Innovation in Retina

EDITED BY EMMETT T. CUNNINGHAM, JR., MD, PhD, MPH, AND PRAVIN U. DUGEL, MD

Dr. Joan W. Miller of Mass Eye and Ear

A retina pioneer and trailblazer for women

JERRY HELZNER, CONTRIBUTING EDITOR

If there were a Mount Rushmore for individuals who have made stellar contributions to retina research, Joan W. Miller, MD, chief and chair of the Department of Ophthalmology, Massachusetts Eye and Ear, Mass General Hospital, and Harvard Medical School would definitely have a place on the mountaintop. (You may now argue over who should have the other three places.)

Joan W. Miller, MD

From almost the beginning of her career as a retina specialist at Mass Eye and Ear, Dr. Miller has been a standout. She is one of only a handful of brilliant young ophthalmologists chosen in the early 1990s to unlock the mysteries of angiogenesis in retinal disease at the legendary Folkman Lab at Harvard Medical School. She went on to be part of a team conducting seminal research in anti-VEGF therapies, which helped contribute to the development of such leading-edge drugs as Macugen (Eyetech) and Lucentis (Genentech). Even more remarkable, at the same time she was conducting anti-VEGF research, she codeveloped Visudyne photodynamic therapy (PDT) for retinal disease with Mass Eye and Ear colleague Evangelos Gragoudas, MD.

PDT: A BREAKTHROUGH IN MEDICAL THERAPY

Visudyne PDT, a two-step treatment combining a photosensitive drug injection in the arm with laser activation in the retina 15 minutes later, was a huge breakthrough when it was approved in 2000 because it was the first pharmacological therapy for AMD. PDT was not a new concept, but Drs. Miller and Gragoudas were able to work out the proper dosing and timing in animal models through a lengthy, empirical trial and error process. PDT is still considered very effective for central serous retinopathy and polypoidal choroidal vasculopathy.

Dr. Miller has been the recipient of prestigious honors, including the 2014 Champalimaud Vision Award for her work in antiangiogenic research and the Mildred Weisenfeld Award for Excellence in Ophthalmology. Dr. Miller has spent her entire professional career at Mass Eye and Ear, where she has achieved numerous “firsts” for a woman, including being named chief of ophthalmology at Mass Eye and Ear and Chair of the Harvard department in 2003, winning the Weisenfeld Award, and, along with Patricia D’Amore and their colleagues, becoming the first women in a group winning the Champalimaud Vision Award.

In an interview, Dr. Miller comes across as unfailingly modest and matter-of-fact. She would just as soon talk about her and her attorney husband’s achievement of “raising three great kids” as she would about her monumental professional career. Indeed, their older son has joined her as a retina specialist at Mass Eye and Ear. Their other son is a construction executive, and their daughter just graduated from the University of Michigan Law School.

A GREAT FOUNDATION FOR RESEARCH

A graduate of MIT, Dr. Miller chose ophthalmology as her specialty after graduation from Harvard Medical School because she felt it offered “a nice blend of medical and surgical competencies.” The retina subspecialty especially appealed to her “because the surgeries were challenging and numerous unmet needs existed.” Little did she know as a medical student that she would play an instrumental role in meeting those unmet needs by greatly expanding the medical therapies available to retina specialists.

One of her early opportunities at Harvard was to be a part of the Folkman Lab under Judah Folkman, MD, a groundbreaking researcher in unlocking the strong connection between angiogenesis and solid tumors. Dr. Miller joined a highly promising young group of ophthalmologists in the Folkman Lab, where they were tasked with finding the linkage between angiogenesis and retinal disease. Her colleagues at this time included Patricia D’Amore and such budding “stars” as Anthony Adamis and David Shima.

“Dr. Folkman wanted ophthalmologists in his lab because he was early in seeing that angiogenesis was a major factor in retinal diseases, just as it is in cancer,” says Dr. Miller.

Dr. Miller appreciated her experience with Dr. Folkman and felt that he was one of a great group of mentors from whom she benefited.

Dr. Folkman had worked primarily with corneal models of angiogenesis. “As a fellow, I developed models more relevant to retinal disease, and tested angiostatic steroids that Dr. Folkman was studying. We then used those same models to investigate the role of VEGF.”

Dr. Miller’s early experiences at Harvard helped shape her preference for conducting collaborative research, with interdisciplinary cooperation when projects were of sufficient scope.

RESEARCH IN ACADEMIA

When asked about the advantages and disadvantages of doing research at an academic institution, Dr. Miller sees more of the former than the latter.

“One major advantage in academia, is that we have the freedom to pursue our own ideas and choose our own path to achieve our research goals,” she says. “On the other hand, we are always challenged for funding. In industry, decisions from above can shut down a whole program even when it is making progress. I think academia and industry need to continue to improve their partnerships because that will yield the greatest success in creating cures for patients. We are still working on those relationships. Efforts such as the Ophthalmic Innovation Summit are doing a lot to build bridges between researchers, venture capital, and industry.”

In discussing the interests of the residents and fellows whom she currently mentors, Dr. Miller notes that they have a wide range of career goals.

“Some want to be researchers and innovators, but others want to be the best clinicians that they can possibly be. For the ones who want to be innovators, I think we need to help them understand some business concepts, such as how to obtain funding for their ideas.”

Dr. Miller says that, as a researcher, she still wants to spend time in the clinic seeing patients.

“I believe the role of the clinician scientist is crucial to research success, she asserts. “You sort of go back and forth between the clinic and the research lab in an iterative process. It’s a good combination for solving problems.”

As the years have passed, Dr. Miller’s research interests have evolved. She believes she has done all she can in the anti-VEGF realm and has moved on to new areas such as finding ways to combat retinal diseases at an earlier stage. She is investigating the role of lipids and inflammation in AMD as targets for therapy. Recently, she and Dr. Demetrios Vavvas published an exciting preliminary finding showing resolution of drusenoid deposits in patients treated with intensive statin therapy, and are planning a larger, multicenter trial. She and Dr. Vavvas are also identifying neuroprotective agents that can help in preserving photoreceptors and therefore vision in a variety of retinal diseases. They have shown that necrostatins (that block necroptosis) and caspase inhibitors (that block apoptosis) can be combined to preserve photoreceptors in animal models of AMD, inherited retinal diseases and experimental retinal detachment. She and Dr. Vavvas hope to get these agents into clinical trial in the near term.

Looking ahead, Dr. Miller believes research into genetics, gene therapy, and gene editing is going to be “huge” and will play an increasing role in the retinal realm “sooner rather than later.”

A CAREER AT ONE INSTITUTION

Dr. Miller has spent her entire professional career at Mass Eye and Ear, achieving a number of “first woman” milestones along the way. In typical Miller fashion, she takes a low-key approach to questions about “glass ceilings” as it applies to her own advancement.

“I just did whatever it took to excel in my work and it got me where I needed to go,” she says simply. “We also had a lot of fun.”

Dr. Miller does not see any real disadvantages in spending an entire career at a single institution.

“We have a large and complex department with 275 faculty members,” she notes. “So we have a large range of opportunities and collaborations. I also have external avenues and relationships, so I do get to see how things are done at other institutions.”

Dr. Miller says that she has taken her role model status more seriously since becoming department chair in 2003.

“The more my role changed to administrator, I began to recognize that I do have these responsibilities. I don’t look at it as being only a role model for women. I just generally like being helpful and enjoying the mentoring process.” RP