Innovation and the clinician-scientist

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Innovation in ophthalmology often arises from unexpected sources, driven by collaboration between researchers and clinicians. Here, 2 pioneering clinician-scientists specializing in the cornea share their insights on the origins of their innovations, the journey to realization, and the essence of being a clinician-scientist.

Edward J. Holland, MD:

The seed of innovation often lies in failure—specifically, the desire to address a patient’s [unresolved problem]. Early in my career, I became involved with high-risk corneal transplant patients who had suffered graft rejections, sometimes multiple times. At that time, we lacked a clear understanding of why these transplants were failing. This led me to focus on these patients and to explore the role of the limbus, the regeneration of the corneal epithelium, and severe ocular surface disease associated with limbal stem cell deficiency. With each layer I uncovered, I felt compelled to address the clinical challenges, guiding me into the emerging field of ocular surface stem cell transplantation.

Shigeru Kinoshita, MD, PhD:

It is crucial to recognize that [although] a novel, brilliant idea may seem to emerge suddenly—perhaps while enjoying a fine wine or during a long flight—innovations in medicine differ significantly from those in mathematics or physics. Transforming an innovative idea into a viable medical treatment is a lengthy process. Even when an idea appears fresh, it has undergone years of experimentation before it can effectively treat patients. Relentless determination is vital, as failures are a constant companion on this journey.

The power of collaboration

Kinoshita:

I believe that the ability to listen carefully and engage in collaborative discussions—not just with mentors but also with peers, students, and even through historical literature—is a key element of success. Throughout my career, I have had the privilege of collaborating with many talented researchers, including Nancy Joyce, PhD; and Eunduck Kay, PhD, who were pioneers in the quest to propagate corneal endothelial cells in vitro. This was once deemed an impossible task, given that corneal endothelial cells cannot replicate in vivo, which makes endothelial dysfunction particularly devastating. Building on their work, my colleagues and I at Kyoto Prefectural University of Medicine [in Japan] were able to reliably reproduce corneal endothelial cells on a collagen substrate, a crucial step toward developing cultured human corneal endothelial cells (CECs).

Holland:

Sometimes, the most critical insights come from outside our field. During the period when I was grappling with the high failure rates in corneal grafts due to limbal stem cell deficiency, I performed cataract surgery on the wife of John Najarian, MD, head of one of the busiest organ transplant centers globally. After I presented my research at his service’s grand rounds, he pointed out that the level of systemic immunosuppression we employed in ocular surface stem cell transplantation was far too low. This was a “light bulb” moment for me. As ophthalmologists, we tend to avoid systemic medications due to potential [adverse] effects, but addressing this challenge required just that. If systemic immunosuppression is essential for kidney, liver, and heart transplants, why wouldn’t it be necessary for the highly vascularized ocular surface? By adopting principles from organ transplant postoperative management and increasing immunosuppression, we began to see significantly improved outcomes.

However, addressing the clinical and scientific challenges was just 1 aspect of what became known as the Cincinnati Protocol for patients with limbal stem cell deficiency. Logistical hurdles also loomed large: we needed to hire a transplant coordinator to manage patients’ lab tests, medical appointments, and [adverse] effects—a service not reimbursed by insurance. Additionally, it was essential to involve specialists in retina, glaucoma, and oculoplastics, as well as transplant nephrologists. Training a cornea specialist to perform the procedure was one thing, but coordinating the entire team was a formidable yet crucial task for success.

Kinoshita:

I recognized that [although] we made significant strides in culturing endothelial cells, that alone wouldn’t solve the problem of limited access to endothelial keratoplasty [EK]. Culturing cells could help mitigate the chronic undersupply of corneal tissue, but the complexity of EK procedures was a considerable barrier. We needed a simpler approach. My team and I proposed injecting healthy CECs directly into the anterior chamber. To aid the cells’ attachment to the posterior corneal surface, including [the Descemet] membrane, we developed a solution incorporating a rho kinase [ROCK] inhibitor. Additionally, thanks to insights from Junji Hamuro, PhD, an esteemed basic scientist, we understood that mature differentiated CECs in vitro were the optimal choice for this procedure. After years of development and animal studies, this technique was first applied to human patients in 2013 and is now being commercially developed by Aurion Biotech.

Holland:

One of the biggest barriers to new ideas is often resistance to change. Despite establishing the scientific validity of the Cincinnati Protocol and publishing our results in peer-reviewed journals, I frequently encounter physicians who are so apprehensive about immunosuppression that they advise patients to accept vision loss instead of pursuing the procedure. This is why we established the Holland Foundation for Sight Restoration: to create ocular surface stem cell transplantation centers of excellence across the US. Our goal is to identify like-minded corneal surgeons and provide them with the resources necessary to overcome the logistical and process-oriented challenges I faced early in my career.

Advice for aspiring clinician scientists

Kinoshita:

Never underestimate the value of being an observant clinician. A career focused solely on basic science would have been too restrictive for me. Continuous interaction with patients and the ability to study disease in real time has enhanced my research and innovation capabilities. Engaging in salon-style discussions with basic researchers can also open avenues for future innovations.

Holland:

I agree. We are fortunate in ophthalmology to have strong collaborations with industry. Early in my medical career, such partnerships were sometimes viewed with skepticism. However, industry cannot develop better products for patients without clinical insights, and many clinicians lack knowledge about commercialization, funding, or conducting FDA trials. Restricting ourselves to isolated silos stifles innovation; when we collaborate, we truly advance our field.

Kinoshita:

I encourage young ophthalmologists to trust their skepticism about the status quo and to think critically about problems. Just because a concept is presented in a textbook does not mean it cannot be questioned. Discarding preconceived notions is often essential when addressing seemingly intractable scientific issues. Honest, objective observation in nature is fundamental to ushering in a new era in ophthalmology.

Holland:

Challenging the status quo is not easy, but if an idea has merit, it is worth fighting for. I advise young ophthalmologists to seek guidance from senior colleagues who have navigated these challenges. Share your ideas and collaborate; this will make your journey more rewarding.