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Foreword

Translational research offers both the opportunity and the challenge for medical research in the decades ahead, as physicians and clinician-scientists work to understand disease by utilizing the vast storehouse of detailed biological information that has been uncovered about the eye and visual system. Ultimately, the practice of medicine, and delivery of care to ameliorate disease, advances best and most effectively upon understanding the causative pathophysiology, as is addressed in this book.

I am delighted to see the advances represented in the chapters of this book. While no one volume can encompass the entirety of the clinical medicine of ophthalmology, the editors have assembled a broad and expert group of clinician-scientists who have written thoughtfully and cogently on many topics of modern ophthalmic disease research. These chapters are multidisciplinary and provide a good source of current knowledge. Clearly much work lies ahead of us to fully understand the causes, biological mechanisms and treatments of ocular and vision diseases. This book, Ocular Disease: Mechanisms and Management, provides a substantial starting point to launch insightful studies that will move our field even closer to rational therapeutics.

One of the drivers of this new understanding of disease comes from the vigorous work of the vision research community over the past two decades, which has led to identifying more than 500 genes that cause Mendelian ocular diseases. These genes encompass a wide assortment of conditions that clinicians diagnose and treat, and no tissues are spared. We have identified genes that cause retinal and macular degenerations, glaucoma, uveitis, cataract and corneal dystrophies, optic neuropathies, and amblyopia, strabismus and ocular motility disorders.

Disease gene discovery recently advanced into the previously intractable realm of the more common and widespread conditions that have genetically complex etiology. In 2005 several groups independently identified the first gene that conveys substantial risk for developing age-related macular degeneration, the complement factor H gene. Shortly thereafter several additional AMD risk genes were identified in the immune pathways, including complement modulatory factors, using the new and powerful techniques of haplotype mapping and genome-wide association studies. This new basic knowledge forced our attention toward the immune cascade as harboring mechanisms that culminate in vision loss from macular degeneration in as many as one in seven of the elderly.

As disease gene identification rocketed ahead, attention turned to genomics and studies of the expression, cellular localization and biological function of the aberrant gene products. It is these considerations that the present book addresses, for ultimately a true understanding of disease mechanisms, in many cases, lies buried within the genomic biology of these diseases.

Studying any one of these genes requires major effort to piece together an understanding of the relationship between gene and disease. Consider, for example, the TIGR/MYOC gene that encodes the protein myocillin that is expressed in the trabecular meshwork. Mutations in this gene result in early onset or even congenital dysregulation of intraocular pressure and leads to severe glaucoma in humans. Yet laboratory-created mice carrying the myocilin gene knockout show only a minimal phenotype. Two lessons are immediately apparent: first, we have a long path ahead to translate genetic discoveries into identifiable mechanisms of disease and pathophysiology that will support rationally designed therapeutic interventions. Second, although our field of eye disease research is amazingly rich in mouse models that generally mimic the human condition with good fidelity across a variety of ocular conditions, the fullest understanding of human disease mechanisms ultimately will require that we turn our attention directly to careful and detailed analysis of disease in human patients, as is considered in this textbook.

The future for treating diseases of the eye and visual system will require novel insight into disease biology. But already we can see major areas of opportunity to employ a new range of therapeutic interventions, from gene therapy to stem cells for regenerative medicine. This new book is the medical companion to the basic textbook Adler's Physiology of the Eye. This companion volume by Levin and Albert tackles the translation of basic knowledge into the realm of medical understanding and practice and thereby highlights that the best of basic and clinical knowledge increasingly have an interdependent existence and future.

Paul A. Sieving, MD, PhD

Director, National Eye Institute, NIH

Bethesda, MD

September 2009