| The Magazine of the CALIFORNIA ACADEMY OF SCIENCES |
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Counterpoints In Science The Shape of Things to Come
How did the many forms of life on Earth come to be? How does the individual life of a creature such as a human being grow and develop from its nearly invisible beginning, to a wormlike embryo, to a fetus that’s practically all head, to a sexually mature man or woman? These questions have baffled us for ages, but today, instead of accepting explanations in the form of myths, divine revelations, or just-so stories, we try to find scientific explanations for these intertwined mysteries: How did multicellular life evolve from single-celled ancestors? How do individual organisms grow and develop from a single cell into a complex animal, plant, or fungus?
As the twenty-first century gets underway, a new branch of the scientific enterprise is rapidly putting together pieces of these ancient puzzles. Formally known as evolutionary developmental biology, the field is referred to by its practitioners as evo-devo. Geneticist Adam S. Wilkins, editor of the evo-devo journal BioEssays, describes the growth and development of this embryonic science in his hefty volume The Evolution of Developmental Pathways (Sinauer 2002). There are strong similarities between the evo and devo halves of this new scientific field. About half a billion years ago, multicellular life suddenly bloomed in the womb of Earth. Dozens of multicellular organisms, representing nearly all the basic types of creatures that live today, sprang up during this “Cambrian explosion.” A somewhat similar “explosion” takes place in a woman’s womb within ten weeks of conception, when a single fertilized human egg cell develops into a complex arrangement of trillions of cells recognizable as a human fetus. As early as the nineteenth century, Charles Darwin and many of his followers realized that growth and development were crucial aspects of evolution. All animal embryos look very much alike in their early stages but develop into such remarkably different creatures as frogs, birds, kangaroos, and whales. Just as species are transformed into other species with different appearances and adaptations over evolutionary time, each individual changes gradually but profoundly in its lifetime. But in Darwin’s day, almost nothing was known about the fundamental processes going on in the embryo and fetus. These processes came to light with discoveries starting in the 1930s. The key to developmental patterns lies in molecular regulators discovered in the 1980s, known as the Hox genes. Hox is an abbreviation for “homeobox,” a small DNA segment of about 180 chemical letters. Virtually identical in all animals from worms to flies and primates, this small number of regulatory genes determines the shape and size of an organism. In contrast to the wild variety of living forms, its molecular structure has remained amazingly constant. Hox genes line up on a chromosome in the same head-to-tail (antero-posterior) order as the segments of the embryo. The first genes in the Hox group define the head, the next group the thorax, et cetera. In that favorite laboratory animal the fruit fly (Drosophila melanogaster), geneticists observed a long time ago that some mutant flies grew legs on their heads where their antennae were supposed to be. At the time, they had no idea of the genetic mechanism. Now it is known that a mutation in one of the Hox genes for the head causes this abnormality, and mutations in other Hox genes cause abnormalities such as extra body segments or extra pairs of wings. There is only one cluster of about 13 Hox genes in insects and four such clusters in mice and other vertebrates, but the antero-posterior line-up of genes is nearly the same in these widely separated species. One big difference between vertebrates and invertebrates, represented by the mouse and the fruit fly, is the arrangement of organs inside the body. The mouse, like all vertebrates, has a spine on its back and its gut and heart in front. In the fruit fly, the major nerve cord runs along the belly, with the gut and heart behind it. Way back in 1822, this switcheroo caught the attention of French biologist Etienne Geoffroy Saint-Hilaire, who suggested that structurally, a vertebrate is an upside-down invertebrate. His contemporary, the famous paleontologist Georges Cuvier, considered this suggestion ridiculous, as have most anatomists since. But now Geoffroy Saint-Hilaire has been vindicated. Three Hox genes have been found that determine dorsoventral (back-to-front) patterning, and the same ones that arrange the dorsal structures in fruit flies arrange the ventral structures in mice. No one would mistake a mouse for a fruit fly, but their genes for developing individual organs like the heart and eyes are remarkably similar. Normal fruit fly embryos have a gene named tinman (for the character in the Wizard of Oz) that is necessary for them to develop hearts. Normal mice have the same gene, and without it, they grow lethally defective hearts. Squids, flies, frogs, and many other animals have such different kinds of eyes that respected evolutionary theorist Ernst Mayr concluded eyes must have evolved independently at least 40 times. However, it was recently shown that each of these distinctive visual organs is under the control of the same ancestral Hox gene. Normal fruit flies have a gene called eyeless because when it’s missing or mutated, their eyes either don’t develop or the eyes are small and vestigial. Variants of eyeless were independently discovered and given different names in squids, mice and humans. Then researchers realized these variants were basically the same Hox gene, in which mutations caused abnormal eye development in all these species. When an extra eyeless gene is inserted into transgenic (genetically modified) flies, the flies may produce small eyes on their antennae, wings, and legs. A similar result is obtained in flies when the gene found in mice is inserted instead of the fruit fly gene, demonstrating that this particular gene hasn’t mutated much in the 500 million years since mice and flies had a common ancestor. These weird off-site eyes don’t see though, because they’re not hooked up to the brain. Evo-devo’s unity in diversity presents a paradox. If the developmental genes have changed so little, how did all creatures great and small get to be so unalike? The answer is that mutations arise in all genes over a long enough period of evolutionary time, and even tiny changes in the Hox genes can have big effects on the shape, size, and overall adaptation of an organism. It has been known for a long time that the appendages of mammals, such as arms in apes, wings in bats, and flippers in whales, are “homologous”—that is, they have a similar developmental origin. Now, for the first time, we can see on the molecular level exactly how these different developmental pathways emerge. The Hox genes can be viewed as a committee of master craftsmen, including sculptors and architects. Each gene has profound effects on the part of the body under its jurisdiction. Working together, they decide the number of segments in the embryo and whether these segments will bear wings, legs, or antennae. Using the same handful of tools, they can create a butterfly or a bat, a snake or an eel, a millipede or a biped. No one raised objections to this research during the decades when extensive genetic evo-devo manipulations were limited to fruit flies, nematode worms, mice, and zebrafish, clarifying the powerful effects of Hox genes on normal and abnormal development in these organisms. But similar manipulations in humans, even though they might prevent common developmental defects like malformations of the heart, might also be dangerous and would raise grave ethical questions. To broaden the sphere of evolutionary knowledge, the genome of our closest living relative—the chimpanzee—is being sequenced. Soon we should be able to track the specific differences in the Hox genes that cause chimps to have small brains, long arms, and short legs, while humans, whose genome is only 1.6 percent different from theirs, develop large brains, shorter arms, and longer legs. Evo-devo is a new frontier, exploring the genetic basis of life in its many shapes and forms. It may well give us new insights into what it means to be alive and to be human, and it is sure to generate new controversies over our expanding ability to influence how living creatures, including humans, grow and develop from their earliest stages. In the realm of ideas, evo-devo confirms Darwin’s vision that all life had a common origin, and shows how the millions of wonderful species that have lived since the Cambrian era are all variations on a single molecular theme—with the Hox genes calling the tune. Jerold M. Lowenstein is professor of medicine at the University of California, San Francisco. jlowen@itsa.ucsf.edu |
