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Evolving Evolution

In 1961, Jacques Monod and François Jacob discovered that E. coli bacteria actually have a mechanism that controls the production of the enzyme for digesting lactose. As unicellular organisms, E. coli bacteria have only several thousand genes, each of which is made up of a specific sequence of DNA. A single one of these genes, present in all E. coli, carries in its DNA the genetic instructions needed to assemble the enzyme that can digest lactose; the DNA is copied into RNA, which is then “translated” to produce the enzyme itself. When there is no lactose present in the bacteria’s immediate environment, the gene is switched off: its DNA is not copied into RNA and the enzyme is not produced. The reason for this, the scientists discovered, is that a protein called a repressor molecule attaches itself to the DNA site where the copying into RNA begins, thus blocking off the DNA and preventing the gene from producing the RNA responsible for the synthesis of the enzyme.

On the other hand, when the E. coli bacteria encounter lactose, the lactose binds itself to this repressor molecule, causing the repressor to be detached from the DNA site. This unblocks the DNA, allowing the gene to be copied into RNA, and produce the enzyme that can digest lactose. In other words, the repressor molecule acts as a switch that controls the gene’s production of the enzyme. Since only a fraction of the total number of genes present in an organism are expressed, or turned on, at any given time, Monod and Jacob conjectured that other genes must be similarly turned on and off.

Although they had not yet found systematic evidence to support these ideas, the discovery of the repressor molecule allowed the two scientists to form a powerful new hypothesis about how genes function. As Jacob recently wrote, in a brief description of the new hypothesis:

It proposed a model to explain one of the oldest problems in biology: in organisms made up of millions, even billions of cells, every cell possesses a complete set of genes; how, then, is it that all the genes do not function in the same way in all tissues? That the nerve cells do not use the same genes as the muscle cells or the liver cells? In short, [we] presented a new view of the genetic landscape.

The deeper significance of the Monod-Jacob model of gene function, and its implications for the nature of evolution, became apparent with the new field of embryo research that arose almost twenty years later.

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In 1894, the English biologist William Bateson challenged Darwin’s view that evolution was gradual. He published Materials for the Study of Variation, a catalog of abnormalities he had observed in insects and animals in which one body part was replaced with another. He described, for example, a mutant fly with a leg instead of an antenna on its head, and mutant frogs and humans with extra vertebrae. The abnormalities Bateson discovered resisted explanation for much of the twentieth century. But in the late 1970s, studies by Edward Lewis at the California Institute of Technology, Christiana Nüsslein-Vollhard and Eric Wieschaus in Germany, and others began to reveal that the abnormalities were caused by mutations of a special set of genes in fruit fly embryos that controlled development of the fly’s body and the distribution of its attached appendages. Very similar genes, exercising similar controls, were subsequently found in nematodes, flies, fish, mice, and human beings.

What they and others discovered were genes that regulate the development of the embryo and exert control over other genes by mechanisms analogous to that of the repressor molecule studied by Monod and Jacob. Eight of these controlling genes, called Hox genes, are found in virtually all animals—worms, mice, and human beings—and they have existed for more than half a billion years.2 Fruit flies and worms have only one set of eight Hox genes; fish and mammals (including mice, elephants, and humans) have four sets. Each set of Hox genes in fish and mammals is remarkably similar to the eight Hox genes found in fruit flies and worms. This discovery showed that very similar genes control both embryological and later development in virtually all insects and animals. (See Figure 1.)

To understand what Hox genes do, scientists needed to observe the activity of the genes in the developing embryos of flies and mice. Using new technologies that allowed them to observe under a microscope the locations of the Hox proteins in these embryos, they were able to identify an overall pattern of how Hox genes behave. A newly fertilized fly egg looks like a tiny football: one end, or pole, will eventually become the head region; the other end will become the tail region. These and other divisions of the embryo in later development actually followed the switching on and off of the Hox genes in different parts of the embryo. (See Figure 2.)

The mechanism that causes the Hox genes to behave in this way is initiated by the release of proteins from the cells of the mother’s body across the newly fertilized embryo. These proteins control the activities of the Hox genes and are released in varying concentrations, causing Hox genes to produce Hox proteins in specific places. As the embryo grows, the production of Hox proteins divides the embryo into a series of segments, or distinct regions, from which subsequent development occurs. Other genes are then activated within each segment, a finer division of the embryo is established, and wings, antennae, and other body parts are formed. In general, scientists reasoned, Hox genes establish the basic division of the embryo into distinct compartments, and each compartment, in turn, establishes the regions of the embryo where development of specific body parts and functions takes place. Still, the details of the mechanisms that a cell uses to establish its position in the embryo remain incomplete.

In fact, Nüsslein-Vollhard and Wieschaus found that within the fly’s embryo there was an overall pattern in which genes were turned on or off; and they saw in this pattern the overall body plan for the full-grown fly. In other words, the activity of the Hox genes, including the formation of compartments within the embryo and the control of other genes that guide development, provided a system of organization that dictated the final adult form of the fly.

The presence of a body plan in the genome, whether of a fly, a whale, or a human, was unexpected by embryologists. Previously, most of them did not think that development of embryos was controlled by genes; they had assumed that the different parts of developing embryos were determined by physical interaction between neighboring cells and that there was no overall division of the embryo according to a genetic plan. Experiments had shown, for example, that removing developing wing tissue from one part of an embryo and implanting it elsewhere still gave rise to a wing, although an abnormal one. Scientists attributed the abnormality to the effects of the neighboring cells in the embryo. This was wrong. In fact it was caused by the disruption of the body plan.

This new understanding of Hox genes was aided by the discovery that the proteins produced by these genes function in a way that is analogous to Monod and Jacob’s repressor molecule. Specifically, although they have different properties, all Hox proteins contain a molecular structure that makes them attach to DNA sites that control genes. This meant that Hox proteins, like the repressor molecule, act as switches that turn neighboring genes on and off.3

Hox genes, as Carroll explains, are in fact one of many kinds of genes that direct embryo development by a mechanism of switches. One example that is not a Hox gene is the gene that controls the development of the eye in fruit flies. If this gene (called Pax 6) is damaged when it mutates, the fly fails to develop eyes. We now know from the experiments described in Carroll’s book that the Pax 6 gene is also found in butterflies, mice, and humans. Indeed, Pax 6 genes are interchangeable. The Pax 6 gene from a fly will turn on genes that make eyes in mice, and the Pax 6 gene from a mouse will turn on genes that make eyes in flies.

It had long been assumed that eyes had evolved independently in different species. The structures of mammalian eyes and insect eyes are very different and it would seem most unlikely that they had followed a similar evolutionary path. Mammalian eyes, for example, have a single lens that focuses an image on the retina. Insects have eyes with many tube-like structures, each tube having its own lens and retina. Yet the discovery of the Pax 6 gene gives us reason to believe that the evolution of the eye in all the animals followed related, and to some extent common, paths, though we cannot completely exclude the possibility that each kind of eye evolved following completely independent pathways. In addition to the Pax 6 gene, genes have been found that control the genes responsible for the development of the different kinds of “hearts”—or mechanisms that pump blood—whether in fruit flies or humans, again suggesting similar evolutionary pathways. Indeed the development of legs, wings, arms, fins, and other fish and marine animal appendages are all under the control of virtually identical genes and, as with the Pax genes, in many cases are interchangeable.

These findings strongly support the Darwinian view that animals descend from one or a few ancestors. However, contrary to the previously accepted neo-Darwinian view, the same findings showed that different animal forms are not primarily a function of distinct gene pools that have evolved over millions of years. How then do similar collections of genes create the enormous diversity of living forms? In Sean Carroll’s view, what creates diversity is the patterns in which genes are turned “on” and “off.” The different appendages found in centipedes, fruit flies, lobsters, and brine shrimp are created by varying combinations of Hox gene activity in the developing insect or crustacean embryo.

Switches,” Carroll emphasizes, “enable the same…genes to be used differently in different animals” [his italics]. In other words, a Hox gene produces a protein that binds to the DNA’s sites where genes copy into RNA and can thus turn genes “on” or “off.”

This has an important consequence for evolution: mutations in Hox genes will affect the ways in which they act within the embryo, thereby altering the proteins’ functions as switches. When the proteins’ functions are changed, in turn, this causes them to control genes that are needed for development of a specific physical trait in new ways. In this view, evolution is largely the consequence of random mutations in genetic switches. Genes remain intact, but under new patterns of control. Their function is altered. Complexity and variety are created, at least in part, by combining the activities of old genes in new ways. Carroll’s view—what we might call the switches hypothesis—emphasizes the importance of changes in patterns of turning genes on and off rather than changes in the genes themselves. However, even the most ardent supporter of the switches hypothesis would admit that not only Hox genes but other genes change as well. But the contribution of these changes to evolution is far less than we had previously believed.

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    No one group found all of the Hox genes. Lewis started his work in the late 1950s, earlier than Nüsslein-Vollhard and Wieschaus, but much of the work of the two groups was contemporaneous. Both groups realized that development was under genetic control. Although Lewis focused on specific Hox genes, Nüsslein-Vollhard and Wieschaus saw the importance of identifying all of the genes that controlled the body plan, and they identified most of them.

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    Hox proteins behave in this way because of a particular genetic feature of the Hox genes that produce them. Within their genetic composition, all eight Hox genes possess a nearly identical section of DNA, called a homeobox. When Hox genes produce Hox proteins, the homeobox region of the Hox genes carries the genetic information to produce a specific part of these proteins called the homeodomain. Once the protein is assembled, its homeodomain attaches to DNA sites that control genes, allowing it to function as a switch.

    It is this particular characteristic that gave the Hox genes their name. In homage to Bateson, the identical sections of DNA were called “homeoboxes,” since they were present in genes that, when mutated, resulted in Bateson’s monsters, or “homeotic” mutants. The term “Hox gene” is a whimsical combination of “homeotic” and “homeobox.”

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