Universalizing Photochemical Theories of Vision: Hecht, Wald, and the Marine Biological Laboratory - From Hecht’s Theoretical Formalism to Wald’s Biochemical Mechanisms

George Wald met Hecht during his first year of graduate school at Columbia University. Shortly after Hecht died, Wald described Hecht’s influence on his work in the following way: “What I did or said or wrote was in a sense always addressed to him” (Dowling 2000). From 1927 to 1932 Wald worked in Hecht’s laboratory at Columbia and it was Wald who would give Hecht’s theoretical formulation of the photochemistry of vision a detailed molecular interpretation. When Wald left Hecht’s laboratory he said it was “with a great desire to lay hands on the molecules for which {S, P, and A} were symbols” (Applebury 1993, 184, with original emphasis). Wald made good on this desire: he showed that the precursor of visual purple, Hecht’s P and A, were also the product of visual purple, Hecht’s S. Visual purple, or rhodopsin, when exposed to light, goes through a stepwise decomposition. Wald had already demonstrated that rhodopsin, when exposed to light, would produce a form of vitamin A, and that opsin proteins combined with vitamin A to create rhodopsin, surprisingly also when exposed to light.

Understanding Wald’s contributions involves having a detailed knowledge of biochemistry, but a conceptual overview, unfortunately leaving out the details of the work, will at least serve to illustrate how Wald filled in Hecht’s formalism with a molecular mechanism. One of the first things Wald discovered was vitamin A in the retina (G. Wald 1933). He then proposed a role for the functioning of that vitamin within the visual process that Hecht had modeled. As an aside,  this was the first time a functional role for vitamin A was described, and it offered a solution to the problem of dietary blindness, known at the time to be a consequence of vitamin A deficiency. The role of vitamin A is illustrated in the below figure.

Referring to the figure, the rhodopsin box is equivalent to Hecht’s S substance, the all-trans and 11-cis retinal/vitamin A boxes are roughly equivalent to Hecht’s product A, and the opsin box equivalent to his product P. Wald showed that, when exposed to light, rhodopsin would quickly go through the stepwise chemical process illustrated by the figure and retinal would separate out from the opsin molecule. Retinal is bound to the opsin molecule easily in its 11-cis state. The different states of retinal (11-cis and all-trans), are different shapes the same chemical constitutes can take. 11-cis fits the opsin molecule well, and all-trans doesn’t. When exposed to light, the part of rhodopsin that is the 11-cis retinal is forced out of its 11-cis configuration, making the bond with the opsin molecule impossible to maintain. There are a number of interesting omissions being made here, for example that light hitting metarhodopsin immediately isomerizes the all-trans retinal directly back into its 11-cis configuration, meaning that rhodopsin was both decomposed and regenerated by light. In his Nobel lecture, Wald expanded upon this aspect of the theory: “In continuous light these opposed reactions achieved a pseudo-equilibrium, a photostationary state, that underlay the steady states of vision in constant illumination” (G. Wald 1967). This molecular solution fills out Hecht’s theoretical formalism and in some sense is the crowning achievement of a research tradition going back at least to Kühne and Boll.

Wald also showed that rhodopsin was not the only rod photopigment: observations that Wald made at the MBL (G. Wald 1967, 294) showed that marine-fish and land vertebrates use the rhodopsin system, whereas freshwater fish use a different pigment, which Wald dubbed porphyropsin for its purple color (Wald 1937; Stabell and Stabell 2009, 140-145). There are lots of interesting details about the different kinds of animals that have the porphyropsin system, for example, “The bullfrog has porphyropsin as a tadpole, and changes to rhodopsin at metamorphosis” (G. Wald 1967, 295). Wald also showed, again confirming the universalism of Hecht, that the difference in chemistry between the two substances lead to almost no difference in their chemical behavior – that is, porphyropsin goes through basically the same cycle illustrated by the above figure (Wald 1938/1939).

Wald described the existence of a cone photopigment by exposing irradiated retinas extracted from chickens first to deep-red light then to white light. Wald knew that rhodopsin is relatively insensitive to red light, so he reasoned that any bleaching effect from the red light exposure would occur with a photopigment other than rhodopsin. This cone pigment looked violet, and so Wald named it iodopsin, or “visual violet”. Wald found a significantly greater concentration of rhodopsin in a single rod than that of iodopsin in a single cone, and used this fact to infer that iodopsin was the molecule of day vision; that is, cones were much less light sensitive and so would serve the process of day vision well (Wald 1949; Wald 1954). He also argued that the Purkinje shift could be naturally explained as a consequence of the rhodopsin system taking over for the iodopsin system as light levels decreased.

Wald said that early in his career “a new life” opened up for him: “the life of molecules” (Wald 1967, 293). It is easy to get lost in the detailed molecular work of Wald, but for him “the pursuit of molecules” did not take him “out of biology, but led [him] more deeply into it” (Wald 1967, 295). Wald’s many contributions to visual physiology and biological chemistry earned him a Nobel Prize in 1967. When reflecting on his relationship with science during his Nobel Lecture, Wald illustrated his romanticism of science beautifully:

When [an experiment] is going well, it is like a quiet conversation with Nature. One asks a question and gets an answer; then one asks the next question, and gets the next answer. An experiment is a device to make Nature speak intelligibly. After that one has only to listen. (Wald 1967, 292)