Visual Pigment Molecules and Retinol Isomers: the Work of George Wald
Year: 2005
Type: article
Abstract: The Neo-b Isomer of Vitamin A and Retinene (Brown, P. K., and Wald, G. (1956) J. Biol. Chem. 222, 865–877) George Wald (1906–1997) was born in New York City. He had an aptitude for mechanics and science from a very young age and was able to successfully construct a crystal detector radio that enabled him and his friends to listen to the 1919 World Series. Wald also had an interest in vaudeville, and he and a friend organized an act that they took to nearby Jewish community centers. His success as a performer suggested a possible future career in law and so he entered Washington Square College of New York University as a pre-law student. However, he soon found that his pre-law studies didn't interest him and felt the need for something “more substantial, more natural, more organic” (1Dowling J.E. Biographical Memoir of George Wald. 78. National Academy of Sciences, Washington, D. C.2000: 298-317Google Scholar). He became a pre-medical student. But by the time Wald was a senior, he had lost interest in his medical courses. Fortunately at this time he happened upon Sinclair Lewis's Arrowsmith and decided to do biological research. After graduating in 1927 he applied to Columbia University for graduate studies in zoology. As a graduate student, Wald worked on the visual performance of Drosophila and human dark adaptation with Selig Hecht. Wanting to know more about the molecules involved in the photoreceptor process, Wald decided to work with Nobel laureate Otto Warburg in Berlin after receiving his Ph.D. in 1932. With Warburg, Wald began to work on rhodopsin. Believing that rhodopsin was a carotenoid-linked protein, he extracted some retinas with chloroform and reacted the extract with antimony trichloride. The solution turned bright blue and had an absorption curve typical of vitamin A (2Wald G. Vitamin A in eye tissues.J. Gen. Physiol. 1934–1935; 18: 905Crossref Scopus (40) Google Scholar). Because vitamin A had just been isolated by Paul Karrer in Zürich, Wald went to Karrer's laboratory to verify his results. In just 3 months, Karrer and Wald confirmed the presence of vitamin A in cow, sheep, and pig retinas. After completing his research in Zürich, Wald went to Heidelberg to work with Nobel laureate Otto Meyerhof, who was featured in a previous Journal of Biological Chemistry (JBC) Classic (3Meyerhof O. Junowicz-Kocholaty R. J. Biol. Chem. 1943; 149 (JBC Classics): 71-92Abstract Full Text PDF Google ScholarMeyerhof O. J. Biol. Chem. 1945; 157: 105-120Abstract Full Text PDF Google ScholarMeyerhof O. Oesper P. J. Biol. Chem. 1947; 170 (http://www.jbc.org/cgi/content/full/280/4/e3): 1-22Abstract Full Text PDF Google Scholar). A fortuitous event in the middle of the summer allowed Wald to make a huge leap forward in understanding visual pigment biochemistry. Everyone was away on holiday when a shipment of 300 frogs arrived in the laboratory. The laboratory assistant was about to release the frogs when Wald asked if he could have them. He extracted dark-adapted and bleached retinas from the frogs and was able to detect a novel carotenoid that was similar to but distinct from vitamin A (4Wald G. Carotenoids and the visual cycle.J. Gen. Physiol. 1935–1936; 19: 351Crossref PubMed Scopus (133) Google Scholar). He called this new substance retinene and found that when rhodopsin was stimulated with light it yielded opsin and retinene. The retinene was then gradually converted to vitamin A. Eventually retinene was renamed retinal, and vitamin A became retinol. It had been known for some time that vitamin A deficiency resulted in night blindness, but it was an unexpected discovery that a vitamin would participate directly in a physiological process. Wald returned to the United States to work in the Department of Physiology at the University of Chicago and started experiments to confirm that the visual cycle was present in vertebrates other than the frog. A year later, in 1934, he assumed his first academic position as tutor in Biochemical Sciences at Harvard. He remained at Harvard for the rest of his academic career, becoming Faculty Instructor in 1939, Associate Professor in 1944, and Professor of Biology in 1948. In the mid-1930s Wald began spending summers at Woods Hole, studying the dark-adapted retinas of certain fish. He found that, like frogs, the rod visual pigments of marine fish contain rhodopsin, and when exposed to light, the rhodopsin releases retinal, which is converted to retinol. Freshwater fish, however, had a different rod visual pigment and yielded a different form of retinal and retinol. He called the new pigment porphyropsin and the new carotenoids retinene2 and vitamin A2. Wald also started studying cone vision in the mid-1930s. Using chicken retinas he extracted a visual pigment that was red-sensitive and called it iodopsin. In the mid-1950s Wald showed that iodopsin bleaches to retinene1 and opsin. His experiments were interrupted by World War II, during which he worked on applied vision research projects for the U. S. Army Board of Engineers. He aided in developing infrared viewing devices as well as studying the spherical and chromatic aberration of the human lens. With the conclusion of the war, Wald returned his focus to visual pigment molecules. He was joined by Paul Brown who became his research assistant and long time co-worker. Brown showed that rhodopsin could be generated simply by mixing retinal and opsin. However, when Wald and Brown tried to assemble rhodopsin in a test tube using retinol, opsin, and several enzymes, they noticed something odd. When they used retinol from fish oil, a rhodopsin-like pigment was produced, but when synthetic retinol was used nothing happened. They soon discovered that this was due to the cis-trans isomerization of retinol and that adding a trace of iodine to synthetic vitamin A in light promotes isomerization allowing the retinol to form a light-sensitive pigment with opsin. Wald and his co-workers identified the different isomers of retinol in order to determine which one was involved in forming rhodopsin. Of all the possible isomers, the 11-cis linkage was thought to be the least probable because the bend caused by the cis linkage caused the molecule to be twisted. This departure from planarity was expected to make the molecule so unstable that it should not be present in nature. However, once Wald and his co-workers synthesized the molecule, they realized that it was reasonably stable in the dark, and they eventually determined that the 11-cis retinol isomer was a precursor to all visual pigments. The JBC Classic reprinted here describes Wald and Brown's preparation of 11-cis retinol, its properties, and its isomerization. This was the first instance of a role for cis-trans isomerization in biology, and the discovery allowed the synthesis of rhodopsin and other visual pigments in the laboratory. Wald eventually showed that light causes 11-cis retinal to isomerize to the all-trans form, which is eventually converted back to the 11-cis form. In the early 1960s Wald turned his attention to color vision and determined the spectral sensitivity functions of the red-, green-, and blue-sensitive cones in normal and color blind human subjects. He also studied the link between vitamin A deficiency and night blindness. In recognition of his work on chemical visual processes in the eye, Wald was awarded the 1967 Nobel Prize in Physiology or Medicine along with Ragnar Granit and Haldan Keffer Hartline. Wald used his fame as a Nobel laureate to speak out on many political and social issues. He was a vocal opponent of the Vietnam War and the nuclear arms race, and in 1980 he served as part of Ramsey Clark's delegation to Iran during the Iran hostage crisis. In addition to his research activities, Wald was actively involved in teaching at Harvard and earned the reputation as one of Harvard's best teachers. He taught a popular introductory biology course and published a laboratory manual based on the course called Twenty-six Afternoons of Biology (5Wald G. Hopkins III, J. Albersheim P. Dowling J.E. Denhardt D. Twenty-six Afternoons of Biology. Addison-Wesley, Reading, MA1962Crossref Google Scholar). Wald gained national attention from the course and was named one of the country's 10 best teachers by Time magazine in 1966. Over the years, Wald received many awards in addition to the Nobel Prize. He won the Eli Lilly Award in 1939, the Lasker Award in 1953, the Proctor Medal in 1959, and the Rumford Prize in 1959. Wald was elected to the National Academy of Sciences in 1950 and to the American Philosophical Society in 1958. 1All biographical information on George Wald was taken from Ref. 1Dowling J.E. Biographical Memoir of George Wald. 78. National Academy of Sciences, Washington, D. C.2000: 298-317Google Scholar. 1All biographical information on George Wald was taken from Ref. 1Dowling J.E. Biographical Memoir of George Wald. 78. National Academy of Sciences, Washington, D. C.2000: 298-317Google Scholar.
Source: Journal of Biological Chemistry
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $3,430
OpenAlex ID: W1599651230