• Retina/Vitreous

    The practice of medicine has changed dramatically over the last few decades. It is far more complex and requires a wider scope of understanding than ever before. In part from major breakthroughs in our understanding of the pathogenesis of diseases, and partly from new molecular based therapies introduced into clinical practice, today’s young physicians leaving training must possess a much larger fund of knowledge than previous generations. For those trainees contemplating a career in academic medicine, the challenge is even greater.

    Traditionally, most physicians entering residency or fellowship programs have aimed to complete as much clinical training as possible so as to enter private practice able to provide the highest standard of patient care. But given the flood of evolving principles that guide the modern medical practice, are we now living in an era where the world of basic science merges with that of clinical medicine? Should we rethink our standard residency and fellowship training template? And if so, how should we change it?

    Molecular Biology and How We Practice Medicine

    Let’s consider these questions. Medical care up to the 1970s relied principally on the physical examination skills of the doctor. Yes, there were myriad diagnostic tests that physicians could order, but most of them were fairly simple in scope. However, in 1985, polymerase chain reaction (PCR) was introduced as a technique to study DNA, and suddenly everything about the practice of modern medicine changed (Clin Chim Acta. 2006;369(2):188–192). PCR, along with other technical breakthroughs, ushered in the era of molecular biology. Because of the rapid increase of these molecular innovations, clinical applications were swiftly realized. Suddenly, PCR became the standard for detecting and quantifying viral DNA. Clinicians were able to order a lab test and quickly determine the presence of viral infections for AIDS, herpes zoster and simplex, and a host of other viral diseases. PCR techniques were developed that detect other infectious agents, as well.

    Along with new diagnostic tools, molecular biology brought many novel therapies to the clinic. Although monoclonal antibody production was introduced in the 1970s, the more recent rapid emergence of treatments utilizing monoclonal antibody therapy resulted from advancements in molecular biology. Monoclonal antibodies specific for immune proteins such as anti-TNF-alpha (infliximab), anticancer strategies targeting the CD20 antigen on malignant cells (rituximab), and antineovascularization therapeutics against vascular endothelial growth factor (bevacizumab [Avastin]) along with a modified antibody containing only the Fab fragment of Avastin (ranibizumab [Lucentis]) are included today in the physician’s armamentarium (Clin Med. 2006;6(4):337–343). PCR and other genetic assays accelerated our understanding and knowledge of genetic disease not only for rare conditions but also for more common diseases such as age-related macular degeneration (AMD) (Science. 2006;311(5768):1704–1705).

    The era of personalized medicine based on genetic traits is already upon us, and our training curricula must reflect that reality. Take, for instance, the use of the anticancer drug trastuzumab (Herceptin). Trastuzumab, which targets the growth-factor receptor HER2, is used to treat breast cancer, but it is effective only in those women whose tumors express high levels of HER2 (Cancer Lett. 2006;232(2):123–138). The pathogenesis of disease is no longer described in histologic or descriptive terms but more often with molecular pathway modifiers. The intricacies of mutations or abnormalities in certain pathways are detailed and applied to many clinical diseases, the specifics of which typically utilize basic scientific terminology. Clearly, basic science has permeated the clinical realm, improving our ability to diagnose and treat patients, yet also demanding that clinicians possess a deeper level of understanding in the foundations of that very science.

    Updating Our Training Programs

    How should training programs for residents and fellows respond to this influx of knowledge? Do clinicians really need to “understand” PCR or a monoclonal antibody? From our perspective, the answer is a resounding yes. Physicians do need to understand the advantages and limitations of PCR, among other new advances.

    Unlike residency training of old, when young physicians were often required to perform a urinalysis or analyze blood smear from patients, it is not reasonable, because of time, complexity, and cost, for today’s residents to perform PCR. But an intricate understanding of the science behind that technology is essential. Residents and fellows need to know when and how often they might get a false positive or false negative, or when they should be cautious using monoclonal antibodies in patients. Should our residents be taught about the binding coefficients of these agents against their targets? Absolutely. Take, for example, the serum levels of an agent that enters the blood stream through an unexpected route, perhaps following an intravitreal injection. The affinity to molecular targets of many present and future agents is so high that even nanogram amounts of a drug can produce significant physiologic activity. It is critical that young physicians should understand this without hesitation.

    Should a basic science lab rotation be required as part of all residency and fellowship training? No—residents and fellows should not expend their energy actually doing the science. Should they be required to attend interactive lectures on the potentially relevant minutiae of molecular biology and how it might pertain to patient care? In our opinion, yes. An interactive discussion on PCR might reveal the problems with mispriming and how that leads to false-positive results. Or how quantitative PCR is limited by the target gene to be analyzed. Experts in monoclonal antibodies could be invited to discuss the pharmacodynamics of these agents, how they might enter the blood stream when injected intravitreally, and how, because of their high affinity, these agents might have actions that we still do not fully understand. Such discussions would provide doctors in training with the understanding they need for clinical practice in this environment.


    The practice of modern medicine is changing fast, and new clinical tools are being introduced at a rapid pace. Basic science concepts and techniques are now an integral part of clinical medicine. Physicians should have an understanding of the practice of basic science and its application in new drugs that are coming into the clinic and that are under clinical laboratory testing. We need to prepare our young physicians for the world of the 21 st century, a world that will be increasingly dependent on complex technologies and where an understanding of these technologies along with solid clinical training will produce physicians who will continue to excel in the future.


    1. Tsongalis GJ, Silverman LM. Molecular diagnostics: a historical perspective. Clin Chim Acta. 2006;369(2):188–192.
    2. Johnston S. Designer drugs: the biologic therapies. Clin Med. 2006;6(4):337–343.
    3. Marx J. Genetics. A clearer view of macular degeneration. Science. 2006;311(5768):1704–1705.
    4. Nahta R, Esteva FJ. Herceptin: mechanisms of action and resistance. Cancer Lett. 2006;232(2):123–138.

    Author Disclosure

    Dr. Csaky is supported by research grants from QLT, Inc., and is a consultant for Allergan, Inc., (OSI) Eyetech, and Novartis AG. Dr. Cousins is supported by research grants from Akorn, Inc., REPLICor, and Carl Zeiss Meditec, and is a consultant for Alcon, Inc., Allergan, Inc., (OSI) Eyetech, and Genentech, Inc. Both authors are on the speakers’ bureau for (OSI) Eyetech/Pfizer, Inc. They have no proprietary interest in any of the products or services discussed in this article.