A Tribute to Dr. John R. Guy

In Memoriam A Tribute to Dr. John R. Guy FIG. 1. Photograph taken in 2012 at the 50th anniversary celebration of the University of Florida Department of Ophthalmology. Left to right, M. Tariq Bhatti, Mable Wilson (administrative assistant to all of us), John R. Guy, and Jonathan D. Trobe. J ohn R. Guy, MD, Professor of Ophthalmology and the Rodgers Research Chair in Ophthalmology at the Bascom Palmer Eye Institute, died on May 26, 2020, at the age of 68 years, after a sudden and brief battle with cancer. John was an accomplished clinician-scientist and one of the world’s premier thought leaders in mitochondrial disease and Leber hereditary optic neuropathy (LHON). John grew up in Queens, New York. He received his Bachelor of Arts degree from New York University and was awarded a Doctor of Medicine degree by the University of Miami School of Medicine. He trained in neurology at Temple University Medical Center and completed an ophthalmology residency at Georgetown University Medical Center. He completed a neuro-ophthalmology fellowship at Wills Eye Hospital and an orbital surgery observership at Moorfields Eye Hospital in London, England. In 1983, John was recruited by Dr. Jonathan Trobe to replace him as the neuro-ophthalmologist at the University of Florida (UF). During his 25-year tenure at UF, he rose from assistant professor to tenured professor, twice voted as the Department Teacher of the Year and honored with the Dean’s Distinguished Professor in Neuro-Ophthalmology. Amazingly, without a PhD degree, John started his early bench research on optic neuritis and was one of the original investigators of the Optic Neuritis Treatment Trial. In the late 1990s, his research focus changed from optic neuritis to LHON. But before that, in the 1980s, John and Dr. Bill Hauswirth were evaluating a family with LHON at UF, but before they could publish their observations, Dr. Doug Wallace published his groundbreaking article that described a single nucleotide change due to a mitochondrial DNA mutation at the 11778 position as the cause 544 of LHON (1). In early 2000, John took 2 separate 6-month sabbaticals from UF to work in Eric A. Schon’s laboratory at Columbia University in New York to learn about mitochondrial DNA. While there, he helped with the publication of the first article that described the successful implementation of allotopic expression of mitochondrial genes (2). With this new knowledge and skill set, John returned to UF and modified a failed National Institutes of Health request for application to LHON providing the seed money needed to continue his research mission. In 2002, he and his colleagues wrote the seminal paper that demonstrated the restoration of adenosine triphosphate synthesis in G11778A cybrids by using allotopic expression, thereby beginning the era of gene therapy as a potential treatment for LHON (3,4). However, John faced a big obstacle based on work published by others that stated allotopic expression did not work and was toxic (5). But, in 2008, a group from Paris, France, independently validated John’s 2002 observation (6). Many more years of bench and animal research were needed for him to show that the recombinant adeno-associated virus was safe and a potentially efficacious vector for allotopic expression (7). All this work lead to John spearheading the National Eye Institute funded, Phase 1, open-label LHON gene therapy trial in 2014 (8). At the time of his passing, John held several grants including a $6 million U10 grant, a $1 million R24 grant, and 2 R01 basic research awards. Among his other honors were the Research to Prevent Blindness Physician-Scientist Award in 2004 and the Class Best of the Best Award from the American Academy of Ophthalmology in 2010. Some of the best people in the world come into one’s life unexpectedly. I first met John as a first-year ophthalmology resident at UF in 1994. I had no idea who he was and how much he would change my life. He is the one who introduced me to and instilled in me the passion for neuroophthalmology. He was not only smart but very generous and caring. As a colleague at UF, he was always there to help me with challenging patients in the clinic and difficult cases in the operating room. Despite both of us leaving UF to work at different institutions, we continued to work together on his LHON gene therapy trial and more importantly remained best of friends until the end of his brilliant life (Fig. 1). M. Tariq Bhatti, MD Ophthalmology and Neurology, Mayo Clinic College of Medicine PERSONAL TRIBUTES About 20 years ago, John and I were both hosted, for different projects, in Eric Schon’s laboratory, at Columbia Bhatti: J Neuro-Ophthalmol 2020; 40: 544-546 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. In Memoriam University. This is how I got to know him, and, using the LHON cybrids constructed from my patients in Italy, John experimented with the very first approach for gene therapy in LHON, published in Annals of Neurology. Since then, we interacted at meetings or for scientific purposes. Frequently, we disagreed on scientific issues, with lively discussions, but we always enjoyed our personal friendship and helped each other. He kept working on the cybrids I left him, continuing to creatively explore new avenues. I already miss his enigmatic sense of humor and his memorable t-shirts with horizontal stripes. I will also remember his visionary and sincere willingness to cure our patients. That was the key point we always agreed on. Valerio Carelli, MD, PhD The purpose of these words is to honor my friend and colleague John Guy, MD. I first met him during his residency years when he rotated as a resident in the Neuroophthalmology Division at Georgetown University. His demeanor throughout those years and his successful career never changed. He was always reserved, bright, and with great sense of humor. He had an easy ability to detect nuances and to raise key questions which led him to the eventual design of “game changing” management in LHON and other impacting investigations in different optic neuropathies. I remember his Grand Rounds presentation as a resident in experimental optic neuritis with Narsing Rao, MD, as his mentor. One could easily predict then that his future career would be extraordinary. His legacy will forever be that of a great physician, great investigator, and great man. Jorge C. Kattah During the past dozen years, I have enjoyed John’s extraordinary intellect and his deep understanding of optic nerve mechanisms while we worked together in clinical studies of LHON. John was a maverick who sang his own tone in his pursuit of novel approaches. His scientific passion was second to none, and he has brought neuroophthalmology research to an unprecedented level during his career. I will not only miss John as a friend and a teacher in our shared intellectual journey but also his understated quirky humor and unique individualism. Byron Lam, MD John Guy was brilliant and insightful. But most of all, everything he did clinically and in the laboratory was entirely based on a selfless desire to help the patient. The LHON community has lost one of its most important champions. Nancy J. Newman, MD I met John Guy when he joined Bascom Palmer in 2008. I learned we both were alumni of the Bronx High School of Science and we were both from Queens, New York. I had just started my career in neuroophthalmology, so I needed John when cases of Bhatti: J Neuro-Ophthalmol 2020; 40: 544-546 progressive optic neuropathy did not make sense. He was the autoimmune optic neuropathy guru and the expert in the use of intravenous immunoglobulin for these conditions. John wrote the longest clinic notes and dictated the examination like if it was part of the story. We enjoyed evenings at Norman Schatz’s restaurant with the residents and fellows, drinking Malbecs, and sharing jokes and stories about times of the past. There will always only be one John Guy. He will be missed but not forgotten. Josh Pasol, MD John Guy was a pioneer. He did not take the well-worn road. He blazed his own scientific trail. John was a brilliant clinical neuro-ophthalmologist and excellent teacher. But, it was as a scientist that he was most impressive. When I got to know him, almost 4 decades ago, he was working on an experimental autoimmune encephalomyelitis animal model of optic neuritis. He did not have a PhD, but he did not hesitate to answer directly, in the laboratory, questions of mechanism, and pathophysiology. Later, he showed great courage again, as well as scientific imagination, when he did the early work on demonstrating how ND4 could be placed into cells through a viral vector to repair dysfunctional mitochondria. That was technically a very difficult task. John met resistance, but remained unfazed. He did the experiments, fought to get the work published, and applied for more grants. His doggedness, his hard work, and his genius earned him the seminal papers, the grants, and a clinical trial for LHON. Over and over again, John was tested by taking the road less traveled. At each stage, John just smiled his enigmatic smile and succeeded. We will miss him. Alfredo A. Sadun, MD, PhD I met John Guy 40 years ago. John was a neurology resident at Temple University when he came to our clinic at Wills Eye for elective and stayed for a fellowship in neuroophthalmology. He has never really left my side since that time. We enjoyed collegiality of intellect and a laughter of cynicism. John’s thirst for knowledge compelled him to be boarded in both neurology and ophthalmology, as he carved his way in the world of science. His achievements were remarkable, and he will be missed. After work at Bascom Palmer, John and I held court for residents and fellows at the River Oyster House, where the learning continued. There will be an empty seat next to me saved for John with all the warmth of my heart. I will miss him. Norman Schatz, MD M. Tariq Bhatti, MD Departments of Ophthalmology and Neurology, Mayo Clinic College of Medicine, Rochester, Minnesota E-mail: [e-mail] 545 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. In Memoriam REFERENCES 1. Singh G, Lott MT, Wallace DC. A mitochondrial DNA mutation as a cause of Leber’s hereditary optic neuropathy. N Engl J Med. 1989;320:1300–1305. 2. Manfredi G, Fu J, Ojaimi J, Sadlock JE, Kwong JQ, Guy J, Schon EA. Rescue of a deficiency in ATP synthesis by transfer of MTATP6, a mitochondrial DNA-encoded gene, to the nucleus. Nat Genet. 2002;30:394–399. 3. Guy J, Qi X, Pallotti F, Schon EA, Manfredi G, Carelli V, Martinuzzi A, Hauswirth WW, Lewin AS. Rescue of a mitochondrial deficiency causing Leber hereditary optic neuropathy. Ann Neurol. 2002;52:534–542. 4. Larsson NG. Leber hereditary optic neuropathy: a nuclear solution of a mitochondrial problem. Ann Neurol. 2002;52:529– 530. 5. Oca-Cossio J, Kenyon L, Hao H, Moraes CT. Limitations of allotopic expression of mitochondrial genes in mammalian cells. Genetics. 2003;165:707–720. 6. Ellouze S, Augustin S, Bouaita A, Bonnet C, Simonutti M, Forster V, Picaud S, Sahel JA, Corral-Debrinski M. Optimized allotopic expression of the human mitochondrial ND4 prevents blindness in a rat model of mitochondrial dysfunction. Am J Hum Genet. 2008;83:373–378. 7. Koilkonda RD, Yu H, Chou TH, Feuer WJ, Ruggeri M, Porciatti V, Tse D, Hauswirth WW, Chiodo V, Boye SL, Lewin AS, Neuringer M, Renner L, Guy J. Safety and effects of the vector for the Leber hereditary optic neuropathy gene therapy clinical trial. JAMA Ophthalmol. 2014;132:409–420. 8. Available at: www.ClinicalTrials.gov. Identifier: NCT02161380. Accessed June 1, 2020 Editor’s note: The following 4 articles pertain to the topic of Leber hereditary optic neuropathy, and are included here as tribute following the In Memoriam to Dr. John R. Guy. 546 Bhatti: J Neuro-Ophthalmol 2020; 40: 544-546 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.