How a multicenter CTSA collaboration resulted in a melatonin research breakthrough

On February 10, eminent science journal Nature published news of a research breakthrough that could change the lives of those impacted by sleep disorders, jet lag and depression. Researchers believe their findings may lead to the development of new molecules to generate responses to help bring sleep patterns and other biological rhythms in line with environmental light and dark cycles.

This is major news for people with circadian disorders. And while the research itself is vitally important, what makes this project even more noteworthy is the manner in which it all came together.

University at Buffalo Clinical and Translational Science Institute (CTSI) Workforce Development Core Director, and KL2 Mentored Career Development Award PI and Lead, Margarita L. Dubocovich, PhD, SUNY Distinguished Professor of pharmacology and toxicology and senior associate dean for diversity and inclusion, Jacobs School of Medicine and Biomedical Sciences, collaborated with researchers at the University of California San Francisco (UCSF) and the University of North Carolina School of Medicine (UNC) to create molecules to selectively bind to MT₁ melatonin receptors on the surface of cells and modulate circadian rhythms. All three institutions are Clinical and Translational Science Awards (CTSA) Program hubs of the National Center for Advancing Translational Sciences of the National Institutes of Health.

Dubocovich says it was this multicenter collaborative effort — she is listed as the last co-senior author, with Brian K. Shoichet, PhD, professor in the Department of Pharmaceutical Chemistry at UCSF, and Bryan L. Roth, MD, PhD, Michael Hooker Distinguished Professor in the Department of Pharmacology at UNC, as co-senior authors — that made possible a breakthrough study reporting the effects of new molecules on circadian rhythms in mice.

As outlined in a Jacobs School news item in February, each institution made a significant discovery.

“We are all internationally-known labs, with well-established research focus and years of experience,” says Dubocovich, explaining that it was the strength of the team as a whole that led to its success. “When you have three teams like that, you can bring them together and do something that none of us could do individually.”

In 2017, Rajendram V. Rajnarayanan, PhD, and Dubocovich were awarded UB CTSI Translational Pilot Studies Program funding for a research project that involved discovery of circadian modulators selectively targeting MT₁ and MT₂ melatonin receptors. The Pilot Studies program provides seed money to investigators to assist them in developing innovative new technologies and therapeutics from the conceptual stage to clinical studies. This particular project identified selective MT₂ ligands and made significant progress towards the discovery of selective MT₁ ligands, the main focus of the research.

As the Dubocovich team was still searching for those selective MT₁ molecules, Shoichet called to ask about her interest in testing — in her circadian mouse models — MT₁ novel molecules they had identified docking a chemical library of over 150 million compounds to the newly elucidated crystal structure of the MT₁ melatonin receptor. Dubocovich was prepared. Thus, a collaboration was made.

Dubocovich believes this joint effort was an example of people, institutions, experience, and ideas coalescing at the ideal moment. This sense of cooperation and partnership to facilitate research is at the heart of translational science, which is often achieved only after years of focused thematic research.

Timing is important, she says. So, too, is having the right team.

“I’ve always said that you have to be prepared for when your opportunity comes,” Dubocovich says. “In this case it’s not only that I was prepared but that everything and everybody came into place. Everything came together.”

Publishing in Nature is a tremendously difficult task, as it only accepts papers on “the most significant discoveries” across all scientific disciplines. The weekly journal has been considered an authoritative voice in the world of scientific research since the 1800s.

CTSI Director Timothy F. Murphy, MD, SUNY Distinguished Professor and senior associate dean for clinical and translational research, says the impact of publishing in Nature is tremendous.

“Nature is probably the single most prestigious scientific journal globally because it has published many papers that have reported the most important scientific breakthroughs,” he says. “Having published this work in Nature attests to the enormous, wide-ranging potential of this research by Dr. Dubocovich and her colleagues as a new and innovative therapy for a broad range of disorders.”

This recent multicenter research project is an example of what Dubocovich calls a “new dimension of science”: large-scale collaboration with no geographic or institutional boundaries.

“It’s how science advances, because you are working with people who not only have the experience and the drive, but also have state-of-the-art resources,” she explains. “You really need all of these elements coming together.”

Among the crucial members of her own team were her graduate students. Dubocovich believes this was a life- and career-altering experience for them.

“This taught the students so much,” she says. “Not only the teamwork but also the experience of participating in a team science project, all the demands of the job and all the rewards, and also the realization of what you need to publish in such a high-profile journal.”

The study was published in the March 26, 2020, print edition of Nature.

“I feel so privileged and lucky to have worked on this,” Dubocovich says. “But luck comes along with hard work and long experiences in the field. That is what drives science. You have to keep focused on research goals and have passion in what you do. And that’s how all of this was built.”