The Shiley Eye Center Rising Star in the West

By Sean Henahan

The Shiley Eye Center, a relatively new arrival in the world of ophthalmology, combines a busy clinic covering all areas of ophthalmology practice with innovative basic science and bioengineering research. A philosophy of physician/scientist collaboration has produced important contributions in the field of ophthalmology, particularly in the areas of digital imaging, glaucoma and refractive surgery.

The Shiley Eye Center is a complex of buildings on the east side of the sprawling UC San Diego campus in the upscale coastal enclave of La Jolla. UCSD is surrounded on one side by the Pacific Ocean and on the other by an impressive array of research facilities. Notable neighbours include the Salk Institute and the Scripps Research Institute. The campus also abuts San Diego's thriving biotech and high tech corridor, home to dozens of start-ups and established biopharmaceutical companies, some of which got their start in the laboratories of UCSD scientists.

An Eye Center Built to Order
Stuart I. Brown, MD is the founder and chairman of the UCSD department of ophthalmology and Director of the Shiley Eye Center. When Brown first arrived at UCSD in 1983, ophthalmology was a small underfunded division of the department of surgery. Dr. Brown, a noted authority on cornea and anterior segment surgery, noted especially for his contributions in paediatric corneal transplants, made sure that ophthalmology immediately gained department status. Next, Dr. Brown set out to hire the best physicians he could find in the different areas of ophthalmology. He was looking for physicians with strong clinical credentials, but who also were interested in pursuing collaborative research at the most basic level.

"Our faculty is unique. My goal as the original recruiter was to find people who were young, smart, brilliant clinicians, but who also had the background and some kind of track record of basic research. Almost all of our faculty are quadruple threats. They see patients in large numbers, they have NIH grants, they teach and they carry out community service. My job has and will always be to provide them independence while supporting their efforts and goals," said Dr. Brown.

The Shiley Center receives only about seven percent of its budget directly from the State of California. The rest is made up of income derived from the clinic, research grants and from fundraising efforts in the community. The Center itself is the result of an impressive fundraising effort. The center is named after Donald Shiley and his wife, Darlene. Mr. Shiley, an engineer, invented the eponymous Shiley heart valve and is a philanthropist who contributed substantial funding to get the Center started.

Hollywood Connection
This being Southern California it is perhaps not surprising to hear of a Hollywood connection. Dr. Brown treated the infant son of Academy Award winning actor Richard Dreyfuss for a congenital corneal condition. After a dozen operations the child's sight was restored. A grateful Dreyfuss and wife rounded up support from hundreds of celebrities. This helped get the momentum rolling, encouraging additional contributions from the local business community.

With sufficient funding to back him up, Dr. Brown now had a dream assignment- to design and build a freestanding modern ophthalmology clinic from the ground up. Keeping in mind the new economies of outpatient surgery, the center was to accommodate the needs of the clinicians, researchers and patients who would occupy the building. For example, in order to optimize the size of OR suites and to provide the most efficiency at the least cost, the OR rooms were designed so that all of the electronics, venting etc. were installed on the ceiling, leaving ample room on the floor for any larger equipment that might be needed. Similarly, examination rooms were built of sufficient dimensions to allow a full array of screening tests.

"We have a very efficient facility. For example, we keep the patient on the same bed in the operating room and in recovery, allowing a smaller staff. <The original concept was that since all our surgery was outpatient we would not do inpatient procedures.> This concept continues to this day. That way we never needed the beds, the food or the oversight that goes with an inpatient facility. The rare trauma cases that require more extensive multi-disciplinary care are seen at the nearby UCSD Medical Center," Dr. Brown explained.

Innovative Glaucoma Research
One of the first 'young, smart, brilliant clinicians' hired by Brown was glaucoma specialist Robert N. Weinreb, MD. With engineering training at MIT, medical training at Harvard University and ophthalmology training at UC San Francisco, Weinreb embodies the Shiley Center ethos of the physician/scientist. Dr. Weinreb has authored more than 600 publications and is noted for contributing significant advances in the biology, pathophysiology, diagnosis and treatment of glaucoma. He is a member of 12 major editorial boards, and also is President-Elect of the Association for Research in Vision and Ophthalmology (ARVO) in 2001-2002.

"This is among the most stimulating scientific and professional environments in the world. At the Shiley Center, we have had the opportunity to interact freely with scientists and clinicians. We can maximize our potential and not be limited by formal boundaries," said Dr. Weinreb.

As Director of the Glaucoma Center at Shiley, Dr. Weinreb juggles a full clinical schedule with the demands of running a research laboratory and mentoring medical students and Residents. He also produces journal articles and makes regular appearances on the conference circuit. Under his direction, his department has developed some of the imaging modalities now standard today.

With collaborators psychophysicist Pamela Sample, Ph.D. and epidemiologist Linda Zangwill, Ph.D., significant and extensive contributions have been made to the development of the confocal scanning laser ophthalmoscope, the scanning laser polarimeter, and short wavelength (SWL) perimetry. Each of these technologies provides sensitive methods for structural and functional testing. With medical informatics specialist Michael Goldbaum, M.D., the results of these studies are being used to implement neural networks for detection and treatment of glaucoma. Moreover, some of these techniques now are being applied to discover and validate the first neuroprotective treatment of glaucoma.

Molecular Genetics
The UCSD glaucoma team has been a leader in the investigation of the molecular and cell biology of glaucoma. Weinreb has worked for 20 years to understand the cellular and molecular biology of the outflow pathway. With neurobiologist James Lindsey, Ph.D., an important cellular and molecular mechanism of prostaglandin action was discovered to explain how they lower IOP. They also have uncovered the molecular mechanism of iris pigmentation associated with the use of some prostaglandins.

His research team is now studying the potential for gene therapy to inhibit the proliferating cells of the episcleral scar that forms following glaucoma surgery, as well as investigating methods of delivering drugs to the optic nerve, retina and choroid via the sclera. <“Drug delivery methods to introduce peptides to the back of the eye could be very important not only in treating glaucoma, but also for ARMD and diabetes,” >he notes.

The Pathway Less Traveled
Considerable glaucoma research has focused on the route of fluid outflow provided by the trabecular meshwork. The secondary route, the uveoscleral outflow pathway, has been considered to be less important. Weinreb believes that it is time to reconsider the importance of the 'secondary' route.
"Some of the most important drugs that we now have for lowering pressure, such as latanoprost, have a major effect on this pathway. We've been directing our efforts at understanding the cellular and molecular mechanisms of the uveoscleral outflow pathway. We recognize now that this pathway might account for as much as half of the total outflow in some healthy and diseased eyes. We see an opportunity for improved treatment," emphasized Weinreb.

The Clinician-Scientist
Dr. Weinreb is a strong advocate of the clinician-scientist.<"We learn the most by having scientists interface directly with clinicians.> Being a scientist makes me a better clinician. It gives me insights into the underlying pathophysiology, pharmacology and basic biology of glaucoma that I might not otherwise have. These insights can then be translated into patient care. Similarly, being a clinician, makes me a better scientist because it enables me to ask clinically relevant questions and apply the clinical knowledge to answer those questions in the laboratory."

Pioneer in Refractive Surgery
The Shiley Center is at the epicenter of the highly competitive Southern California LASIK market. There are nine excimer lasers within a one-mile radius of the center. In this milieu, the Shiley Center is not a high volume center, averaging 100 to 150 cases a month. Rather, the Shiley Center concentrates on offering the highest quality of service for primary procedures, while also acting as a referral center for secondary refractive procedures.

"We are not a high pressure service. We mostly get referrals from other patients. We also do a lot of secondary LASIK, fixing problems from previous operations. While our LASIK volume is growing at maybe 10% year, our rate of treating problem cases is growing at a much higher rate," says David J. Schanzlin, MD, Director, Keratorefractive Surgery at Shiley. Dr. Schanzlin, immediate past-president, International Society of Refractive Surgery, was among the first surgeons to perform LASIK in the US.

"The kinds of things we are seeing are cases where the preoperative screening was not as thorough as it should have been. For example, we see patients who had pupils that were larger than the treatment zone, so they have problems with glare and halos at night. We also see patients who have wrinkles in the flap, where the flap was not refloated promptly. We are also seeing an increasing number of cases with corneal ectasia. This is a real concern. Creating ectasia is not doing these patients any favours. In most cases these problems could have been avoided with proper topography testing, and care," he noted.

Intacs
The Shiley Center is also involved with Intacs research in the US. Dr. Schanzlin and colleagues are concluding a phase III FDA study of expanded optical zone for INTACS™, evaluating treatment from -1.0 D to -4.5 D. In this regard, the US trails behind Europe and Canada, where this indication is already approved.

<"I'm very excited by the INTACS™ research coming from European researchers,> particularly Drs. Pallikaris, Saganos and Colin. They are looking at using INTACS™ as a way of strengthening the cornea in the ectatic situation. Dr Colin did the early work with keratoconus, managing to get patients off the corneal transplant list by putting INTACS™ in, with outstanding results. At our center we are conducting studies of INTACS for keratoconus, as well as ectasia after LASIK," Dr. Schanzlin said.

Star Wars, Astronomy and the Eye
Southern California has for many years been a center of aerospace and defence research and development. When President Ronald Reagan persuaded Congress to support his Strategic Defence Initiative, 'Star Wars' missile shield, considerable funding became available in the field of adaptive optics. Researchers in the UCSD Engineering School did some of the early work with adaptive optics in an attempt to eliminate aberrations created by the atmosphere. While the original research was first applied to laser targeting, it also soon found applications in astronomy, and eventually, in ophthalmology.

"At UCSD we have an astronomy group and an engineering group that continue to evolve this technology in their own fields. We have direct access to these spin-offs. We submitted a grant to develop a new way to do wavefront sensing that will give us online corneal topography and wavefront instantaneously. If this works we have a way to do a feedback system with our lasers that will allow us to measure, treat, measure and retreat for very accurate results. <Instead of focusing lasers to shoot down satellites, we can use that same technology to make eyes see better,>" Dr. Schanzlin explained. .

LASIK sans Microkeratome
Dr. Schanzlin's group is also involved with intrastromal laser research. He believes this tool, originally developed at UCSD, shows great promise for creating LASIK flaps more safely and accurately. Ongoing research at the Shiley Center is also evaluating the use of the intrastromal laser to make channels for INTACS™, as well as for creating intrastromal ablations for the treatment of hyperopia and myopia. This technology will also revolutionise many other areas of ophthalmic surgery including corneal transplants, corneal surgery and cataract surgery, he predicted.

Retina Division
Another early recruit at the Shiley Center was William R. Freeman, MD, Co-Chief of the Retina Division and director of the Joan and Irwin Jacobs Retinal Research Center at Shiley Eye Center. Starting with almost no resources, Dr. Freeman's efforts created a program that now brings in more than $1 million in grants per year. Those grants cover a wide range of basic and clinical research. While the retina clinic sees plenty of cases of common disorders such as macular degeneration and diabetic retinopathy, Dr. Freeman also designed the program from the beginning to make sure less common diseases such as CMV retinitis, ocular cancer and ocular albinism were not neglected.
Working with HIV clinical researchers at UCSD, Dr. Freeman and colleagues developed some of the treatments now standard for CMV retinitis. In particular, his group did the research supporting the use of intraocular therapy for CMV retinitis, work that eventually moved the field away from the use of toxic systemic therapy. The research continues, with a number of new antiviral compounds under evaluation.

The idea of using local therapy carried over into research now being conducted on the treatment of ARMD and other diseases. A major focus of the research is the development of anti-angiogenic compounds and the vectors with which to deliver them directly to the eye. In collaboration with UCSD gene therapy researchers Dr. Theodore Friedmann and Flossie Wong-Staal, MD, Shiley researchers are evaluating several compounds that could block new vessel growth not only in ARMD but also in diabetic retinopathy, retinopathy of prematurity and in ocular tumours.

<"It is becoming clear that we will probably need multiple angiogenesis inhibitors to treat these diseases.> It is unlikely that one would do the job. That is where a center like ours comes in. It would be unlikely for any single company to work with two different drugs and get a combination treatment through the FDA approval process. We provide a neutral center of excellence, where we can get the research going. Location really matters. We are surrounded by a lot of biotechnology companies, and can also draw on the resources of this great university," said Freeman.

Zapping Drusen
Freeman’s group is also part of a group in the US studying the potential of the pulse diode laser for treating drusen. After the incidental observation that drusen faded spontaneously in the eyes of patients receiving laser treatments, subsequent research revealed that laser treatment appeared to stimulate immune cells to phagocytose the drusen. Clinical studies conducted at the Shiley Center also showed that the drusen fade with less intense treatment using the IRIS pulsed diode laser. This suggests it may be possible to effect retinal pigment epithelial cells without effecting the rods and cones. An ongoing study could help reduce the incidence of choroidal neovascularization.

Ongoing projects are looking at everything from second generation photodynamic therapy and retinal translocation surgery to oral fluorescein as an alternative to the intravenous route for angiography.

Informatics, Please
Michael H. Goldbaum, M.D. is Co-Chief of the Retina Division at the Shiley Center. An original faculty member chosen by Dr. Brown, he is best known for his pioneering work in the development of silicone oil for the treatment of macular holes. More recently, Dr. Goldbaum has become the guru of informatics at the Shiley Center. Consulting with Dr. Terri Sejnowski, a leading expert in neurocomputing at the Salk Institute, Dr. Goldbaum is working with Shiley’s Drs. Weinreb, Linda Zangwill and Pamela Sample on developing 'smart systems' that can aid diagnosis of a current case by computerized analysis of digitized images of the ocular fundus.

Straying from retinal medicine, Dr. Goldbaum also collaborates with glaucoma researchers. One of his projects involves the development of artificial neural networks to improve measurement of visual fields One of the goals is to streamline the process of testing for glaucoma.

<"We are aiming for earlier detection and better prediction.> A lot of good data have accumulated over the years not only in glaucoma but also in cornea and other fields of ophthalmology. That data has information in it that people haven't been able to extract. That is what we are trying to do now, says Dr. Goldbaum.

Ophthalmology Meets Engineering
Dirk-Uwe Bartsch has been involved with many of the largest research projects at the Shiley Center, in areas ranging from refractive surgery to glaucoma and retinal diseases. Yet Bartsch is not a physician but an engineer. No occasional collaborator, his office and laboratory are squeezed in among basic science labs and clinical facilities at the Shiley Center.

Dr. Bartsch began his US research career as one of a number of scientists studying laser imaging in ophthalmology and adaptive optics. Post-doctoral research in the early days of the Shiley Center blossomed into a long-term relationship.
"We have a unique opportunity here to have patient interaction and contact. Before, when I was working in the bioengineering department at UCSD, in many cases we didn't really know what the end use of the project was that we were working on. Here at the Eye Center we have the immediate need to help a particular disease or even a particular patient. That is a much more direct system of interaction. The great thing is that if we need additional resources that the normal ophthalmology department can't offer, we have an entire engineering school to rely on," notes Dr. Bartsch.

Dr. Bartsch was a key figure in the development of the confocal scanning laser ophthalmoscope for angiography. That instrument is now commercially available as the
Heidelberg Retina-Angiograph.

"Years ago, we had the idea based on a specific clinical need where we wanted to be able to do an ICG (Indocyanine green) angiography, but we were not happy with any of the existing instruments. So we asked Heidlelberg Engineering to build the instrument to our specifications. We were extremely happy with the instrument," notes Dr. Bartsch.
Shiley Center researchers continue to collaborate with colleagues in Europe. After developing an instrument for retinal topography, some of the researchers at Heidelberg Engineering, GmbH in Dossenheim, Germany came to UCSD to assist in the first clinical trials of that instrument. The German company subsequently set up an American company (Heidelberg Engineering, Inc.) not far from UCSD.

Dr. Bartsch's interest in adaptive optics continues. He recently received an NIH (US National Institutes of Health) grant to study the application of adaptive optics in ocular melanoma. His ongoing work suggests that the scanning laser ophthalmoscope provides sufficient resolution to visualize circulation inside the tumor. This suggests it may be possible to use this tool to improve prognoses in these patients, helping to determine whether the tumour is slow or fast growing. This information could guide clinicians on the use of radiation treatment. The NIH grant will enable Bartsch to attempt to improve the resolution of the instrument through the use of adaptive optics.

European Perspective
Dr. Bartsch is a native German with permanent resident status in the US. He received his undergraduate education in Germany and both his M.S. and Ph.D. in Bioengineering at UCSD. He was recruited to the Shiley Center while doing post-doctoral work in the department of ophthalmology. This background gives Bartsch a unique perspective on the research culture at UCSD:

"The culture of California is very innovative. There is a frontier mentality that encourages risk taking. This helps us to start new research projects. Several of my European colleagues have come over here to start research because it so much easier to start something new. In Europe, for example, it would take from one to two years to get approval for a study of a new drug. Our turnaround is quicker here. We can get the OK from a review committee within a month. It is also much easier to get funding here."

Meeting the Many Needs of Thyroid Patients
Patients visit from around the world to take advantage of another specialty center within the Shiley Center, the Thyroid Clinic. The clinic brings together in one place all of the specialists a thyroid patient might need, including an oculoplastic surgeon, Don Kikkawa, M.D.; a neuro-ophthalmologist, Leah Levi, M.D.; and strabismus specialist, David Granet, M.D. In this way they provide coordinated care for the full range of ocular problems experienced by patients with thyroid disease.

After a thorough screening examination, patients are followed for several months to determine disease stability. Patients who have severe exophthalmos might first undergo orbital decompression to alleviate the pressure and disfigurement. Secondly, if patients have any misalignment of the eyes causing diplopia, strabismus surgery is performed, if necessary. Finally, eyelid surgery is performed to deal with retraction and excess soft tissue.

Dr. Kikkawa has recently submitted a manuscript studying graded orbital decompression based on exophthalmometry values. "We have found that we can tailor the amount of decompression necessary to achieve predictable symmetric results, minimizing complications."

"We realized that patients with ophthalmology-related thyroid problems would be seeing three specialists or more. It occurred to us that if we could get the three of us in the same place at the same time, we could benefit patients. We work together to plan each patient's care. The results have been spectacular. We make a point of making the patients part of the team. <The days of the doctors talking among themselves in lowered voices while the patients wait really are over,"> said Dr. Granet.
Dr. Granet has developed an enhanced adjustable suture technique to help align the eyes.

This allows the surgeon to move the sutures more easily during the post-operative adjustment period. The enhanced procedure allows the surgeon to wait for several days after the surgery, allowing the patient to recover. This means patient comfort is enhanced, and the results are better, says Dr Granet, adding:
"When you operate on an adult and get their eyes straight again and they come back and tell you they got a promotion, or got married, or are simply able to look people in the eyes now, it makes your day. You feel you have accomplished something. That is a special part of what we do."

The Thyroid Eye Center also conducts leading research. Current projects include an ongoing study of the use of Botox (botulinum toxin) for treatment of strabismus and as an adjunct to orbital decompression."We are also studying the psychological issues, such as depression, that are associated with thyroid disease," notes Dr. Levi.
Ratner Children's Eye Center

Dr. Granet also wears another important hat at the Shiley Center, as Director of the Abraham Ratner Children's Eye Center. One of the few free standing paediatric eye facilities in the world, the Ratner Center was designed specifically to enhance the experience of the child, while providing state of the art facilities
The Ratner Center sees a steady stream of young patients with amblyopia, strabismus, routine refractive errors, as well as patients with more extreme conditions such as retinopathy of prematurity, and genetic and craniofacial disorders.

Dr. Granet believes that amblyopia and most refractive problems are best treated with the conventional approach, that is, patching and spectacle correction, based on the patient's needs. He is not an advocate of using LASIK in paediatric patients, except in exceptional circumstances.

<"We are very concerned about the use of LASIK and related procedures in adolescence.> However, too many parents might opt for the “easy way out”. With good compliance we have great success with standard treatment. Kids are growing animals. We have no idea what the long-term effects might be. Young children with amblyopia should be the last ones to get LASIK, at least until we can get more data," he stressed.

Community Outreach- the Heart of the Shiley Center
Community outreach and education are one of the core values Dr. Brown introduced at the founding of the Shiley Center. The Center sponsors two comprehensive programs in the Greater San Diego area that target two neglected groups at either end of the age spectrum- preschool students and the elderly with age-related eye diseases.

As the Director of Community Ophthalmology Outreach and Education Programs at the Shiley Center, Barbara Brody, M.P.H., has developed a number of outreach programs for patients with ARMD. Under her guidance, a registry of thousands of people with ARMD in San Diego County has been underway for three years. That program compiles demographic information and promotes improved community access options for ARMD patients. Participants also receive newsletters at no cost that keep them up to date on the latest research and treatment developments.

<"We now have a San Diego county registry of almost everyone who knows they have macular degeneration.> Using computerized geographic information system (GIS) mapping, we have a database of information on where people live in terms of the nearest highways, bus routes, grocery stores, and hospitals. This makes the registry a powerful advocacy tool for us to use to help make the community more aware and to bring them sorely needed transportation. We are working with local authorities to encourage them to make some accommodation to vision-impaired people in terms of lighting, marking curbs, elevators- anything that is impediment to functioning," she said.

The Community Ophthalmology team has also received a grant from the National Eye Institute to study the psychological effects of ARMD of patients and evaluate the potential benefits of psychosocial intervention. Brody has already developed a model intervention for providing group support and self-management tools in order to help patients live with advanced macular degeneration.

Free Preschool Screening and Treatment
Brody also oversees an innovative community program that aims to screen and assure needed follow-up care for every preschool child in San Diego for amblyopia and other eye disorders. Children are screened at their preschools by multilingual screening technicians and student volunteers. The program recently launched an 'EyeMobile' to make the rounds of preschools, starting with those in economically disadvantaged areas. The EyeMobile is a mobile eye clinic containing everything needed for follow up care for children who fail vision screening. The EyeMobile is staffed by a multilingual paediatric optometrist, a clinic manager-driver, multilingual screening technicians, and student volunteers.

The program can screen and treat up to 60 children per day. If a child needs glasses and cannot afford them, the glasses will be made right on the spot and delivered to the child. Patients with amblyopia will be followed and referred to appropriate treatment.
<"It is very exciting to be able to get involved with the prevention and detection of childhood eye disorders.> Data indicates that only one third of US children under the age of three are screened for amblyopia and other problems. The program will help us reach these young children while we have the chance to do the most good. We get so much of our support from the community, I feel it is essential that we give something back in the form of outreach, research and community service," says Dr.Brown.

Expanding Horizons
The Shiley Center sees some 50,000 patients per year. The rate is growing at 15% per year. Patients come from around the world to take advantage of the broad range of facilities available. The Center has outgrown its original facilities faster than anyone thought possible. Plans are already underway to make significant additions. Ground has now been broken for two new buildings that will expand the space available for both research and clinical work in the glaucoma and retina divisions.