Ординатура / Офтальмология / Английские материалы / Retinal Degenerations biology, diagnostics, and therapeutics_Tombran-Tink, Barnstable_2007
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Retinal
Degenerations:
Biology, Diagnostics, and
Therapeutics
EDITED BY
Joyce Tombran-Tink, PhD
Colin J. Barnstable, DPhil
RETINAL DEGENERATIONS
OPHTHALMOLOGY RESEARCH
JOYCE TOMBRAN-TINK, PhD, AND COLIN J. BARNSTABLE, DPhil
SERIES EDITORS
Retinal Degenerations: Biology, Diagnostics, and Therapeutics, edited by Joyce TombranTink, PhD, and Colin J. Barnstable, DPhil, 2007
Ocular Angiogenesis: Diseases, Mechanisms, and Therapeutics, edited by Joyce TombranTink, PhD, and Colin J. Barnstable, DPhil, 2006
RETINAL DEGENERATIONS
BIOLOGY, DIAGNOSTICS,
AND THERAPEUTICS
Edited by
JOYCE TOMBRAN-TINK, PhD
and
COLIN J. BARNSTABLE, DPhil
Department of Ophthalmology and Visual Science,
Yale University School of Medicine,
New Haven, CT
© 2007 Humana Press Inc.
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Library of Congress Cataloging-in-Publication Data
Retinal degenerations : biology, diagnostics, and therapeutics / edited by Joyce Tombran-Tink and Colin J. Barnstable. p. ; cm. -- (Ophthalmology research)
Includes index.
ISBN 1-58829-620-2 (alk. paper)
1. Retinal degeneration. I. Tombran-Tink, Joyce. II. Barnstable, Colin J. III. Series. [DNLM: 1. Retinal Degeneration. WW 270 R438239 2007]
RE661.D3R482 2007 617.7'35--dc22
2006024144
PREFACE
For centuries, humans have tried to explain the complex process of vision and find effective treatments for eye diseases. Perhaps the oldest surviving record of ancient ophthalmic practices is the Babylonian code of Hammurabi that over 4000 years ago, mentioned fees for eye surgery—and penalties for unsuccessful operations that led to loss of the eye. Babylonian medicine was controlled by priests who directed the work of skilled surgeons. The earliest records of Egyptian medicine date from almost the same time. The Ebers Papyrus, dating back to more than 3500 years ago is a superbly preserved document in which a section outlines a relatively advanced system of diagnosis and treatment of various ocular pathologies. The text reveals that ancient Greek and Egyptian physicians prescribed “liver juice” for night blindness. This was obtained from roasted and crushed ox liver. We now know that their prescription contained a remarkable amount of vitamin A. It was only within the last century, however, that we have recognized the importance of vitamin A to the function of photoreceptors and visual acuity and that its deficiency can result in night blindness.
Egyptian ophthalmological practices were held in high esteem in the ancient world and so were their medical institutes, called “peri-ankh,” which existed since the first dynasty. Herodotus, the fifth century BC Greek historian, comments on the specialization of the physicians: “Each physician treats just one disease. Some treat the eye, some the teeth, some of what belongs to the abdomen and other internal diseases.” The profession was so organized that there were even specific titles to describe the physicians: “swnm” for the Lay Physician, “imy-r swnw” for the Overseer of Physicians, “wr swnw” for the Chief Physician, and “shd swnw” for the Inspector of Physicians. Qualified female physicians were also popular at the time. Peseshet (imyt-r swnwt), the first documented female physician in history, practiced during the fourth dynasty and was given the title “Lady Overseer of the lady physicians.”
Many ocular diseases and their treatment were also known in Asia as well. During the golden age of his reign, the Yellow Emperor (2696–2598 BC) of China composed his Neijing Suwen or Basic Questions of Internal Medicine, also known as the Huangdi Neijing. Within this text are descriptions of eye diseases including descriptions of floaters within the eye, small eyes, corneal diseases as well as the use of needle penetrations to alleviate some diseases. Modern scholarly opinion holds that the extant text of this Treatise was compiled by an eponymous scholar between the Chou and Han dynasties more than two thousand years later than tradition reports, although some parts of the extant work may have originated as early as 1000 BC.
Although medical specialties were highly developed in Egypt and in other parts of the world, progress in the field remained static for centuries because ancient medical practices were bound by galling fetters of supernatural beliefs, and rigid notions that the disease originated from hostile spirits and angry gods stifled innovative observations.
Nevertheless, it is still fascinating to examine a few of the ancient theories and to compare them to our modern knowledge. Interest in how the human visual system works
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dates back at least to the time of Aristotle, the prominent fourth century BC philosopher. His explanation for the mechanism underlying human vision was that the object being viewed altered the “medium” between the object and the eye of the viewer. The object is then perceived when the altered transparent medium propagates to the eye, suggesting that the object itself had innate properties that allowed vision. Democritus (425 BC) proposed that the emissions from the object viewed entered the eye and formed an image, but could not explain how a single object could generate enough emissions to create sight if many people were viewing it simultaneously. Vigorous debates ensued and the intromission perception of vision, accepted by scholars such as Democritus and Epicurus (342–270 BC), was refuted and replaced by an opposing view that the eyes sent out emissions to the object in view and that those rays promoted vision. Plato (427–347 BC) introduced the concept of “ocular beams” projecting from the eye at great speed and in a straight line to interact with objects in view. The objects deflected the beams back to the eye, which, in turn, transmitted these rays along hollow tubes connecting the eye with the brain to create sight. The extromission model of visual cognition then became a widely accepted scientific dogma by many scholars and persisted until the early 1600s, although not without challenge and modifications from theorists who had difficulties integrating this proposal with prior beliefs. Aristotle pointed out that it was unreasonable to think that a ray from the eye could reach as far as the stars and Galen (AD 129–AD 216) argued that larger images could not fit through the tiny pupils of the eye. Alexandrian vision theorists considered the lens to be the seat of vision, a view that Galen promoted when he found the retina lining the posterior aspect of the lens in a strategic position to serve as a mirror to reflect the object viewed. Needless to say, speculation was rife and sparked much controversy and the schism was too wide to be easily bridged. Although inaccurate, these early concepts have spawned our interest in developing experimental scientific methods from which we have gained our understanding of the visual process today.
It must also be noted that during the Dark Ages of Western civilization, knowledge of the eye and eye diseases was maintained and developed in the Arab world. Ophthalmic departments were important components of hospitals and many surgical procedures
perfected. The earliest anatomical drawings of the eye are in Hunayn ibn Ishâq’s Book of the Ten Treatises on the Eye. After the fall of the Roman Empire, Arabic philosophers
carried on Greek science and mathematics. One of the greatest of these Arabians was Alhazen (965–1040), who defended the intromission concept of vision. He was the first to propose that the eye is a receiver, a dark chamber through which light enters carrying information from the outside world. He argued that if the air and the eye are transparent, light from objects would reach and enter the eye; therefore, visual rays are unnecessary to explain vision (Alhazen’s De aspectibus). Translations of Arab ophthalmic texts into Latin promoted the revival and development of ophthalmology that occurred in the renaissance period in Europe.
By the 1600s, Leonardo da Vinci (1452–1519) and Felix Plater (1536–1614) largely
promoted a historical shift in thinking by endorsing the concept of a “camera obscura” in vision. Felix Plater’s De corporis humani structura et usu of 1583 is the first published
work in which the retina is identified as the target of light—“the retina and not the lens was the receiving plate of the eye.” Alessandro Achillini (1466–1533) may have been the first to challenge the idea of the crystalline lens as the main organ of sight. In 1543,
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Andreas Vesalius’ De humani corporis fabrica alluded to the retina as the “seat of vision” as well, but it was not until the 17th century that modern theories of vision and the role of the retina in this process was born as the focus shifted from the lens and the cornea to the retina as that structure of the eye required for the detection of light. Johannes Kepler of Germany and René Descartes of France, both avant-garde physicists of their time,
applied the physical concepts of light rays and geometric optics to the visual process. As a result Kepler, in Ad Vitellionem paralipomena (1604), proposed that the lens re-focused
intromitted rays on the retina, creating a real optical image which he called “pictura.” This proposal was quite controversial and stirred up yet another debate in the scientific community since it had long been accepted that if rays were crossed within the eye, the image created would be reversed and inverted causing us to see the world upside down. This dilemma of vision was recognized since antiquity, and scholars such as Fabri de Peiresc (1580–1637) and Pierre Gassendi (1592–1655) of France set out to refute Kepler’s retinal inversion hypothesis. Their experiments eventually culminated in a proposal for the existence of a “retina mirror” that would upright the image on the retina by reflecting it back toward the center of the eye. Others such as Christopher Scheiner were among the first to embrace Kepler’s optical analogy of the eye and the camera obscura and, in 1619, he provided the first direct observation of image formation on the retina. The theory that the retinal image is inverted was eventually confirmed by the landmark experiment of Descartes in 1637, which showed the first direct evidence that visual images were inverted as a result of being focused onto the retina by the lens. What Descartes did was quite amazing. He surgically removed an eye from an ox, scraped the sclera from the back of it to make the orb transparent, then he placed the eye on the ledge of a window as if the ox were looking out of the window. He then looked at the back of the eye and saw an inverted image of the scenery outside.
At the end of the 18th century, however, our knowledge of the retina was still rudimentary. Although Briggs described fibers in the retina in 1678 and Mariotte identified the blind spot in 1681, it was not until 1819 that the astute Irish physician, Arthur Jacob, provided us with the first anatomically detailed description of the retina. Jacob described the retina as “the most beautiful specimen of a delicate tissue which the human body affords.” He described a layer in the eye consisting of three sublayers: a limiting, a nervous, and a choroid layer. The nervous layer, which became known for a time as “Jacob’s Membrane,” consists of the rods and cones.
Identification of the rods and cones, however, should probably be credited to Leeuwenhoek, pioneer of the microbe world, who was the first to perform microscopic examination of the retina and noted images of these cells during his studies in 1684. These highly specialized photoreceptors were rediscovered in 1834 by Treviranus and so named because of their microscopic appearance. Perhaps one of the greatest achievements in cell biology that promoted his findings was the development of the compound microscope. A new realm of observation was ushered in with the increasing technical sophistication of this instrument and largely brought about the dawn of the cellular theory and our knowledge of the retina.
The pace quickened in the last 200 years, and our understanding of the visual process has increased dramatically since Aristotle, Plato, and Galen. What followed was a series of significant advances in retinal biology. Additional research showed that the rod and cone cells were responsive to light. Max Schultze (1825–1874) discovered that the cones
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are the color receptors of the eye and the rod cells are not sensitive to color but very sensitive to light at low levels. Helmholtz invented the ophthalmoscope in 1851. Then in 1854, Mueller proved that photoreception occurs in the rods and cones. In 1866, Holmgren discovered the electroretinogram. In 1893, Ramon y Cajal’s “La retine des vertebras” was the first complete description of retinal neuroanatomy as revealed by Golgi stain. This work, which carefully classified retinal cell types by anatomical criteria, remains the benchmark of retinal anatomy and in the century following its publication, we have come to appreciate that almost all of Ramon y Cajal’s retinal cell types can also be identified by unique sets of molecular and physiological properties. In 1925, Holm demonstrated that vitamin A deficiency causes night blindness. The chemical structure of vitamin A and its precursor, β-carotene, was unraveled in 1930 by Swiss researchers. In 1933, Wald found vitamin A in rhodopsin, Stiles and Crawford demonstrated directional sensitivity of rods and cones, and Cooper, Creed, and Granit demonstrated the first electronically amplified human electroretinogram. In 1938, Selig Hecht showed the exquisite sensitivity of rod cells by demonstrating that a single photon can initiate a response in a rod cell.
Identification and understanding of retinal diseases has lagged behind that of diseases of the cornea and lens, but closely followed the increasing knowledge of retinal anatomy. Color blindness was first described in detail by the English chemist and physicist John Dalton (1766–1844). Many of the degenerative diseases were carefully described only toward the end of the 19th century through the first half of the 20th Century. For example, Retinitis pigmentosa was first described clinically in 1853 by van Trigt (1), X-linked forms of the disease by Usher in 1935 (2), and X-linked retinoschisis by Haas in 1898 (3). Hutchinson and Tay (1875), and Robert Walter Doyne (1899), were the first to describe whitish spots (drusen) in the macula, a condition frequently leading to age-related macular degeneration.
Discoveries made in the last two centuries have increased our understanding of how the retina works at the biochemical level and therapeutic strategies that should be developed to slow its dysfunction. We have come a long way since the discovery of the rods and cones. In the last few years, we have seen convincing results from experiments conducted in the laboratory and in clinical trials with growth factors, micronutrient supplements, antibodies, and small molecules that offer hope for retinal degenerations. We have made advances in nanotechnology, cell and molecular biology, ocular genetics, gene manipulation and delivery methods, and cellular transplantation, which now have wide-range implications for the future of blinding eye diseases.
The early pioneers who preceded us in the field were at the vanguard of science during their time and their investigative approach laid the foundation for mature scientific discovery and for the development of new therapies to combat retinal degenerative diseases. Regrettably, despite these advances, few therapies lived up to their alleged claims or to the hope that they aroused. Clearly, there are numerous difficulties encountered in developing treatments and we cannot predict which therapy will result in the best outcomes, but it is important that we continue to foster collaborative efforts to pursue several distinct therapeutic initiatives. It is our goal to continue at the frontline of science with the same passion, persistence, and vision as our forerunners. We hope that our contemporaries in
the lab, the clinic, and the industry will be challenged by the recent advances described in Retinal Degenerations: Biology, Diagnostics, and Therapeutics by respected leaders
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and by the potential to develop innovative strategies to translate investigative research into viable therapeutics for retinal diseases.
Joyce Tombran-Tink, PhD
Colin J. Barnstable, DPhil
References
1.van Trigt, A.C. (1852–1853) De oogspiegel. Nederlandisch Lancet, third series, Utrecht, 2d, 417–509.
2.Usher, C.H. (1935) On a few hereditary eye affections. Trans. Ophthal. Soc. UK 55, 164–245.
3.Haas, J. (1898) Ueber das Zusammenvorkommen von Veraenderungen der Retina und Choroidea. Arch. Augenheilkd. 37, 343–348