Kenneth Polse is currently Professor of the Graduate School at UC Berkeley and the recently appointed Director of the Berkeley Clinical Scientist Development Program (BCSDP). In a teaching and research career spanning more than three decades, much of his research has been "translational," relying on teams of basic scientists and clinical researchers. Given his background and his recent appointment with the BCSDP, it seemed like a good time for an interview about Translational Research. [Interviewed by J. Fiorillo]

JF: We're going to explore "translational research" (TR) as it applies to the eye and vision. How would you define "TR"?
KP:  Translational Research can be defined as research that focuses on bridging the gap between laboratory discovery and patient care.

JF:  In your view, why is it so important for basic scientists and clinicians to become more involved in TR studies and clinical trials?
KP:  Exciting and potentially sight-saving discoveries are being developed at a unbelievably rapid rate. Unfortunately, there is an enormous gap between laboratory discovery and patient care. What we need are groups of basic and clinical scientists to work together to develop, evaluate, and, if appropriate, promote those discoveries that might improve eye care. This is best achieved by basic and clinical scientists working as a team and each contributing expertise with the common goal of improved eye care.

JF:  Have you seen an increase in interest among institutions that might fund future TR studies, especially at the federal level?
KP:  Good research is always fundable. The problem is that clinical research is subject to the same critical review process as is basic science research when competing for Federal funding, for example, with the National Institutes of Health (NIH). So here is the problem — although many clinicians have good ideas for research projects, they lack the training to develop the appropriate research protocols or experimental designs required to successfully compete for extramural funding.

JF:  I assume pharmaceutical companies might also become involved if the payoff were worth the investment. Do you think they could be interested, and how might translational researchers attract funding from the private sector?
KP:  Actually, clinician scientists do receive substantial funding from the pharmaceutical industry. This is how industry tests their products both in development and in the field. However, there is a potential danger in having drug companies sponsor research. First, there is always the concern over conflict of interest, and, second, drug companies tend to be less critical of the investigators' training and research approach. Both of these factors can and have led to incorrect conclusions. Unfortunately, there are too many examples of this in the public domain.

JF:  TR has its own recently established publication, the Journal of Translational Medicine. What about interest in TR on the part of other major research publications, such as the Journal of the American Medical Association — have they been giving more space for presenting the results of TR studies?
KP:  ARVO [Association for Research in Vision and Ophthalmology – JF] recently formed a task force to explore the feasibility of starting a Journal of Translational Ophthalmology. I believe there is a good chance it will happen. Other specialty fields will probably do the same.

JF:  I wonder, too, about political and public support for TR. Often the public has had difficulty with the idea of its tax dollars going to what they see as abstractions or knowledge-for-knowledge sake. They'd rather see their money spent on studies that have direct or obvious clinical benefits. Wouldn't TR fit nicely into such a paradigm?
KP:  Yes, the public will be able to easily relate to TR and believe that their money is well spent. However, it is important to remember that TR must be first-rate. Research that is directly applicable to the public welfare must still be done with the same scientific rigor as we find in basic research.

Metering changes in corneal fluorescence provided the basis for in vivo measurements of corneal pH, which in turn allowed the study of corneal response to low oxygen levels during contact lens wear (see below).

JF:  Would you mention some of the challenges facing basic scientists and clinicians in TR? For example, some scientists lack a sufficient understanding of what's required to apply their insights to the treatment of human patients. It's a problem of bringing novel ideas from the laboratory into the real world, isn't it?
KP:  I think there is lack of understanding on both sides. Clinicians do not fully understand basic science, and vice versa. That is why the most productive research will stem from the team approach. Because of the need to obtain funding, most basic scientists who seek NIH support will have a good idea of the key areas that need exploration. However, clinician scientists who work in the area would add to basic science discoveries by providing a more complete understanding of the area of intended study in relation to its public health significance.

JF:  Would you go so far as to say that without TR, few insights from the laboratory would ever prove useful to the clinician?
KP:  I would not go that far. Some new discoveries can have almost immediate applications and very little TR might be necessary. This would not be the norm, however, but it is possible.

JF:  It's intriguing to anticipate a world of research with an increasingly wide range of interdisciplinary collaborations. Could you identify the kinds of basic science disciplines that might offer potential discoveries for application to the clinical eye and vision setting?
KP:  There are many and I might miss a few as I run down the list. Basic science disciplines such as cell and molecular biology, engineering, chemistry, computer science, nanotechnology, neuroscience, physics, and experimental psychology are some that most investigators would agree could move clinical eye care forward. Remember, too, that each of these disciplines has subdivisions, so the basic science field is very large.

JF:  From a clinical perspective, what are some of the eye and vision problems that could benefit from TR studies and clinical trials?
KP:  When diagnostic protocol, preventative therapy, or treatment regimens appear to offer improvement over the current standards for the field, a clinical trial is usually warranted. Sometimes the trial needs to test a commonly believed but yet untested hypothesis regarding treatment, prevention, or diagnosis. For example, during the past 10 years, the field has seen some exciting clinical trials that have modified the way we diagnose and treat eye disease. One very good example is the study involving the treatment of ocular hypertension. Before this study, clinicians differed considerably about whether patients who had high intraocular pressure but no other signs of glaucoma (e.g., field loss or optic nerve damage) really needed to be treated. The Ocular Hypertension Treatment Study (OHTS) was a randomized controlled clinical trial which showed that lowering IOP does have a marked effect on the prevention of optic nerve morbidity. Early treatment should therefore be given to patients with high IOP and no other signs of glaucoma to lower ocular pressure. This is an excellent example of the importance of high-quality TR and how it might alter the way we treat patients.

JF:  I would imagine that unusual combinations of expertise from different scientific disciplines could lead to clinical applications hardly dreamed of just a few years ago. Would you agree?
KP:  Absolutely. It was not long ago that engineers and clinicians hardly communicated. In my own experience, the interaction of a petroleum engineer, the late Professor Irving Fatt, and several clinician scientists at Berkeley Optometry enabled us to carry out a series of basic and clinical research projects exploring the role of oxygen in contact lens wear. The basic science that Professor Fatt developed provided the foundation for many exciting and interesting experiments, such as determining critical oxygen levels needed to maintain normal physiology, the effects of hypoxia on corneal structure and function, and the effects of oxygen-permeable lenses on contact lens wear success. Without such a unique combination of talents, this most likely would not have happened. There are many other examples in the eye care field.

JF:  So you were one of the early pioneers on the Berkeley campus to engage in interdisciplinary collaborations related to eye and vision research. Could you tell us more about TR projects in your laboratory?
KP:  Several examples come to mind, but let me briefly discuss the Contact Lens Extended Wear Study (CLEWS), because it provides an excellent example of basic research leading to a translational study, which in turn led to new discoveries. Without going into too much detail, the CLEWS study, which was sponsored by the NIH, began with a series of basic science studies done in collaboration with Professor Joe Bonanno (now at Indiana University School of Optometry). We explored the effects of hypoxia on corneal pH using fluorometric technology. Joe developed a strategy for making human in vivo measurements of corneal pH. Considerable laboratory work was needed to develop the instrumentation and make the technique applicable to human testing. We verified that human corneal pH could be measured by metering changes in corneal fluorescence [see figure in column 1 – JF] and were able to develop a technique for testing on human subjects. The basic experiments provided sufficient evidence to formulate a hypothesis that insufficient oxygen levels (corneal hypoxia) led to altered corneal pH, which in turn caused changes in corneal health. Then we had to translate basic science into a clinical application. We did this using a randomized controlled clinical trial to study the outcomes of patients exposed to low and high levels of oxygen while wearing contact lenses for extended wear. The results of this study provided some very interesting outcomes and several clues about the pathogenesis of adverse responses to contact lens wear — such as infection and inflammation. So the project went from a basic laboratory discovery (that we could measure human corneal pH) to testing an important clinical hypothesis (that hypoxia causes corneal acidosis and leads to adverse corneal responses).

JF:  One concern among translational researchers is the limited communication from clinicians back to the basic scientists. In your TR projects, did you see reciprocal gains from the collaborations — in other words, did your cross-disciplinary colleagues also benefit from their work in the clinical realm, or apply what they learned to additional investigations in their disciplines?
KP:  Yes, the cross communication was critical to the success of many of my clinical studies. Outcomes resulted in additional basic science studies and vice versa. A good example is our tear mixing laboratory, where basic scientists from chemical engineering and clinical researchers at Berkeley Optometry have been working together to understand and eventually develop contact lenses that flush trapped debris more efficiently from under soft contact lenses than do most currently available soft lenses. The chemical engineers design hydrodynamic models to predict both eye and contact lens parameters that control tear flushing. From these studies, prototype lenses are developed to test the hydrodynamic model on human subjects. The clinical outcomes provide important feedback to the basic scientists, who adjust the hydrodynamic model and devise more prototype lenses for testing. So the process goes back and forth and, ultimately, there will be an improved contact lens.

JF: Let's turn to the Berkeley Clinical Scientist Development Program (BCSDP). I know that you and other faculty here at Berkeley are excited about it. First, would you describe briefly the organizational structure and goals of the BCSDP?
KP:  It's an important new clinical training program funded by the NIH. We have assembled some the best clinical scientists in the world to mentor experienced clinicians in patient-based eye and vision research. For most trainees this will be an opportunity for a career shift, allowing them to apply their clinical skills toward research as they acquire advanced, multidisciplinary training. When they complete the program, they are expected to compete for intramural funding. If the program is successful — and we expect it to be — it will help establish greater numbers of clinician scientists in eye and vision research. [See BCSDP]

JF: The BCSDP is funded by the NIH. Is the BCSDP a typical TR training program, or does it have any unusual components with respect to other eye and vision TR programs?
KP:  The BCSDP is perhaps more ambitious that other NIH clinical training programs. This is because we have been able to make use of the wide resources of the Berkeley and UCSF campuses with a group of outstanding mentors from many different disciplines. So it will be possible for clinicians to obtain intensive training in fields that may not be available in other programs. For example, there will be opportunities for clinician scientists to apply areas as diverse as ophthalmology, cell biology, epidemiology, chemistry, and bioengineering.

JF: I would assume that some of these mentors probably never thought about collaborating on vision research. What has been the reaction so far among the mentors?
KP:  Very exciting! When you think about it, these mentors are leading scientists in their field and their training can be easily translated over to eye research. An epidemiologist who has done no work in eye research could easily mentor a clinician in vision-related epidemiological studies. The same would be true in infectious disease, cell biology, engineering, and so on. This is what makes the BCSDP so exciting and enriching for the trainee.

JF: Have you seen a strong response from candidates wanting to apply to this new program?
KP:  We just began recruiting in January 2006, but the response has been very good. Of course, we're seeking highly qualified and talented clinicians who want to take on a career in academia or research. There are many challenges for the trainees considering this career shift, but I suspect that we will continue to have a healthy number of very qualified applicants.

JF: I know you don't have a crystal ball, but assuming the BCSDP and other TR training programs prosper in the next 5-10 years, how long do you think it will be before TR research provides significant innovative results that clinicians might use in the prevention, diagnosis, and treatment of eye and vision disorders and disease?
KP:  You are correct, I do not have a crystal ball, and if there's one thing I have learned over the years in my clinical research, it is not to be too presumptive about predicting the future course of events. However, having said that, I would guess it is going to take 10-15 years to train a sufficient number of clinician scientists before we will begin to see viable, full-scale optometric research programs in translational research. There are currently very few ODs who have the training to do cutting-edge research, and the available training programs only allow a small number of candidates. In most cases, the programs will require around five years of training, so you can see that it is going to take some time to develop a sufficient group of clinician scientists who can make a significant impact on programs within academic optometry and on clinical eye and vision research.

JF: Do you have any other comments that you would like to make?
KP:  You have not asked me what my dreams are for optometry relative to TR. Let me try to answer my own question. One important reason that optometry has moved forward over the years as a profession has been its solid research base to complement the clinical practice of optometry. For example, in my particular area, the basic and clinical science of contact lenses has made optometry pre-eminent in this area of practice. It is my belief that for our profession to continue to advance, we must maintain a strong research presence in the newer areas of practice in which the profession is not yet fully involved on a research basis, for example, the diagnosis and treatment of eye disease. In order to do this, we need both basic and translational scientists to move the research forward. Much of this can and should be supported by academic optometric institutions. But to realize this goal, both the profession and the leaders in academic optometry must be focused on training a critical mass of talented translational researchers to apply basic laboratory discoveries to patient care. My dream is therefore to see a well-trained group of talented clinical scientists within academic optometry who will teach, do cutting-edge research, and move the optometric profession in a positive direction. My concern, however, is that if we do not do this, we will become a profession of "medical technicians." For me, that would be a most unfortunate outcome. The bottom line is, for a profession to exist as an innovative and primary force, it must contribute to the knowledge base. So for a profession in the health sciences, this means an active and productive program in basic and translational research.

John Fiorillo, Editor
Principal Publications Coordinator

Kenneth Polse, OD, MS
Professor of the Graduate School
Director, BCSDP

For more about translational research, see the article on "A Beautiful Language" in the current issue of Berkeley Optometry Focus — Ed.