Retina Society 2017 (Day 1): Retinal Vascular Diseases


Yoshihiro Yonekawa, MD Mass Eye & Ear / Boston Children's Hospital RETINA Roundup Co-Editor Evangelos Gragoudas is one of the giants in our field. Dr. Gragoudas and his colleagues pioneered proton therapy for uveal melanoma, developed photodynamic therapy (PDT) for neovascular age-related macular degeneration (AMD), and introduced anti-VEGF treatment for various retinal pathologies. His contributions have touched millions of patients throughout the world. Dr. Gragoudas is the director of the Retina Service at Mass Eye & Ear, and the Charles Edward Whitten Professor of Ophthalmology at Harvard Medical School. He has trained generations of residents and fellows, many who are now leaders in our fields, including numerous departmental chairs.

gragoudas-lectureImage source

The best perk of working at Mass Eye & Ear for me, is that I can ambush Evan Gragoudas for advice, wisdom and funny stories, usually in the cafeteria while he is having sushi lunches, or in his office in between many meetings. He is our Godfather. Or, as we like to call him, the Greek Father. This week we sat down in his office with RETINA Roundup in mind, and I asked Dr. Gragoudas some questions. As all residency and fellowship interviewees that come through Mass Eye & Ear have experienced first hand, Dr. Gragoudas is a famous interviewer -- he was an even better interviewee. Please enjoy the transcribed conversation below. All paragraphs are filled with laughter that cannot be fully expressed in writing, but those who know Dr. Gragoudas will be able to imagine it every other line:

Dr. Gragoudas' Calling

How did you develop your interest in ocular oncology? It's a unique specialty that helps patients with pathology that scares away most ophthalmologists. It was luck. I was a vitreoretinal fellow here when Charlie Regan was the service director. He had a grant to investigate proton therapy to treat retinoblastoma in a monkey model. Charlie became acting chief, and didn't have time to do experiments anymore. So Ian Constable, who later became departmental chair in Perth, Australia, took over the animal studies. He was returning back to Australia though, and told me, "Well, Evan, I have these monkeys that I irradiated. I'm leaving. Why don't you take over this project?" I had no clue about ocular oncology, and had seen just 3 to 4 melanoma patients in my life at the time. I was also planning on going back to Greece. So I said to myself, "Okay, let's get this done, publish a few papers, and go." Looks like you wrote more than just a few papers, and your escape plan didn't work that well. Exactly. There was another fellow here in the pathology lab, Nick Zakov, who helped me with the pathology of the monkeys that had been irradiated. The studies progressed well. I started working on melanoma, and developed a very good collaboration with the group at the General (Massachusetts General Hospital). We received grants to treat humans with uveal melanoma, and the rest is history. I became attached to ocular oncology, and we learned more as we grew and grew.

Developing a Niche Practice

How did you grow your oncology practice? And when did something that was initially unexpected become a life long passion? Well, it was a gradual process. I was doing general vitreoretinal surgery for many years, and gradually saw more patients with tumors, for two reasons: (1) I was the only ocular oncologist in our area, so the number of patients was steadily increasing, and (2) The more patients I saw, the more I became interested in ocular oncology. Reading about it, presenting data, seeing results. As many of you know, I set up a streamlined clinical and research program where we have a registry and all patients we treat are followed over time. There is satisfaction on many levels. We learn more and more as we see and treat more patients. You publish, contribute to the field, and before you know it, you love what you are doing because you are making a difference.

Mentorship

2018.05.16_Evan Gragoudas So many people consider you to be their mentor. Who was your mentor who guided you early in your career? My number one mentor was Ephraim Friedman. He was the chair of ophthalmology at Boston University (BU), when I was a resident there. At the time, he was doing research on blood flow in macular degeneration, and we published papers together on the natural history of AMD. Eph was so enthusiastic about his research. As a young person in academics, one of the best things that can happen is to find a mentor who can inspire you to increase your interest in investigation. To inspire you to make discoveries. Eph was also a great mentor for writing papers, because he had the patience, which sometimes I don't. At the time, my English was much, much worse than now. Even worse than now? You have no idea. No idea. I still remember, he was chair at the time, and we would sit outside on the steps at BU, looking at my handwritten paper. I had written half a page with great effort, and he asks me, "What do you want to say?" I tell him, and he replies, "Okay, write this down." And it was just two short lines. Ephraim inspired me. He was the best mentor that I met, who taught me the pleasures of making discoveries. Just superb.

Publishing

Would you say that those first papers are the ones you feel most attached to? I think as authors, we have sentimental attachments to certain papers. I would say the paper I am most attached to is my best paper, and it was about treating choroidal melanomas with proton beam irradiation. You've written dozens of papers about proton therapy for melanoma. The very first one. The one I described the technique and the first patients treated. Which year do you publish the paper? Let me see. It was in the 70s. (Dr. Gragoudas pulls out his "abbreviated" CV that is 100 pages long). It was published in AJO in 1977. I treated the first patients with protons in 1975. There were not that many in number, but this paper was a lot of fun to write. It was something really original. And don't forget, leading up to that time, most eyes with melanoma were enucleated. But coincidentally, a new idea actually helped our goal of eye salvage therapy. Dr. Zimmerman, who was the director of the AFIP at the time, had written a paper suggesting that enucleation may increase the rate of metastatic disease. So patients with melanoma were anxiously trying to find a new treatment that avoided enucleation. And this was exactly the time when protons and plaques started being used.

Career Advice

What would be your one advice to our readers on how to approach their careers? The most important thing is to be in the right environment, which nurtures young talent and encourages achievement. I like to say, "You cannot grow flowers in a desert." The environment here in Boston provided all the opportunities that lead to the three areas that I feel most proud of: proton therapy for tumors, PDT and anti-VEGF.

The Right Environment

evangelos-s-gragoudas-mdImage source

We started from animals and we went all the way to humans, saving vision now all around the world. The right people were at the right place, at the right time, and we managed to work together to achieve all of this. The developments could have certainly happened at other places also, and quite a lot of this is by chance, but our network here helped to work towards common goals. Remember, great things can be happening around you that you may not realize. So be in an environment that is stimulating, where people are doing exciting things left and right, and keep your eyes open. So outside of what you consider a job, have a little bit more excitement in your life, try some research, try to find something new. And you won't believe the satisfaction you can get, by doing something that no one else has done and improving the field.

Proton Therapy

So for protons, it was a pediatrician who was seeing children with retinoblastoma. He was sending the patients to Charlie Regan. This pediatrician left, but then there was a neurosurgeon at the Harvard cyclotron who was treating pituitary tumors with protons. He talked to Charlie and asked, "Why don't you use this to treat tumors?" And that's how it started. He was here, also at the General, at the cyclotron, and knew the right people.

Genesis of Photodynamic Therapy

The same thing with PDT. Photodynamic therapy was attempted previously with different dyes without much success. The team at the General was doing things outside the eye with a new dye. Joan Miller and myself decided to use this dye to treat choroidal neovascularization. Joan was working on the monkey model that showed great results, and we quickly developed the treatment protocol.

Anti-VEGF Stories

Same thing with anti-VEGF agents. Tony Adamis, who was a cornea fellow with us, was working with Judah Folkman. Tony came to me here, and was sitting in the chair you are sitting in now, and says, "Evan, I think I have something we have to work on together. To treat patients with macular degeneration." And you can imagine my surprise. That you have a cornea fellow, wasting my time talking about macular degeneration, which he knows nothing about? But he was Greek so I could tolerate him. Joan was working on the animal model. Tony got in touch with Napoleone Ferrara at Genentech, and rhuFab was developed - which you know is the present ranibizumab (Lucentis, Genentech). The fellows were working on many of the experiments. Magda Krzystolik who you know worked on some of these original experiments. In one monkey eye, you inject the rhuFab before you do the laser to induce choroidal neovascularization, and in the other eye you inject saline. The one with rhuFab: no neovascularization. The control eye: vessels grow. You treat these vessels with rhuFab: they go away. It was just incredible. Was that was the most exciting moment in your career? Treating the first patient with melanoma with protons was the most exciting, at the time, because I was obviously very young, and I hadn't accomplished anything to write home about yet. So I did something new, first time in the world, and it was very exciting. Very exciting.

Life Outside of Medicine

2018.05.16_Evan Gragoudas Yoshi Let's change gears a bit. You've asked many resident interviewees what their favorite books are. As a literature buff, which books are your personal favorites? I have a lot of favorites. Well, I like... I have too many. I like Russian literature a lot. Dostoevsky, Tolstoy, and Turgenev. British writers also. When do you like to read? After hours? When you travel? I cannot sleep without reading. I read 20-30 pages of a book every night before sleeping. Also when I travel, and whenever there is free time. What else do you enjoy doing? I like going to concerts. Visiting museums. Theater. When I was younger I liked to play tennis a lot. I believe you played soccer also? Well, I was playing soccer when I was in Greece. But after I came here, soccer was not very popular to say the least. So I started playing tennis. What are some of your favorite quotes? Here are some for the young people. Remember we were talking about luck? One I like is, "Be lucky by keeping your eyes open." Here are more: "Consult the wisdom of your colleagues." "Great ideas come when you least expect them." Which is really true. "Don't take yourself too seriously." That's a really good one. I like that. "Enjoy science as an adventure." Another one is by Henry Poincaré. He is a physicist and mathematician, who says, "Science is made with facts, as a house is made with stones. But a collection of facts is no more a science than a pile of stones is a house." The idea is that you have facts, you have science, but you have to interpret the facts and put them together properly to make good science. The last one that I'm going to finish with is by Steven Hawkings. You know the guy? Yes "The enemy of knowledge is not ignorance, but the illusion of knowledge."