a 2009 visit to the Medical Center.
Legendary Vanderbilt scientist Stanley Cohen, Ph.D., talks to students during a 2009 visit to the Medical Center.

When Tom Daniel, M.D., joined the Vanderbilt University faculty in December 1986, Stanley Cohen, Ph.D., had just been awarded the Nobel Prize in Physiology or Medicine for his discovery of epidermal growth factor (EGF).

“Stanley was part of the reason I came to Vanderbilt,” said Daniel, who recently retired as chair of Research at Celgene. “He was a sort of cultural anchor for me considering Vanderbilt as a rich intellectual environment in which my research could advance.”

Tom Daniel, M.D.
Tom Daniel, M.D.

Cohen invited Daniel to join a weekly journal club, and the two began a long friendship that included frequent discussions about experiments.

“I shared my data, and he often came and talked to me about his data,” Daniel said. “We had a very special relationship working in parallel fields.”

To honor his mentor — now 93 and Distinguished Professor of Biochemistry, Emeritus — Daniel has made a generous gift to Vanderbilt to establish the Stanley Cohen Innovation Fund. The new fund will support innovative and high-risk research — the type of research for which Cohen is known, and which seldom receives early-stage support from federal agencies or other large-scale funders.

“This is such an appropriate way to honor Stanley, because it’s intended to stimulate the kind of high-risk research that he did that was very fundamental in nature — asking simple questions where the payoff is potentially huge,” said Lawrence Marnett, Ph.D., dean of Basic Sciences for the School of Medicine.

A legendary story

Today, therapeutics that target the EGF receptor — the cell-surface protein that transmits the EGF “message” — are being used to treat lung, colon and head and neck cancers.
“Of all biomedical science, the EGF story has been legendary,” Daniel said.

That story began in the Department of Zoology at Washington University in St. Louis.
In 1953, Cohen joined Rita Levi-Montalcini, M.D., with whom he shared the 1986 Nobel Prize, to isolate a nerve growth factor she had discovered in mouse tumors.

During studies of the nerve growth factor in extracts from mouse salivary glands, Cohen noted some curious “side effects” that did not appear to be related to nerve growth. He observed that crude extracts injected into newborn mice produced early eyelid opening and early tooth eruption in the baby mice.

After moving to Vanderbilt in 1959, Cohen focused on these “side effects.” He said in his Nobel lecture that his training in embryology convinced him “that any substance that altered the timing of specific developmental processes would be of biological significance.”

He purified and determined the protein sequence of the factor, which he called epidermal growth factor because it stimulated the proliferation of epithelial cells in the skin and cornea.

Cohen had “a fantastic ability to focus, in this case on EGF and nothing else,” said Graham Carpenter, Ph.D., professor of Biochemistry, emeritus. Carpenter came to Vanderbilt in 1973 as a research fellow in Cohen’s laboratory and joined the faculty four years later.

“He was probably the best experimentalist I’ve ever met. He spent an immense amount of time just thinking about how to test a hypothesis.”

That thinking often happened as Cohen walked the hallways, smoking a pipe, or — after smoking was prohibited — carrying a pipe in his mouth, Carpenter said. The pipe was a thinking tool that usually got left behind when he stopped for conversations.

“He had a whole box of pipes in his office, and the pipes ended up all over Medical Center North,” Carpenter said. “He had a very relaxed way about him, the way he dressed, the way he entered into casual conversations, but there was a lot of intense stuff going on inside him.”

Cohen and Carpenter, together with other colleagues, characterized the EGF receptor and the cascade of events that stimulate cell growth.

At the time that Cohen received the Nobel Prize, an intriguing link between EGF and cancer had been established: the “oncogene” from a virus that caused cancer in chickens had been shown to be similar to the human EGF receptor. It was soon discovered that overactive EGF receptors could drive the growth of human cancers — setting the course for the development of a host of anti-cancer drugs.

A research legacy at Vanderbilt

Carlos L. Arteaga, M.D., Donna S. Hall Professor of Breast Cancer Research and director of the Center for Cancer Targeted Therapies at Vanderbilt-Ingram Cancer Center, sees Cohen’s legacy reflected in his own career. After coming to Vanderbilt in 1989, Arteaga studied the EGF receptor and the related ERBB2 oncogene to understand how growth factor signaling can induce breast cancers and to develop strategies for blocking those signals.

“Dr. Cohen opened a field of biology that allowed me to focus the most critical part of my career — the beginning — on ways to interfere with signaling by the family of EGF receptors in cancers that are dependent on these molecules,” Arteaga said.

Arteaga continues to study signaling by growth factor receptors and oncogenes in breast tumor cells and to develop targeted therapies and biomarkers of drug action in breast cancer.
Other Vanderbilt investigators are also continuing a tradition of EGF-related research.

Robert Coffey, M.D., Ingram Professor of Cancer Research, studies the role of EGF receptor signaling in the gastrointestinal system. Coffey and his colleagues discovered that a colon cancer drug that blocks EGF receptor signaling can reverse Ménétrier’s disease, a rare, debilitating stomach disorder.

Raymond Harris, M.D., Ann and Roscoe R. Robinson Professor of Nephrology, and his team are investigating the role of EGF signaling in both recovery from acute injury and as a mediator of kidney damage in diabetic nephropathy.

A fund for the future

During his years as a Vanderbilt faculty member, Daniel practiced nephrology, directed a basic science laboratory focused on the molecular determinants of endothelial function and held key leadership roles.

He co-directed the Medical Scientist Training Program for students pursuing both M.D. and Ph.D. degrees, served as a program leader in the newly formed Vanderbilt-Ingram Cancer Center and founded translational research efforts for the cancer center.

“Tom is very intense and very clever, and he remains very dedicated to Vanderbilt,” Marnett said.

Daniel joined Immunex Corp. in 2000 as senior vice president for Research. At Immunex, he built an oncology research division and advanced collaborations leading to the development of the EGF receptor-targeted colon cancer drug, panitumumab.

After serving as vice president of Research at Amgen and chief scientific officer and director at Ambrx, Daniel joined Celgene in 2006.

There, he put together a team that has built a pipeline of oncology and inflammatory disease therapeutics. The group has discovered why the drug thalidomide — a drug that was removed from the market for causing birth defects — is active against multiple myeloma.

“In doing so, we’ve opened a whole new field of drug action and discovery,” Daniel said.

Daniel has maintained his ties to Vanderbilt and serves on the VUMC Biomedical Science Advisory Board. After one board meeting, he called Marnett to discuss his desire to stimulate innovative research at Vanderbilt, research for which it is difficult to obtain funding from traditional sources. They concluded that a fund to support this type of research should bear Cohen’s name as a way to honor his legacy.

Grants will be awarded from the fund each year. The first two $100,000, one-year grants have been awarded to:

• Anne Kenworthy, Ph.D., and Charles Sanders, Ph.D., to explore the potential for pharmacological targeting of proteins in different membrane domains; and

• David Calkins, Ph.D., to study how the energy of brain astroglia cells may be harnessed to prevent neuronal aging.

“We want to encourage people to take a chance, to swing for the fences, to tackle a really big problem. These grants offer our investigators a chance to develop approaches and test the feasibility of tackling big problems,” Marnett said. “The commitment Tom has made is catalytic. We need to continue to raise money for the fund, which deserves to have a very high profile.”

Daniel noted that current funding mechanisms are inadequate to identify researchers who might have the impact of a Stanley Cohen.

“It’s important not just for Vanderbilt, but also for the world, for catalytic innovative research to be done in Stan’s name,” he said.

With his gift to establish the Stanley Cohen Innovation Fund, Daniel hopes to bring increased attention to Cohen’s legacy of innovative research.

“We have an opportunity to recognize the impact of Stan’s work and to heighten awareness of it,” Daniel said. “He really changed the landscape, not just for Vanderbilt, but for patients, and certainly for the entire scientific and medical community.”