François Jacob, one of the pioneers in molecular biology, was interviewed a few years ago for an educational video now used in Harvard’s new undergraduate biology curriculum (Life Sciences 1b: “Genetics, Genomics, and Evolution”). Reflecting on an earlier time, Jacob reminisced:
When I started in biology in the 1950s, the idea was that the molecules from one organism were very different from the molecules from another organism. For instance, cows had cow molecules and goats had goat molecules and snakes had snake molecules, and it was because they were made of cow molecules that a cow was a cow. And then it turned out, a little bit later, that certain molecules were very similar from one species to another, for instance, hemoglobin. The hemoglobin of horse or cow or human turned out to be very similar, and progressively…it turned out that more and more molecules of various organisms were very similar.
The discovery that the subunits of DNA and proteins have similar sequences in very different organisms is one of the least appreciated but most important discoveries in twentieth-century biology. Not only are the sequences of such macromolecules similar, they are more similar among more closely related organisms. In particular, when the sequences of macromolecules are compared among groups of organisms, the evolutionary relationships among the organisms are almost always in close agreement with those inferred from anatomy, physiology, and development. The molecular evidence shows incontrovertibly that species have come into being gradually throughout the history of life on Earth. Darwin could not have dreamed of such a spectacular confirmation of his theory of descent with modification. For creationists, this must be a nightmare, for any sensible model of creationism would predict cows to have cow molecules, goats to have goat molecules, and snakes to have snake molecules.
So creationists have shifted ground to promote a theory called “intelligent design,” which asserts that the complexity of features such as the vertebrate eye or the molecular motor that drives the flagellum in bacteria must have arisen instantaneously as a result of purposeful and intelligent design. Although the designer is not specified, this sly dissimulation is a transparent attempt to dodge the Supreme Court rulings in Epperson v. Arkansas (1968) and Edwards v. Aguillard (1987) holding that the First Amendment prohibits any state from requiring teachers to promulgate “the principles or prohibitions of any religious sect or dogma” (Epperson v. Arkansas 393 U.S. 97).
In The Plausibility of Life, Marc W. Kirschner and John C. Gerhart ’58 propose a theory for the origin of variation that demystifies the evolution of novelty and complexity. It is a milestone book full of new and insightful ideas. I recommend it without hesitation. Most evolution books written for the general public are dumbed down and have little new to say, but Kirschner and Gerhart walk the tightrope with spectacular success, using clear, nontechnical language, brilliantly chosen examples, and numerous illustrations.
Exploring the evolutionary implications of the developmental mechanisms that have been discovered in the past 30 years, Kirschner (Walter professor of systems biology and head of that department at Harvard Medical School; see “Seeing Biological Systems Whole,” March-April, page 67) and Gerhart (professor of the graduate school, division of cell and developmental biology, at the University of California, Berkeley) conclude that the origins of novelty and complexity are implicit in the physiology and development of organisms themselves. The key is what they call “facilitated variation.” By this they mean that an organism does not merely tolerate environmental perturbations or developmental accidents, but in fact adjusts to the disturbances and incorporates them into its physiology or development. This buffering facilitates variation in traits by channeling environmental or genetic irregularities into integrated pathways of response. Furthermore, random inputs in the form of environmental perturbations or genetic mutations do not produce random outputs, because the outputs are shaped by the organism’s adaptive responses. Although genetic mutations may be random in their effects on the DNA sequence of an organism, facilitated variation implies that they may be far from random in how they affect the development of the organism. Facilitated variation therefore views the organism itself as playing a central part in determining how environmental and genetic variation is expressed.
Most evolutionary change actually takes place withina background of nonevolution. Innovations are actually quite rare. Darwin was well aware of the conservatism and asked
Why, on the theory of Creation, should there be so much variation and so little real novelty? Why should all the parts and organs of many independent beings, each supposed to have been separately created for its proper place in nature, be so commonly linked together by graduated steps? Why should not Nature take a sudden leap from structure to structure?
It would comfort Darwin to know that evolution at the molecular level is even more conservative than at the morphological level. The fundamental life processes evolved early and have remained essentially unchanged for the past two billion years at least. These conserved core processes include the major metabolic pathways for synthesizing or degrading small molecules, the structural and regulatory components of the cell, the mechanisms of DNA replication, transcription of DNA into RNA, use of RNA to specify the structure of proteins (the genetic code), and the regulatory mechanisms that control transcription and translation. Among multicellular organisms, most of the novelties in body plan had already occurred by the Cambrian period (543490 million years ago), although some innovations, such as paired appendages in vertebrates, appeared in more recent periods, the Ordovician (490443 million years ago) or Silurian (443417 million years ago).
While the core life processes are conserved, a riot of variation and innovation is found in morphology, development, and behavior. Kirschner and Gerhart attribute this to several general features of physiology and development. First, genetic regulatory signals are simple and weak (often consisting of extremely short stretches of DNA that regulatory proteins can bind with), and therefore can readily arise or disappear through mutation. Second, signaling between cells is usually permissive and elicits a preprogrammed developmental pathway; this implies that simple signals can do apparently highly complex things. For example, eggs of the American alligator develop as females if incubated at 86°F, but as males if incubated at 91°F. What tips the balance is the quantity of the hormone estradiol that is produced, which acts as a switch that releases the female developmental program already present.
The third feature of organisms that promotes facilitated variation is exploratory behavior and the stabilization of essentially random processes. For example, when neurons grow out from the developing spinal cord, they extend their long, thin axons in essentially random directions. Most of these cells undergo programmed cell death. The neurons that survive are those with axons that happen to have entered the appropriate target tissues, where they receive a protein survival factor that inhibits the programmed cell death. The comings and goings of programmed cell death are important in many examples of evolutionary innovation. The embryos of essentially all vertebrates, for example, have digits connected by webs of skin. In most mammals and most birds, cells in the interdigital regions of the feet usually undergo programmed cell death, but in the development of ducks and geese, a developmental signal cancels the death program, resulting in the seemingly marvelous webbed feet so adapted to an aquatic life style.
Evolutionary novelty is also facilitated by the compartmentation of the embryo. Animal embryos at a middle stage of development form a few dozen compartments with relatively weak linkages among them. As development proceeds, these are subdivided successively into smaller compartments nested within larger ones. In vertebrate development, there may be as many as 200 kinds of compartments. Any of these can grow or shrink in size, or change in shape, quite independently of the others, which allows developmental and evolutionary change while maintaining overall coordination consistent with the body plan of the organism. Examples abound, such as the neck of the giraffe, the trunk of the elephant, or the antlers of the deer. Most important: the same genes, signaling molecules, and pathways can be used for different purposes in each compartment, without compromising a different use of the same components in another compartment.
Neural crest cells provide an excellent example. These cells, unique to vertebrates, originate along the dorsal region of the developing spinal cord but then migrate to various regions of the embryo. Their ultimate fate is determined by where they come to rest. In birds, one subpopulation migrates to the region of the mouth where the cells help form the beak, and another subpopulation migrates to the embryonic heart where the cells help form the valves. There is also communication between compartments that keeps development coordinated. Beak neural crest cells transplanted from a duck to a quail will form a ducklike beak. At the same time, the transplanted cells send out signals that regulate genes in nearby quail tissue so that the oddly shaped beak is smoothly incorporated into the head. These same processes, by the way, help explain the variety of beak shapes and sizes in Darwin’s celebrated Galápagos finches. The development of different types of beak results from differences in the timing and amount of a signaling protein produced, but each beak type fits smoothly into the head owing to communication between compartments.
The coordination of developmental processes is very different from intelligent design. If we were to redesign the airfoil of an airplane, we would also need to redesign the fuselage to attach it securely. This is intelligent design, where linkages are tight and connections inflexible. But if an embryonic bird carried a mutation affecting growth of wing bones, compartmentation and exploratory behavior would cause the muscles to form and be innervated and vascularized, and the wing in turn to be covered with skin and feathers and properly attached to the body. Here the linkages are loose and the connections robust. It would be very difficult to change the size or shape of a bird wing if doing so required nearly simultaneous and independent mutations affecting bone growth, muscularization, vascularization, feathering, and body attachment. But facilitated variation implemented through the coordination of developmental processes makes such changes relatively straightforward. The mutations need not even be creative: they need only elicit the developmental potential that is already present.
Facilitated variation may sound suspiciously like a theory of “evolvability,” in which organisms acquire processes and traits that promote their future evolution. Such theories are frowned upon by most evolutionary biologists, because evolution for evolvability presupposes an unnatural ability to foresee future needs. But Kirschner and Gerhart assure us that facilitated variation has evolved, not for the sake of evolvability, but because it allows each individual organism to cope with its own environmental and developmental accidents. They say that
organisms are always changing and responding to change. In the course of life, they alter their physiological state and behavior. They have mechanisms to resist extremes of temperature, to adapt to variations in the food and water supply, and to modify their response to predators….Furthermore, adaptability of the organism is perhaps even more extensive toward the changing internal conditions wrought by embryonic development….Phenotypic variation, and along with it evolutionary change, is facilitated by simple regulatory tweaks to existing physiological and developmental processes that long ago were designed so that the organism could adapt to its environment.
As it happens, facilitated variation also enhances evolvability, but this is incidental; the distinction is captured in the nice turn of phrase that “getting better at evolving is not the same as evolving for the better.”
As an evolutionary geneticist, I am assuredly impressed with the ability of organisms to undergo evolutionary change and occasionally to stumble upon an innovation that is so useful it is retained in the lineage for millions of years afterward. But I find it equally impressive that there are obvious improvements that evolution seems incapable of bringing about. Darwin stressed the limitations in his comment that “natural selection will not produce absolute perfection, nor do we always meet, as far as we can judge, with this high standard under nature.” The vertebrate eye, wonderful as it is, is far from perfect as most readers wearing glasses will agree. More seriously, I find it paradoxical that a minimum of 15 percent, and perhaps as many as 50 percent, of fertilized eggs in humans, many of which have major chromosomal abnormalities, undergo spontaneous abortion. A reproductive system whose failure rate would be regarded by any respectable engineer as catastrophic hardly seems the work of intelligent design, unless the Intelligent Designer has a very high tolerance for abortion.
Kirschner and Gerhart consider facilitated variation a major advance in completing the theory of evolution by means of random mutation and natural selection. It may seem odd that the theory of evolution needs completing. Because Darwin published The Origin of Species in 1859, the field may appear old and mature. This is a false impression. Even today, in regard to the origin of species, we have limited experimental data bearing on the genetic changes that take place as new species are being formed. (Despite its title, Darwin’s book is primarily about the plausibility of natural selection.)
Evolutionary biology has grown so slowly because many of its major advances have depended on discoveries or techniques in genetics, molecular biology, and developmental biology. Genetics came of age only in the first half of the twentieth century, and the genetic basis of speciation is only now being worked out in a small number of experimental organisms. Molecular biology flowered in the second half of the twentieth century, and the field of molecular systematics, which exploits the discovery that the molecules of cows are more similar to those of goats than they are to those of snakes, is still in its early stages. Developmental biology has flourished in the past 30 years, but still there are many examples of morphological and physiological adaptations in which, while we can guess more or less intelligently at the underlying molecular or developmental mechanisms, we lack experimental tests of these hypotheses. We still know little of how life as we know it began, or how the core processes of life evolved.
Although Kirschner and Gerhart make a strong case for facilitated variation, it remains at this point only a hypothesis whose predictions need to be tested. If it withstands critical experimental scrutiny, it may well become incorporated into general evolutionary theory. At this early stage, facilitated variation merely suggests that the origin of novelty and complexity might be rather more straightforward than previously appreciated. Because of facilitated variation, random mutations do not have random effects on the organism: their effects are shaped by physiology and development. Moreover, complex adaptations need not require multiple favorable mutations occurring nearly simultaneously, because weak regulatory linkages, permissive signaling, compartmentation, and exploratory behavior can allow a single mutation to elicit a major organismal response. In this manner, evolutionary novelty and complexity can emerge from adaptive mechanisms perpetuated in the genomes of the organisms themselves not, as proponents of intelligent design would have us believe, from mysterious forces operating outside the realm of observation, experiment, and scientific understanding.
Higgins professor of biology Daniel L. Hartl, a member of the department of organismic and evolutionary biology, is a leading educator and researcher in evolutionary genetics.