Innovation and the clinician scientist

The unique relationship between ophthalmologists and industry allows patients to benefit from technological innovations driven by clinical insights. Image credit: ©Lahiru – stock.adobe.com

Innovation in ophthalmology comes from surprising sources, but usually involves collaboration among researchers and clinicians. Here, two pioneering clinician scientists specialising in the cornea discuss their innovations, how they brought them to fruition and what it means to be a clinician scientist.

Edward J. Holland, MD: The seed of innovation is usually failure. It’s about seeking to treat a patient with a problem that you can’t solve. Early in my career, I got involved with high-risk corneal transplant patients who had already experienced a graft rejection—sometimes multiple graft rejections. At the time, we really didn’t understand why the transplants were failing.

I started focusing on those patients and, as time went on, learned more about the role of the limbus, the regeneration of the corneal epithelium and severe ocular surface disease associated with limbal stem cell deficiency. I kept uncovering layers of a clinical problem that I had to try to solve and that led me into the emerging field of ocular surface stem cell transplantation.

Shigeru Kinoshita, MD, PhD: It is important to understand that while a novel, brilliant idea can emerge suddenly—upon waking, while drinking fine wine, during a flight or when taking a train—novel ideas in medicine are very different from those in mathematics or physics. Turning an innovative idea into a viable medical treatment doesn’t happen quickly. Even when it seems like an idea is brand new and innovative, the reality is that it has probably taken years and years of experiments to refine the initial spark of an idea into something that can be successful in treating patients. It takes relentless determination, because there are always failures along the way.

The power of collaboration to overcome barriers

SK: I believe that the ability to listen carefully and discuss problems collaboratively—not just with mentors but with peers and students, and even through reading fine articles published long ago—is a critical element of success. I have had the opportunity in my career to collaborate with many gifted researchers, including Nancy Joyce, PhD, and Eunduck Kay, PhD, who were early pioneers in the quest to propagate corneal endothelial cells in vitro. This was once considered an impossible task. After all, the fact that corneal endothelial cells are unable to replicate in vivo is what makes corneal endothelial disease, or endothelial dysfunction of any sort, so devastating. Building on that work, my colleagues and I at Kyoto Prefectural University of Medicine were able to reliably reproduce corneal endothelial cells onto a collagen substrate, which was the first step in eventually developing cultured human corneal endothelial cells [CECs].

EH: Sometimes the critical insights come from outside our own field, so I think it is important to be curious about and open to ideas from other areas of medicine. Around the same time that I was struggling to figure out why patients with limbal stem cell deficiency were so prone to fail their corneal grafts, I happened to perform cataract surgery on the wife of John Najarian, MD, [at that time] the head of one of the busiest organ transplant centers in the world. He asked about my research and invited me to present at his service’s grand rounds.

When I described our corneal transplant challenges, his immediate response was that the level of systemic immunosuppression we were using in ocular surface stem cell transplantation was so low as to be useless. That was a lightbulb moment for me. As ophthalmologists, we typically avoid systemic medications with the potential for systemic side effects, but to solve our problem, that was exactly what was needed. If systemic immunosuppression was required for kidney, liver and heart transplants, why shouldn’t it be necessary for the vascularised ocular surface of the eye? By adopting the principles of organ transplant postoperative management and significantly increasing immunosuppression, we began to have much better results.

But solving the clinical and scientific challenges were just one piece of the puzzle in what would ultimately become known as the Cincinnati Protocol for patients with limbal stem cell deficiency. There were also logistical challenges: we needed to hire a transplant coordinator to manage the patients’ lab tests, medical appointments and side effects. That isn’t a reimbursable service so we had to figure out how to pay for it. We also needed to involve retina, glaucoma and oculoplastic specialists as well as transplant nephrologists. Even if you teach a cornea specialist how to do the procedure, coordinating this whole team can be an overwhelming burden but is critical for success.

SK: Similarly, I knew that even though we had made excellent progress on culturing endothelial cells, that alone wasn’t enough to truly solve the problem of limited access to endothelial keratoplasty (EK). Creating cells could help to address the chronic undersupply of corneal tissue, but the difficulty of EK procedures was also a significant barrier. What we really needed was a less complex procedure.

My team and I came up with the idea of injecting healthy CECs directly into the anterior chamber. To facilitate the cells’ attachment to the posterior corneal surface, including Descemet membrane, we formulated a solution that included a rho kinase (ROCK) inhibitor to assist the cells in attaching to the cornea. Furthermore, thanks to Junji Hamuro, PhD, an eminent basic scientist, we realised that mature-differentiated CECs in vitro are the preferred choice for this procedure for many scientific reasons. After many years of development and animal studies, this technique was used to treat a series of human patients beginning in 2013 and is now being commercially developed by Aurion Biotech.

EH: Sometimes the biggest barrier to new ideas is resistance to change. Despite establishing the scientific validity of the Cincinnati Protocol and publishing our results in peer-reviewed journals, I still regularly hear that doctors are so fearful of immunosuppression that they recommend patients simply accept vision loss rather than undergo the procedure. That’s why we started the Holland Foundation for Sight Restoration: to establish ocular surface stem cell transplantation centers of excellence across the US. Our hope is that we can identify like-minded corneal surgeons and provide them with the resources to overcome some of the logistical and process-oriented hurdles that I faced early on.

Advice for the budding clinician scientist

SK: Never underestimate the value of being an observant clinician. For me, a career in basic science would have been too limiting. Learning through continuous contact with patients and having the ability to study disease in my patients is what has made me a better researcher and innovator. Salon-style discussions with basic researchers can also sometimes open doors for future innovation.

EH: I agree. I also think we are fortunate in ophthalmology to have very good collaboration with industry. When I first got into medicine, that was sometimes frowned upon. But industry can’t make better products for our patients without clinical insights. And most clinicians have no idea how to commercialise an idea, raise funding or successfully conduct an FDA clinical trial. If we restrict ourselves to our own silos, it stymies innovation, but when we work together, we can truly make progress.

SK: I encourage young ophthalmologists to trust their own skepticism about the status quo and not be afraid to think about a problem differently. Just because you read something in a textbook, that doesn’t mean you can’t question it. Sometimes, throwing out your assumptions is essential if you are going to tackle what appears to be an intractable scientific problem. I always believe that honest, truly objective observation in nature is crucial for ushering in a new era in ophthalmology.

EH: Disrupting the status quo isn’t easy, but if it’s a good idea, it’s worth fighting for. I do advise young ophthalmologists to seek out senior ophthalmologists who’ve been in the trenches and fought these battles. Share your ideas and collaborate with others, and it will make your own journey that much more rewarding.

Edward J. Holland, MD | E: eholland@holprovision.com

Holland is the director of Cornea Services at Cincinnati Eye Institute and professor of ophthalmology at the University of Cincinnati in Cincinnati, Ohio. He is a senior scientific advisor to Alcon and serves on the medical advisory board for Aurion Biotech.

Shigeru Kinoshita, MD, PhD | E: fmstoph@koto.kpu-m.ac.jp

Kinoshita is professor and chair of Frontier Medical Science and Technology for Ophthalmology at Kyoto Prefectural University of Medicine in Kyoto, Japan. He serves on the medical advisory board for Aurion Biotech and is a consultant for KOWA Company Ltd., and Senju Pharmaceutical Co., Ltd.