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Walter Gehring: Master Control Genes and the Evolution of the Eye

Q: What fascinates you about the eye?

A: The eye is an absolutely fascinating organ because it's an organ of extreme perfection, as Darwin has called it. We are able to adjust the focus, we are able to [adjust] the chromatic operation, that is, the color changes as they occur, and we are able to adapt to very dark light at night, or to very bright light during the day, and so on. We have photoreceptors which are capable of sensing individual quanta of light, which is the most sensitive reception you can get. We can use lenses to focus the light onto our retina. And we use essentially the eye, at least the human eye, like a camera. Instead of a film, you have a retina in the back, with photoreceptor cells, and this makes the eye a very fascinating organ.

Furthermore, various animal groups have evolved very different types of eyes. The insects have evolved a compound eye, which consists of many individual eyes with individual lenses. The squid, for example, has evolved an eye very similar to us, although it's from a completely different phylum. Then, there are even mirror eyes. So the scallop -- most people probably don't know that scallops also have eyes -- they have shiny eyes, because they have a mirror in the back, a parabolic mirror. Scallops have actually two systems: they have a lens in front, which projects onto one retina, and they have a mirror in the back, which projects onto a second retina, to collect all possible light.

Q: How did these different kinds of eyes evolve?

A: The traditional idea is that the eyes evolved separately into separate animal phyla. An insect eye looks so different from a human eye that one would assume intuitively that this must have arisen quite differently in evolution. There was a separate sort of construction, which was invented differently from the human eye. In the squid, for example, the eye develops as an invagination of the skin; that is, the skin forms a little cavity, a little bulb, inside. In our case the brain forms an invagination, a bulb which is moving outwards, towards the skin. One traditionally thought that this would be a fundamental difference.

We come to a very different conclusion. We have found that there is the same underlying genetic basis in all animal phyla. You have the same genes that are involved in eye development. Therefore, we now consider it much more likely that the eye was sort of invented only once in evolution. Then the various animal phyla used this basic construction of a very simple eye to diverge and to make various forms of the eye.

Q: What got you thinking that there might have been one and only one evolution of the primitive eye?

A: This was a pure accident, or serendipity. We stumbled upon a gene in the fruit fly, which was already known from humans, and was known from the mouse. And the gene in the mouse is called "small eye," because when it is mutated the eye is much reduced in size, and when you remove both copies of the normal gene and replace them by a mutated gene, then the eyes are totally missing.

Much to our surprise, the same gene causes eyeless[ness] in the fruit fly. That came as a total surprise, because we thought that the fruit fly eye was in no way a homologous, a similar structure as in humans. We subsequently found this gene to be present in all animal groups, down to flat worms.

You have to think that there are some 2,000 genes involved in making a fruit fly eye, and probably a similar number of genes to make a human eye. And so it came as a surprise that a single gene could block eye development completely -- both in the fruit fly and in humans. This was the same gene.

We thought of this gene as a sort of master switch. You can compare this to an electrical switch: When you come into a house, you can switch on the current with the main switch, and then all of the lights can go on in the house. We think of this gene something like that for the eye development. This is the master switch which switches on a program of some 2,000 genes, which then gradually unfolds.

So I had the relatively crazy idea. At that time it was a really crazy idea which nobody believed -- that there might be this single universal master control gene responsible for formation of an eye. And we think it was the same in the mouse as in the fruit fly, and these have evolved separately for hundreds of millions of years. This seemed an also strange idea. But I wanted to test it.

Now, how do you test such an idea? My idea was relatively simple: To induce an eye in a different place -- let's say, to put an eye on the wing or on a leg of the fruit fly. And this is now possible by using genetic manipulation. You can direct, you can target, the expression of the gene -- in this case the Pax-6 gene, the supposed master control gene -- and make it work on a wing or on a leg. And when we did that, indeed, we were capable of inducing a complete compound eye on an antenna, on a wing, or on a leg. This was taking a single master control gene, switching on a cascade of some 2,000 genes, and they make a complete eye. We actually showed, later, that the fruit flies can see with these eyes.

But now the question was, How universal is this? I made an even bolder claim, that this was the universal master control gene. This question we tested by taking the mouse gene and putting it into fruit flies. To everybody's surprise, the mouse gene works perfectly well and can induce a compound eye in the fruit fly. Now, this is not a mouse eye, of course, because the mouse gives you only the main switch, and then switches on the developmental program, which is built into the genome of the fruit fly. Therefore you get a Drosophila [eye] with the mouse switch.

Now, we've also done the reciprocal lately. We've put the fly gene into a frog, which is also a vertebrate, an amphibian. In the frog we can induce a frog eye with the Drosophila gene. That nails it down that, at least between vertebrates and the insects, this universal rule is obeyed.

Since this Pax-6 gene works both when you put the mouse gene into fruit flies and when you put the fruit fly gene into frogs, we think that there is a common underlying genetic plan for the eye, and that on top of this program, this eye developmental program in the mouse and in the fruit fly, is the same gene.

We also know that on the bottom of this cascade there is the same visual pigment, which we also have, called rhodopsin. This is the light-absorbing pigment which allows you to sense the light, convert the light signal into a nerve impulse which is sent from the eye to the brain. So both the top of the cascade and the bottom of the cascade are absolutely shared.

And we are now determining how much is shared in between, but we already know that the second in command, the one which is right below Pax-6 in the hierarchy, is also shared between mammals, flies, and even flat worms.

The conclusion would be that these parts are exchangeable, that the program is the same, from which one eventually will conclude that the eye was "invented" only once in the course of evolution -- invented, of course, in quotation marks.

Q: Can you describe what that original common ancestor of all eyes might have been like?

A: This was already postulated by Darwin, and it's remarkable how correct he was, in retrospect. What he says is that the prototypic eye probably would consist of two cells only: a photo-receptor cell -- which he called a nerve, which is absolutely correct; it's a nerve cell which is photosensitive, which has rhodopsin -- and a pigment cell. The function of the pigment cell is to shield the light from one side. This gives the owner of this eye a big advantage, because they can see which direction the light comes from. So this is already a direction discriminating eye.

And then, he thinks, from this prototype, then selection could set in and make all of these wonderful eye types -- the eye of an eagle, or of a squid, or of a Drosophila, a fruit fly. Interestingly enough, a considerable time later a Japanese group found a flat worm which has exactly this minimal prototypic eye, which is only consisting of a single photoreceptor and single pigment cell. And these animals, of course much to my satisfaction, they also have a Pax-6 gene.

Q: What does this suggest to you, in terms of how eyes evolved and how such complex things can arrive in very simple steps?

A: The conclusion which was suggested by this finding was that the eye evolved probably only once, and that the same master switch is used to switch on the eye program in fruit flies as it is in humans. And this was a completely revolutionary thought, because the end product looks very different but is basically built of the same elements -- it's a retina with photo-receptors; it has a lens which projects light onto this retina; and it's basically the same principle but in a different form. That's why we consider it very likely that from the original prototype -- which are just the master control gene and the nuts and bolts, which is the rhodopsin gene, and so on -- that from this prototype, the various eye types have radiated out in various directions.

And this happened very early in evolution. We already know that in the Cambrian times, which is 500 million years ago, the trilobites already had highly evolved compound eyes, just like the fruit fly does. So the eye must have evolved very rapidly, because it confers a selective advantage which is tremendous for the individual who can see.

Before eyes really could have evolved, it was necessary to evolve photosensitivity, light sensitivity. We have made recent progress in understanding light sensitivity, by the discovery of certain photo pigments which confer light sensitivity.

We are now considering the most interesting question of how photosensitivity, light sensitivity, evolved in the course of evolution. What was the advantage of seeing light and dark and being able to distinguish light from dark? And in this case, we have to consider that life comes out of the ocean, that the most primitive organisms were living as single cells in the ocean. The problem with sunlight is that it contains a very heavy UV component: Ultraviolet light is very detrimental to single cells if they get too much of it. Therefore, it was advantageous for the organisms to escape sunlight during the day -- that is, to go down in the ocean and to come back up during the night.

Interestingly, you can still see this in, nowadays, plankton. That is, if you measure where the plankton is, it comes up at night and it goes down during the day, strongly supporting the idea that the advantage was to avoid UV radiation and that made it so powerful an evolutionary factor.

Evolution is tinkering. Even at the gene level, you see that the Pax-6 gene belongs to the Pax gene family, and when you look at this gene family you can see that there are nine Pax genes known in mice. When you look at their structure, you see that they didn't evolve de novo, from scratch. When new genes are formed, they are combined from bits and pieces of old genes, like a tinkerer does. He takes a little nail from there and a little screw from there and puts them together, and that's exactly what we see at the gene level here.

We also see that [at] the eye level -- of course, there is a lot of tinkering involved. You start from a very primitive prototype, and as soon as this prototype forms, then selection can set in. Selection, then, favors the good constructions, the eyes which work rather well and which allow [the organism] to gather more information than if you have a primitive eye. And that accelerated the evolution, and, at the end, it looks all streamlined.

But if you look at the intermediates, you find that tinkering was used to accomplish this excellence.