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Disease Area Infectious diseases, Neurological, Immunology, Genetics, Cancer

Rage Against the Dying of the Light

Who were your mentors

I was very lucky that, when I did my residency at the University of Illinois, an incredible group of people were based there who really shaped my career: Morton Goldberg, Gholam Peyman, Lee Jampol, Joel Sugar, and Gerald Fishman. They supported my aspirations and I have to credit them all.

What one piece of your research have you found the most rewarding?

I was a first-year resident during the AIDS crisis. People were dying from the disease, but they were first going blind from cytomegalovirus (CMV) retinitis. Many would tell me that they were more concerned about blindness than death – it was terrible. At that time, there was a new drug that had yet to be approved by the FDA, called BWB759U. It was being considered for systematic use in CMV retinitis cases, as well as CMV pneumonitis and gastrointestinal problems. It occurred to me that, if I could inject BWB759U directly into the eye, I might be able to help these people. With the approval of Morton Goldberg – then Chairman of the University of Illinois Hospital – and the help of Gholam Peyman and my future wife, Colleen Howe, we did some ERG studies on rabbits and showed that the drug would create very little toxicity. A patient who was rapidly losing vision wanted to receive the drug on a compassionate plea basis – and we managed to save his vision! That drug was subsequently named ganciclovir and went on to save the vision of countless others.

We are always uncovering new frontiers – anyone who says there are no boundaries left is wrong!

How rapidly did other clinicians follow suit and administer the drug to AIDS patients?

Pretty quickly. After we published the toxicity study, a doctor in Minnesota injected it into somebody else’s eye and published on that, and it then became the way to do things. That’s not to say there was no pushback. People said, “It can be given systemically, so why inject it intravitreally?” The problem with systemic administration is that you struggle to achieve the levels of efficacy needed to rapidly diminish disease spread in the eye.

How quickly did you start to see an effect?

Patients noticed that their vision loss was halted almost immediately. It was transformative because it made me realize that this is what I want to do. This is how I want to spend my time – trying to improve peoples’ lives.

Was that one of your proudest moments?

I’ve had a few others that are just as important, but I think this was the start of wanting to pursue academic translational medicine. In terms of key milestones, I would say that some of my most important work has been when I have caused a shift in how people think about – or take care of – a disease. My children choosing to go into medicine is another source of pride for me.

Tell us about your other key milestones.

At Illinois, the thought was that patients with sickle cell disease would need exchange transfusions before undergoing surgery – the rationale being that you needed to take out the sickle red cells and replace them with normal red cells. Unfortunately, at that time, exchange transfusions required pints and pints of blood, which was problematic because of the risk of hepatitis and HIV.

When I left Illinois to do my fellowship at Bascom Palmer in Miami, I found that they were doing surgeries without exchange transfusions. I came home and told my wife, “I can’t believe this.” But the patients did great! We wrote a paper (1) saying, “Wait a second – with modern vitrectomy techniques, oxygenation, lots of fluid, and no use of a buckle or a very mild buckle, you don’t need to do the exchange transfusions and you forgo the risk.” That was the end of the exchange transfusions!

When I got to the University of Iowa, I saw that there was a relationship between patients that had something called pars planitis – now known as idiopathic (intermediate) uveitis – and a family history of multiple sclerosis (MS) or optic neuritis. So a couple of colleagues and I showed that there truly was an association between the two conditions; they shared the same genetic background. Later, in Milwaukee, we showed that there was a relationship between the severity of the disease and smoking, a modifiable risk factor.

More recently, we showed that vitreoretinal lymphoma (very difficult to diagnose in the absence of a good biomarker) has one genetic modification – MYD88, a gene that is seen in at least 77 percent of cases. You can do a PCR for this mutation and, if it’s present, you have vitreoretinal lymphoma. This has now become the standard way to diagnose the condition. The nice thing about knowing that MYD88 is the cause of vitreoretinal lymphoma in most patients is that we can then target therapeutics accordingly.

Lately, we have tried to update ocular oncology by using more modern medical terms. For instance, we have brought minimal residual disease – a medical oncology concept – into the ocular oncology space.

Finding ways to improve patients’ lives is my raison d’être; it keeps pushing me forward.

Have you seen a direct improvement in vitreoretinal lymphoma diagnosis and treatment?

Now that the disease can be detected earlier, we can use targeted drugs to combat it. Early diagnosis leads to early, local treatment instead of systemic treatments (and central nervous system involvement). Making the diagnosis earlier is very important for the patient’s wellbeing and quality of life.

What are your predictions for the use of gene therapy in ophthalmology?

I think that we are always uncovering new frontiers – anyone who says there are no boundaries left is wrong! The more we cut down the brush, the more we see that there is still a lot to be explored. The important thing is to know the history; as George Santayana wrote, “Those who cannot remember the past are condemned to repeat it.” The key is not to let prior history taint how you move forward.

When I got into vitreoretinal lymphoma, people thought that it led to death within a year and not much could be done about it. Likewise, with CMV retinitis, people accepted that blindness was inevitable. To this day, I still remember a patient telling me that it was God’s will. I hate that. I recall the Dylan Thomas line, “Rage, rage against the dying of the light.” That’s our duty.

Is that acceptance of fate – that there is “nothing to be done” – still echoed by some in the medical community?

Unfortunately, yes. But, in my opinion, if they truly believe that there is nothing to be done, it should be their duty to try and change that. That’s why we go into medicine. My goal is to abolish the idea that “that’s just the way it is.”

You recently took a sabbatical at Moorfields in London, UK. What did you take away from the experience?

It’s nice to see how different people can have such disparate views on the same disease. I worked with a brilliant team and we had great repartee, but in the UK they see things in a different way than we do in the US. We had a lot of back-and-forth while we were writing a chapter together. It was really a worthwhile learning experience. Our group was mainly focused on genetic eye disease, which isn’t my strong suit at all. But they were all exceptional, and they helped me to learn more about what I would consider a weak point in my training. I respect them all tremendously.

I actually got a really nice email from Alan Bird, a god of medical retina, a few days ago. He said, “It was such a good give and take.” I miss them and would love to see them again. Hopefully, they will come to visit us at Wills.

You took up an endowed chair position at Wills Eye earlier in the year. What have been the highlights of working at Wills so far?

It has been great! We’ve already had a paper accepted with Carol Shields, Tatyana Milman, and a group in Austria on minimal residual disease in uveal melanoma. Tatyana Milman and I are discussing a new classification way to treat inflammatory eye diseases. It’s yet another awakening for me. Every place I’ve been has helped expand my mind – that’s the fun thing about academics.

What do you like to do outside work?

I exercise, I go walking with my wife, I listen to classical music, and I learn new things. My family is extremely important and I want to thank them for their support along the way.

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