By Emily Leclerc, Waisman Science Writer
David Gamm is adept at keeping multiple things in focus. Gamm, MD, PhD, is a Waisman investigator, director of the McPherson Eye Research Institute, and professor of ophthalmology and visual sciences. With one eye trained on patients, he treats children in the pediatric ophthalmology clinic. The other eye is keenly focused on research as he studies how to coax stem cells into a treatment for degenerative diseases of the retina. Gamm’s work in both these areas brings him a unique perspective and influence on the convergence of translational research and medicine.
Gamm, alongside his pediatric ophthalmology practice, has been an investigator at the Waisman Center since 2003. Throughout the past two decades, he has been researching how to use stem cells to treat currently incurable retinal degeneration diseases like retinitis pigmentosa and macular degeneration. This pursuit is rooted in the many patients that he has cared for throughout his time as an ophthalmologist.
“It is a privilege and a luxury to be able to apply available knowledge to help people where they are at that moment. It is truly rewarding to help a child or an adult that has an eye or vision problem using established treatments or strategies. That is something that I can do to make a difference today,” Gamm says. “But there are so many patients that don’t have anywhere to turn for answers.” Seeing this need in the people passing through his care only reinforced his desire to establish a research career focused in translational work to hopefully directly impact such patients.
After completing his medical and doctoral degrees at the University of Michigan-Ann Arbor, Gamm came to UW-Madison in 1999 to continue his training as a resident. “[UW-Madison] was – and is – a very well-respected residency program with a history of dynamic chairs who are strongly committed to research. It was during that time that I became familiar with human pluripotent stem cell research, which was born here,” Gamm says. Although his doctoral training had nothing to do with stem cells and a foray into stem cell work would be an entirely new endeavor for Gamm, he saw the potential it had to help patients.
“It seemed to me that if I was going to go this route of starting fresh from a research perspective, this was really the best way to do it,” Gamm says. “Here’s this brand new, fresh out of the wrapper field that has tremendous promise. But no one knew where it would lead or if it could be harnessed for use anywhere in the body, much less in such a delicate tissue as the retina. But if it could be done, I was sure there was no better place in the world to try to do it than here.”
After residency, Gamm decided to stay on at UW-Madison as faculty but he needed to decide where he was going to establish his lab. There were several options including the comfortable one of staying close to the excellent vision researchers within his department that he had already established relationships with. But they weren’t the stem cell experts he needed to learn from most. In the early 2000s, the Waisman Center just so happened to have a brand-new stem cell core and a talented staff of established stem cell researchers, right across the street from the UW Hospitals. “I threw myself into the deep end, learning from a group of stem cell researchers I had never met before – mostly hoping that I didn’t bother them too much – and they welcomed and taught me without reservation. They cared about what I was trying to do, too,” Gamm says.
With a huge assist from Daniel Albert, MD, MS, emeritus professor of the department of ophthalmology and visual sciences and the founding director of the McPherson Eye Research Institute, and renowned stem cell scientist Clive Svendsen, PhD, as well as the backing of Marsha Mailick, PhD, then-director of the Waisman Center, Gamm started his lab at the Waisman Center in 2003. He now had a dedicated space to study the potential of stem cells to treat degenerative retinal diseases.
The first several years were tough for Gamm, who worked largely by himself for the first three years before hiring his first research assistant. He didn’t see the results he was hoping for and only came across small glimpses of potential. “There were lots of opportunities to say this isn’t going to work,” Gamm says. “But I’m stubborn, and more importantly, people didn’t stop encouraging me. They gave me the spine to keep going when I maybe couldn’t find it myself.” Then in 2009, Gamm and his first postdoctoral researcher, Jason Meyer, PhD (now an associate professor at Indiana University), became the first to generate three-dimensional aggregates of early retinal cells (called optic vesicles) from human induced pluripotent stem cells (iPSCs). It was proof of concept.
That finding not only solidified his lab but also led to a Wisconsin Alumni Research Foundation (WARF) patent. Several years later in 2011, Gamm was able to coax the 3D retinal aggregates to form human retinal tissues, or organoids. The organoids provide a more practical and efficient way to grow and study healthy retinal tissue. In 2016 he collaborated with Fujifilm-Cellular Dynamics International to co-found his company, Opsis Therapeutics, which is moving stem cell therapies for degenerative retinal conditions into human clinical trials. The ultimate idea behind Gamm’s work is to one day be able to grow healthy retinal cells that can be transplanted into a patient’s eye to replace damaged or dead cells. This would hopefully be able to restore some measure of vision.
Today, Gamm’s lab has a three-pronged approach to this treatment goal. Opsis funds a section of his lab, headed by Joe Phillips, PhD, that is doing the preclinical work necessary to get transplantation products to clinical trials. The second part, led by Divya Sinha, PhD, is using the stem cell-derived retinal cells as a model to study and hopefully advance gene and pharmacological therapies for earlier stages of disease. The third, led until her recent retirement by Beth Capowski, PhD, is using the same models to further investigate the basic science behind retinal cell and tissue development. With each discovery and step forward, no matter how small, the hope for a treatment for at least some currently untreatable retinal diseases draws nearer.
This year, Gamm and his lab published a paper that shows that the retinal cells grown from human pluripotent stem cells are capable of forming connections, called synapses, with other cells. But despite this important step forward, Gamm remains cautious when talking about his work. The idea of transplanting new cells into the eye to restore vision is a glossy one and one Gamm’s lab has made impressive strides toward. But, there is still a long road ahead. “You have to crawl before you can walk, and walk before you can run,” Gamm says. “It is important to have realistic expectations, and first and foremost, we need to be as safe as possible.”
Gamm remains optimistic about the future and continues to pursue this translational research with the goal of being able to help the patients he sees in his clinics to whom he can’t currently offer effective treatments. And even if he is not the one to bring the therapy all the way to the bedside, he feels privileged to be able to contribute to advancing the field. “To put one foot in both arenas,” Gamm says, “to actively help people in the moment, and then also be involved in what is undoubtedly a career long or multi-career-long effort to fill in huge treatment gaps is an honor.”
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