- Email: [email protected]
Teruo Nishida, MD, DSc
Personal Personal Profile Profile Teruo Nishida, MD, DSc An internationally acclaimed expert on the dynamics of corneal cell biology and wound healing, Teruo Nishida has broken new ground in our understanding of the roles played by nerve and epithelial growth factors. Alongside his active research career and clinical practice, Dr. Nishida serves as dean of Japan’s Yamaguchi University Graduate School of Medicine, where he simultaneously chairs the department of ophthalmology and serves as vice director of the university’s affiliated hospital. In 2007, Dr. Nishida received the Japan Medical Association’s Medical Award, its highest honor, and in 2001 he received the Cornea Society’s Castroviejo Medal. Dr. Nishida now serves on the Cornea Society’s board of directors, as well as on the international advisory committee of the World Cornea Congress. He remains the honorary president of the Asia Cornea Society, which he helped found.
THE OCULAR SURFACE What drew you to become an ophthalmologist and pursue research in ocular healing? TERUO NISHIDA When I graduated from medical school, I never imagined that I would become an ophthalmologist. I am the first son of a gastroenterologist and so, according to Japanese tradition, I was to succeed to my father’s profession. However, a few months before medical school graduation, I decided to delay my clinical career for a few years to pursue basic medical research and earn my PhD in biochemistry. I took a position as a research associate at Ehime University. Unfortunately— or fortunately, as it turned out—inadequate research facilities at Ehime ©2009 Ethis Communications, Inc. All rights reserved.
56
prompted me to go elsewhere. The position I eventually took was as a research scientist at the Eye Research Institute of the Retina Foundation, now the Schepens Eye Research Institute, in Boston. There, under the supervision of Dr. Noritsugu Mukai, I worked on the cell biology and immunology of adenovirus-induced retinoblastoma cells. My daily conversations with Dr. Yozo Miyake, one of Japan’s leading retina surgeons, changed the course of my career. When I returned to Osaka University in 1980, I started residency training in ophthalmology. At Osaka, I had the privilege of knowing the chairman of the ophthalmology department, the cornea specialist Prof. Reizo Manabe. Dr. Manabe kindly allowed me to pursue my retina research in his laboratory each night, after my clinical duties were done. In our many conversations, he encouraged me to switch my research focus to the cornea, which he described as “rather simple” compared to the retina. So inspired, I began my career in cornea research. TOS Please describe your groundbreaking work on fibronectin, neurotransmitter and growth factors in corneal healing. NISHIDA While in Boston at the Retina Foundation, I studied the adhesion of retinoblastoma cells. This background became key when I made the switch to cornea research. Epithelial migration—the first step in epithelial wound healing—requires the
adhesion of epithelial cells to the underlying matrix. In particular, I wanted to understand the role that the adhesive protein fibronectin plays in corneal epithelial cell migration. I found that when the cornea is injured, fibronectin appears at the injury site and epithelial cells migrate to it.1 I also established an assay model that enabled me to quantify the effects of various agents on epithelial cell migration.2 Using this system, I reported that the addition of fibronectin eye drops improved epithelial wound closure in rabbits.3,4 From these findings, we progressed to clinical trials that demonstrated the benefits of fibronectin eye drops in patients with persistent epithelial defects of the cornea.5 We purified the fibronectin from each patient’s own blood.6 My fibronectin studies became the foundation of my lifelong work on corneal wound healing and regeneration. For instance, during two decades treating patients with fibronectin eye drops, I saw that many of those who develop persistent epithelial defects of the cornea have lowered corneal sensation. This led to my work on neurotransmitters and corneal wound healing. In 1996, I reported that the sensory neurotransmitter “substance P” and insulin-like growth factor-1 (IGF-1) synergistically stimulate corneal epithelial migration both in vitro and in vivo.7,8 However, both substance P and IGF-1 are bioactive throughout the body. So administration of these compounds can cause unfavorable side effects. To avoid these adverse effects, we identified the minimum essential sequences of amino acids contained in these two agents. They turned out to be the four-amino-
THE OCULAR SURFACE / JANUARY 2009, VOL. 7, NO. 1 / www.theocularsurface.com
PERSONAL PROFILE / Teruo Nishida, MD, DSc
acid peptide FGLM-amide, from substance P, and the four-amino acid peptide SSSR, from IGF-1.9,10 Using eye drops prepared from these two peptides, we have been treating the persistent epithelial defects associated with neurotrophic keratopathy.11-13 TOS What are some of the most gratifying clinical applications of your research?
ing and strengthening our school. One of the ways I have tried to encourage young researchers is by continually improving the school’s academic and scientific atmosphere. TOS Please describe the importance of the honors you have received for your innovative work.
NISHIDA For me, the greatest honors have included the 2001 Castroviejo Medal NISHIDA I see my major from the Cornea Society clinical contributions as the and, in 2007, awards from development of fibronectin the Japanese Ophthalmotreatment for epithelial logical Society and the Jadefects and the developpan Medical Association. ment of FGLM-amide plus These awards for research SSSR eye drops for neuroand clinical work were parYamaguchi University Graduate School of Medicine, Yamaguchi, Japan. trophic keratopathy. I have ticularly meaningful to me always tried to use clinical in light of my tremendous challenges to guide my laboratory in 1993, this was one of the smallest administrative responsibilities. As research and, conversely, to apply my academic departments in all of Japan. I’ve mentioned, my ophthalmology laboratory findings in ways that help No one was interested in research. department used to be the weakest my patients. Or, to put it another way, Since then, I have given countless lecin Japan. Building it into a premier I’m grateful to my patients for guiding tures to medical students, extolling the research department has required that my research. avenues of research available to them I remain in my office throughout the in ophthalmology. I also spend a lot year to tackle administrative duties, TOS What are some of the unanof time encouraging young ophthalclinical work, and laboratory superviswered questions that you would like mologists to pursue scientific studies. sion. For 3 years after becoming chairto answer? Gradually, the number of graduate man, I could not attend a single overstudents joining my department has seas meeting, because leaving town NISHIDA I would like to clarify the increased. Some come with a great risked the crash of everything I had mechanisms behind corneal stromal interest in basic science, others in apestablished. Of course, the number of melting in a way that will enable us to plied vision research. my publications decreased, and I felt stop the progression of corneal ulcerAt the same time, I continue to frustrated at not being able to more ation. Also, although I won’t be able spend a lot of time in the surgical fully pursue my research in corneal to complete this work in my lifetime, I theater. These two aspects of my physiology and pathology. would like to develop medical and surwork illustrate our department’s dual So you can imagine my pleasure gical approaches to treating congenital mission—advancing research in a when I received that phone call, in corneal diseases. Over the course of my way that improves the visual welfare the summer of 2000, from Dr. Mark career, I’ve been disheartened by our inof people worldwide and at the same Mannis—telling me that I was being ability to preserve and improve vision time providing the best eye care posawarded the Castroviejo Medal. It in such patients over the long term. sible for the Yamaguchi community. meant so much to be recognized by the Since I was elected dean of graduinternational community for my sciTOS Please describe your approach to ate studies last April, I have certainly entific work here in Japan. The award developing the Department of Ophthalfound my new responsibilities a stark provided great encouragement that mology at Yamaguchi University and tell contrast to those of department chair. helped me redouble my scientific work. us how you became the dean of YamaI spend a lot of time talking with other Of course, I was also delighted to guchi’s Graduate School of Medicine. administrators, in particular discussreceive the ophthalmological award ing the graduate school’s future. Here from our Japanese society. Even more NISHIDA When I was appointed proagain, I believe that young faculty meaningful was the Medical Award fessor and chairman of ophthalmology members will be the key to developfrom the Japan Medical Association. THE OCULAR SURFACE / JANUARY 2009, VOL. 7, NO. 1 / www.theocularsurface.com
57
PERSONAL PROFILE / Teruo Nishida, MD, DSc
This, the association’s highest honor, was recognition from all the physicians and surgeons in Japan, not just ophthalmologists. So it was a very special form of encouragement. TOS Please describe some of your many international collaborations and friendships. Which are of particular importance to your work and why? NISHIDA I have had the great fortune of becoming friends with many colleagues the world over. It is hard to name just a few. The most important, perhaps, is Dr. Peter Laibson. When I first published on fibronectin treatment for corneal trophic ulcers, Dr. Laibson invited me to lecture on the subject at Wills Eye Hospital, in Philadelphia. Since then, he has remained my greatest mentor. Whenever I have questions related to ophthalmology or even life in general, I go to him and he gives me the clues I need. In addition, I trace the origin of my current projects to many wonderful discussions with my friends Dr. Mannis, Dr. Ted W. Reid, and Dr. Christopher J. Murphy, when we were all at the University of California, in Davis. We were young enough then that we often sat over coffee until midnight at a café near the campus, discussing the role of corneal nerves in wound healing. Since then, we’ve remained good friends, despite having settled in far-flung places. TOS What are some of the ways you would like to see others advance your work? NISHIDA The path between the bench and the clinic can be a short one in cornea research. However, it has been 25 years since I first reported the efficacy of fibronectin eye drops.
58
Today this treatment still awaits wide acceptance by the ophthalmic world. Admittedly, one of the reasons has been the lack of commercially available, biologically active fibronectin. Clearly, I would like to see wider interest and use of this potentially sight-saving treatment. Our current projects with peptides derived from substance P and IGF-1 are now moving into the commercial stage with an interested pharmaceutical company. This will mean a relative falloff in our publication of associated scientific research. It is now vital that others pursue clinical research to confirm efficacy. These periods of waiting for research to translate into clinical practice are the most difficult for me. For now, I know it is important that we all remain persistent in seeking answers to the questions posed by our research and our patients’ needs. W REFERENCES 1. Suda T, Nishida T, Ohashi Y, Nakagawa S, Manabe R. Fibronectin appears at the site of corneal stromal wound in rabbits. Curr Eye Res 1981;1:553-6 2. Nishida T, Nakagawa S, Awata T, Ohashi Y, Watanabe K, Manabe R. Fibronectin promotes epithelial migration of cultured rabbit cornea in situ. J Cell Biol 1983;97:1653-7 3. Nishida T, Nakagawa S, Nishibayashi C, Tanaka H, Manabe R. Fibronectin enhancement of corneal epithelial wound healing of rabbits in vivo. Arch Ophthalmol 1984;102:455-6 4. Nakamura M, Sato N, Chikama T, Hasegawa Y, Nishida T. Fibronectin facilitates corneal epithelial wound healing in diabetic rats. Exp Eye Res 1997;64:355-9 5. Nishida T, Ohashi Y, Awata T, Manabe R. Fibronectin. A new therapy for corneal trophic ulcer. Arch Ophthalmol 1983;101:1046-8 6. Nishida T, Nakagawa S, Awata T,
Nishibayashi C, Manabe R. Rapid preparation of purified autologous fibronectin eyedrops from plasma. Jpn J Ophthalmol 1982;26:416-24 7. Nishida T, Nakamura M, Ofuji K, Reid TW, Mannis MJ, Murphy CJ. Synergistic effects of substance P with insulin-like growth factor-1 on epithelial migration of the cornea. J Cell Physiol 1996;169:159-66 8. Nakamura M, Ofuji K, Chikama T, Nishida T. Combined effects of substance P and insulin-like growth factor-1 on corneal epithelial wound closure of rabbit in vivo. Curr Eye Res 1997;16:275-8 9. Nakamura M, Chikama T, Nishida T. Synergistic effect with Phe-Gly-Leu-MetNH2 of the C-terminal of substance P and insulin-like growth factor-1 on epithelial wound healing of rabbit cornea. Br J Pharmacol 1999;127:489-97 10. Yamada N, Yanai R, Kawamoto K, Nagano T, Nakamura M, Inui M, Nishida T. Promotion of corneal epithelial wound healing by a tetrapeptide (SSSR) derived from IGF-1. Invest Ophthalmol Vis Sci 2006;47:3286-92 11. Chikama T, Fukuda K, Morishige N, Nishida T. Treatment of neurotrophic keratopathy with substance-P-derived peptide (FGLM) and insulin-like growth factor I. Lancet 1998;351:1783-4 12. Nishida T, Chikama T, Morishige N, Yanai R, Yamada N, Saito J. Persistent epithelial defects due to neurotrophic keratopathy treated with a substance pderived peptide and insulin-like growth factor 1. Jpn J Ophthalmol 2007;51:442-7 13. Yamada N, Matsuda R, Morishige N, Yanai R, Chikama TI, Nishida T, Ishimitsu T, Kamiya A. Open clinical study of eye-drops containing tetrapeptides derived from substance P and insulinlike growth factor-1 for treatment of persistent corneal epithelial defects associated with neurotrophic keratopathy. Br J Ophthalmol 2008;92:896-900
THE OCULAR SURFACE / JANUARY 2009, VOL. 7, NO. 1 / www.theocularsurface.com
THE OCULAR SURFACE What drew you to become an ophthalmologist and pursue research in ocular healing? TERUO NISHIDA When I graduated from medical school, I never imagined that I would become an ophthalmologist. I am the first son of a gastroenterologist and so, according to Japanese tradition, I was to succeed to my father’s profession. However, a few months before medical school graduation, I decided to delay my clinical career for a few years to pursue basic medical research and earn my PhD in biochemistry. I took a position as a research associate at Ehime University. Unfortunately— or fortunately, as it turned out—inadequate research facilities at Ehime ©2009 Ethis Communications, Inc. All rights reserved.
56
prompted me to go elsewhere. The position I eventually took was as a research scientist at the Eye Research Institute of the Retina Foundation, now the Schepens Eye Research Institute, in Boston. There, under the supervision of Dr. Noritsugu Mukai, I worked on the cell biology and immunology of adenovirus-induced retinoblastoma cells. My daily conversations with Dr. Yozo Miyake, one of Japan’s leading retina surgeons, changed the course of my career. When I returned to Osaka University in 1980, I started residency training in ophthalmology. At Osaka, I had the privilege of knowing the chairman of the ophthalmology department, the cornea specialist Prof. Reizo Manabe. Dr. Manabe kindly allowed me to pursue my retina research in his laboratory each night, after my clinical duties were done. In our many conversations, he encouraged me to switch my research focus to the cornea, which he described as “rather simple” compared to the retina. So inspired, I began my career in cornea research. TOS Please describe your groundbreaking work on fibronectin, neurotransmitter and growth factors in corneal healing. NISHIDA While in Boston at the Retina Foundation, I studied the adhesion of retinoblastoma cells. This background became key when I made the switch to cornea research. Epithelial migration—the first step in epithelial wound healing—requires the
adhesion of epithelial cells to the underlying matrix. In particular, I wanted to understand the role that the adhesive protein fibronectin plays in corneal epithelial cell migration. I found that when the cornea is injured, fibronectin appears at the injury site and epithelial cells migrate to it.1 I also established an assay model that enabled me to quantify the effects of various agents on epithelial cell migration.2 Using this system, I reported that the addition of fibronectin eye drops improved epithelial wound closure in rabbits.3,4 From these findings, we progressed to clinical trials that demonstrated the benefits of fibronectin eye drops in patients with persistent epithelial defects of the cornea.5 We purified the fibronectin from each patient’s own blood.6 My fibronectin studies became the foundation of my lifelong work on corneal wound healing and regeneration. For instance, during two decades treating patients with fibronectin eye drops, I saw that many of those who develop persistent epithelial defects of the cornea have lowered corneal sensation. This led to my work on neurotransmitters and corneal wound healing. In 1996, I reported that the sensory neurotransmitter “substance P” and insulin-like growth factor-1 (IGF-1) synergistically stimulate corneal epithelial migration both in vitro and in vivo.7,8 However, both substance P and IGF-1 are bioactive throughout the body. So administration of these compounds can cause unfavorable side effects. To avoid these adverse effects, we identified the minimum essential sequences of amino acids contained in these two agents. They turned out to be the four-amino-
THE OCULAR SURFACE / JANUARY 2009, VOL. 7, NO. 1 / www.theocularsurface.com
PERSONAL PROFILE / Teruo Nishida, MD, DSc
acid peptide FGLM-amide, from substance P, and the four-amino acid peptide SSSR, from IGF-1.9,10 Using eye drops prepared from these two peptides, we have been treating the persistent epithelial defects associated with neurotrophic keratopathy.11-13 TOS What are some of the most gratifying clinical applications of your research?
ing and strengthening our school. One of the ways I have tried to encourage young researchers is by continually improving the school’s academic and scientific atmosphere. TOS Please describe the importance of the honors you have received for your innovative work.
NISHIDA For me, the greatest honors have included the 2001 Castroviejo Medal NISHIDA I see my major from the Cornea Society clinical contributions as the and, in 2007, awards from development of fibronectin the Japanese Ophthalmotreatment for epithelial logical Society and the Jadefects and the developpan Medical Association. ment of FGLM-amide plus These awards for research SSSR eye drops for neuroand clinical work were parYamaguchi University Graduate School of Medicine, Yamaguchi, Japan. trophic keratopathy. I have ticularly meaningful to me always tried to use clinical in light of my tremendous challenges to guide my laboratory in 1993, this was one of the smallest administrative responsibilities. As research and, conversely, to apply my academic departments in all of Japan. I’ve mentioned, my ophthalmology laboratory findings in ways that help No one was interested in research. department used to be the weakest my patients. Or, to put it another way, Since then, I have given countless lecin Japan. Building it into a premier I’m grateful to my patients for guiding tures to medical students, extolling the research department has required that my research. avenues of research available to them I remain in my office throughout the in ophthalmology. I also spend a lot year to tackle administrative duties, TOS What are some of the unanof time encouraging young ophthalclinical work, and laboratory superviswered questions that you would like mologists to pursue scientific studies. sion. For 3 years after becoming chairto answer? Gradually, the number of graduate man, I could not attend a single overstudents joining my department has seas meeting, because leaving town NISHIDA I would like to clarify the increased. Some come with a great risked the crash of everything I had mechanisms behind corneal stromal interest in basic science, others in apestablished. Of course, the number of melting in a way that will enable us to plied vision research. my publications decreased, and I felt stop the progression of corneal ulcerAt the same time, I continue to frustrated at not being able to more ation. Also, although I won’t be able spend a lot of time in the surgical fully pursue my research in corneal to complete this work in my lifetime, I theater. These two aspects of my physiology and pathology. would like to develop medical and surwork illustrate our department’s dual So you can imagine my pleasure gical approaches to treating congenital mission—advancing research in a when I received that phone call, in corneal diseases. Over the course of my way that improves the visual welfare the summer of 2000, from Dr. Mark career, I’ve been disheartened by our inof people worldwide and at the same Mannis—telling me that I was being ability to preserve and improve vision time providing the best eye care posawarded the Castroviejo Medal. It in such patients over the long term. sible for the Yamaguchi community. meant so much to be recognized by the Since I was elected dean of graduinternational community for my sciTOS Please describe your approach to ate studies last April, I have certainly entific work here in Japan. The award developing the Department of Ophthalfound my new responsibilities a stark provided great encouragement that mology at Yamaguchi University and tell contrast to those of department chair. helped me redouble my scientific work. us how you became the dean of YamaI spend a lot of time talking with other Of course, I was also delighted to guchi’s Graduate School of Medicine. administrators, in particular discussreceive the ophthalmological award ing the graduate school’s future. Here from our Japanese society. Even more NISHIDA When I was appointed proagain, I believe that young faculty meaningful was the Medical Award fessor and chairman of ophthalmology members will be the key to developfrom the Japan Medical Association. THE OCULAR SURFACE / JANUARY 2009, VOL. 7, NO. 1 / www.theocularsurface.com
57
PERSONAL PROFILE / Teruo Nishida, MD, DSc
This, the association’s highest honor, was recognition from all the physicians and surgeons in Japan, not just ophthalmologists. So it was a very special form of encouragement. TOS Please describe some of your many international collaborations and friendships. Which are of particular importance to your work and why? NISHIDA I have had the great fortune of becoming friends with many colleagues the world over. It is hard to name just a few. The most important, perhaps, is Dr. Peter Laibson. When I first published on fibronectin treatment for corneal trophic ulcers, Dr. Laibson invited me to lecture on the subject at Wills Eye Hospital, in Philadelphia. Since then, he has remained my greatest mentor. Whenever I have questions related to ophthalmology or even life in general, I go to him and he gives me the clues I need. In addition, I trace the origin of my current projects to many wonderful discussions with my friends Dr. Mannis, Dr. Ted W. Reid, and Dr. Christopher J. Murphy, when we were all at the University of California, in Davis. We were young enough then that we often sat over coffee until midnight at a café near the campus, discussing the role of corneal nerves in wound healing. Since then, we’ve remained good friends, despite having settled in far-flung places. TOS What are some of the ways you would like to see others advance your work? NISHIDA The path between the bench and the clinic can be a short one in cornea research. However, it has been 25 years since I first reported the efficacy of fibronectin eye drops.
58
Today this treatment still awaits wide acceptance by the ophthalmic world. Admittedly, one of the reasons has been the lack of commercially available, biologically active fibronectin. Clearly, I would like to see wider interest and use of this potentially sight-saving treatment. Our current projects with peptides derived from substance P and IGF-1 are now moving into the commercial stage with an interested pharmaceutical company. This will mean a relative falloff in our publication of associated scientific research. It is now vital that others pursue clinical research to confirm efficacy. These periods of waiting for research to translate into clinical practice are the most difficult for me. For now, I know it is important that we all remain persistent in seeking answers to the questions posed by our research and our patients’ needs. W REFERENCES 1. Suda T, Nishida T, Ohashi Y, Nakagawa S, Manabe R. Fibronectin appears at the site of corneal stromal wound in rabbits. Curr Eye Res 1981;1:553-6 2. Nishida T, Nakagawa S, Awata T, Ohashi Y, Watanabe K, Manabe R. Fibronectin promotes epithelial migration of cultured rabbit cornea in situ. J Cell Biol 1983;97:1653-7 3. Nishida T, Nakagawa S, Nishibayashi C, Tanaka H, Manabe R. Fibronectin enhancement of corneal epithelial wound healing of rabbits in vivo. Arch Ophthalmol 1984;102:455-6 4. Nakamura M, Sato N, Chikama T, Hasegawa Y, Nishida T. Fibronectin facilitates corneal epithelial wound healing in diabetic rats. Exp Eye Res 1997;64:355-9 5. Nishida T, Ohashi Y, Awata T, Manabe R. Fibronectin. A new therapy for corneal trophic ulcer. Arch Ophthalmol 1983;101:1046-8 6. Nishida T, Nakagawa S, Awata T,
Nishibayashi C, Manabe R. Rapid preparation of purified autologous fibronectin eyedrops from plasma. Jpn J Ophthalmol 1982;26:416-24 7. Nishida T, Nakamura M, Ofuji K, Reid TW, Mannis MJ, Murphy CJ. Synergistic effects of substance P with insulin-like growth factor-1 on epithelial migration of the cornea. J Cell Physiol 1996;169:159-66 8. Nakamura M, Ofuji K, Chikama T, Nishida T. Combined effects of substance P and insulin-like growth factor-1 on corneal epithelial wound closure of rabbit in vivo. Curr Eye Res 1997;16:275-8 9. Nakamura M, Chikama T, Nishida T. Synergistic effect with Phe-Gly-Leu-MetNH2 of the C-terminal of substance P and insulin-like growth factor-1 on epithelial wound healing of rabbit cornea. Br J Pharmacol 1999;127:489-97 10. Yamada N, Yanai R, Kawamoto K, Nagano T, Nakamura M, Inui M, Nishida T. Promotion of corneal epithelial wound healing by a tetrapeptide (SSSR) derived from IGF-1. Invest Ophthalmol Vis Sci 2006;47:3286-92 11. Chikama T, Fukuda K, Morishige N, Nishida T. Treatment of neurotrophic keratopathy with substance-P-derived peptide (FGLM) and insulin-like growth factor I. Lancet 1998;351:1783-4 12. Nishida T, Chikama T, Morishige N, Yanai R, Yamada N, Saito J. Persistent epithelial defects due to neurotrophic keratopathy treated with a substance pderived peptide and insulin-like growth factor 1. Jpn J Ophthalmol 2007;51:442-7 13. Yamada N, Matsuda R, Morishige N, Yanai R, Chikama TI, Nishida T, Ishimitsu T, Kamiya A. Open clinical study of eye-drops containing tetrapeptides derived from substance P and insulinlike growth factor-1 for treatment of persistent corneal epithelial defects associated with neurotrophic keratopathy. Br J Ophthalmol 2008;92:896-900
THE OCULAR SURFACE / JANUARY 2009, VOL. 7, NO. 1 / www.theocularsurface.com