The thoroughness and novelty of the “Heidelberg screens” (as the experiments came to be known) and their importance for revealing the mechanisms of regulatory control during animal embryogenesis won the attention of the Nobel committee. In 1995, the committee awarded the Nobel Prize in Medicine or Physiology to Nüsslein-Volhard and Wieschaus. “This work was revolutionary,” University of Cambridge geneticist Daniel St. Johnston explained, “because it was the first mutagenesis in any multicellular organism that attempted to find most or all of the mutations that affect … the essential patterning genes that are used throughout development.”2
That’s the story as it is usually told. And it’s correct, as far as it goes. But the mutant fruit flies obtained by Nüsslein-Volhard and Wieschaus tell another story—one less widely known, but one containing important clues for the unsolved mystery of the origin of animal body plans.
Wieschaus himself alluded to these clues in a memorable interaction at the 1982 meeting of the American Association for the Advancement of Science (AAAS). After a session on the processes of macroevolution in which Wieschaus had presented a paper, one audience member asked him what he meant by the term “strong” as he used it to describe the mutations he and Nüsslein-Volhard had induced in flies. Wieschaus explained with a laugh that “strong” certainly did not mean alive. Without exception, the mutants he studied perished as deformed larvae long before achieving reproductive age. “No, dead is dead,” he joked, “and you can’t be more dead.”3
Another questioner then asked Wieschaus about the implications of his findings for evolutionary theory. Here Wieschaus responded more soberly, wondering aloud about whether his collection of mutants offered any insights into how the evolutionary process could have constructed novel body plans. “The problem is, we think we’ve hit all the genes required to specify the body plan of Drosophila,” he said, “and yet these results are obviously not promising as raw materials for macroevolution. The next question then, I guess, is what are—or what would be—the right mutations for major evolutionary change? And we don’t know the answer to that.”4
Thirty years later, developmental and evolutionary biologists still don’t know the answer to that question. At the same time, mutagenesis experiments—on fruit flies as well as on other organisms such as nematodes (roundworms), mice, frogs, and sea urchins—have raised troubling questions about the role of mutations in the origin of animal body plans. If mutating the genes that regulate bodyplan construction destroy animal forms as they develop from an embryonic state, then how do mutations and selection build animal body plans in the first place?
The neo-Darwinian mechanism has failed to explain the generation of new genes and proteins needed for building the new animal forms that arose in the Cambrian explosion. But even if mutation and selection could generate fundamentally new genes and proteins, a more formidable problem remains. To build a new animal and establish its body plan, proteins need to be organized into higher-level structures. In other words, once new proteins arise, something must arrange them to play their parts in distinctive cell types. These distinctive cell types must, in turn, be organized to form distinctive tissues, organs, and body plans. This process of organization occurs during embryological development. Thus, to explain how animals are actually built from smaller protein components, scientists must understand the process of embryological development.
FIGURE 13.1
Figure 13.1a (left): Christiane Nüsslein-Volhard. Courtesy Wikimedia Commons, user Rama. Figure 13.1b (right): Eric F. Wieschaus.
The Role of Genes and Proteins in Animal Development
As much as any other subdiscipline of biology, developmental biology has raised disquieting questions for neo-Darwinism. Developmental biology describes the processes, called ontogeny, by which embryos develop into mature organisms. Within the past three decades the field has dramatically advanced our understanding of how body plans arise during ontogeny. Much of this new knowledge has come from studying so-called model systems—organisms that biologists can easily mutate in the lab, such as the fruit fly Drosophila and the nematode Caenorhabditis elegans.
Although the exact details of animal development can vary in bewildering ways depending on the species, all animal development exemplifies a common imperative: start with one cell, end with many different cells. In most animal species, development begins with the fertilized egg. Once the egg divides into its daughter cells, becoming an embryo, the organism begins heading toward a well-defined target, namely, an adult form that can reproduce. Arriving at that distant target requires the embryo to produce many specialized cell types, in the correct positions and at the right time.
Cell differentiation involves coordinating the expression of specific genes in space and time, as the number of cells, taking on their different roles, rises from one to two to four to eight, doubling and doubling until it reaches thousands, millions, and even trillions, depending on the species. The number of cell divisions and the total number of cells reflects the number of different cell types the adult needs. This in turn requires producing different proteins for different cell types.
For example, the specialized digestive proteins that service the cells lining the adult intestine differ from proteins expressed in a neuron found in the nerve tract of a limb. They must differ because each performs dramatically different functions. So, during development, the appropriate genes must be turned on, or “up-regulated,” and turned off, or “down-regulated,” to ensure the production of the correct protein products at the right time and in the right cell types.
Specific proteins play active roles in regulating the expression of genes for building other proteins. The protein actors playing these coordinating roles are known as transcriptional regulators (TRs) or transcription factors (TFs). TRs (or TFs) usually bind directly to specific sites in DNA, either preventing (repressing) or enabling (activating) the transcription of specific genes into RNA. TRs or TFs convey instructions about which genes to turn on or turn off. Their three-dimensional geometries exhibit characteristic DNA-binding features, including a specific domain of 61 amino acids that wraps around the DNA double helix. Other transcription factors include the zinc finger and leucine zipper motifs that also bind to DNA. Transcriptional regulators and factors are themselves controlled by complex circuits and signals transmitted by other genes and proteins, the overall complexity and precision of which is breathtaking.
Painstaking genetic research—performed by Nüsslein-Volhard and Wieschaus and many other developmental biologists5—has uncovered many of the key embryonic regulatory genes that help switch cells into their differentiated adult types. This research also uncovered a profound difficulty cutting to the very core of the neo-Darwinian view of life.
Early-Acting BodyPlan Mutations and Embryonic Lethals
To create significant changes in the forms of animals requires attention to timing. Mutations in genes expressed late in the development of an animal will affect relatively few cells and architectural features. That’s because by late in development the basic outlines of the body plan have already been established.6 Late-acting mutations therefore cannot cause any significant or heritable changes in the form or body plan of the whole animal. Mutations that are expressed early in development, however, may affect many cells and could conceivably produce significant changes in the form or body plan, especially if these changes occur in key regulatory genes.7 Thus, mutations that are expressed early in the development of animals have probably the only realistic chance of producing large-scale macroevolutionary change.8 As evolutionary geneticists Bernard John and George Miklos explain, “macroevolutionary change” requires changes in “very early embryogenesis.”9 Former Yale University evolutionary biologist Keith Thomson concurs: only mutations expressed early in the development of organisms can produce large-scale macroevolutionary change.10
Yet from the first experiments by geneticist T. H. Morgan systematically mutating fruit flies early in the twentieth century until today, as
many model species have been subjected to mutagenesis, developmental biology has shown that mutations affecting bodyplan formation expressed early in development inevitably damage the organism.11 (See Fig. 13.2, for examples.) As one of the founders of neo-Darwinism geneticist R. A. Fisher noted, such mutations are “either definitely pathological (most often lethal) in their effects,” or they result in an organism that cannot survive “in the wild state.”12
Normal development in any animal can be represented as an expanding network of decisions, where the earliest (upstream) decisions have greater impact than those occurring later. Regulatory genes and their DNA-binding protein products help to control this unfolding network of decisions—such that if regulatory proteins are altered or destroyed by mutation, the effects cascade downstream into the whole developmental process. The earlier the failure, the more widespread the destruction. Geneticist Bruce Wallace explains why early-acting mutations are thus overwhelmingly likely to disrupt animal development. “The extreme difficulty encountered,” he observes, “when attempting to transform one organism into another … still functional one lies in the difficulty in resetting a number of the many controlling switches in a manner that still allows for the individual’s orderly (somatic) development.”13
Nüsslein-Volhard and Wieschaus discovered this problem in experiments performed on fruit flies after their first Nobel Prize–winning efforts. In these later experiments they studied protein molecules that influence the organization of different types of cells early in the process of embryological development. These molecules, called “morphogens,” including one called Bicoid, are critical to establishing the fruit fly’s head-to-tail axis. They found that when these early-acting, bodyplan-affecting molecules are perturbed, development shuts down. When mutations occur in the gene that codes for Bicoid, the resulting embryos die14—as they do in all other known cases in which mutations occur early in the regulatory genes that affect bodyplan formation.
There are good functional reasons for this, familiar to us from the logic of other complex systems. If an automaker modifies a car’s paint color or seat covers, nothing else needs to be altered for the car to operate, because the normal function of the car does not depend upon these features. But if an engineer changes the length of the piston rods in the car’s engine, and does not modify the crankshaft accordingly, the engine won’t run. Similarly, animal development is a tightly integrated process in which various proteins and cell structures depend upon each other for their function, and later events depend crucially on earlier events. As a result, one change early in the development of an animal will require a host of other coordinated changes in separate but functionally interrelated developmental processes and entities downstream.15 This tight functional integration helps explain why mutations early in development inevitably result in embryonic death and why even mutations expressed somewhat later in development commonly leave organisms crippled.
Looking more closely at a specific experimental result of this kind further illuminates the problem. A mutation in the regulatory Ultrabithorax gene (expressed midway in the development of a fly) produces an extra pair of wings on a normally two-winged creature. Although an extra set of wings may sound like a useful piece of equipment, it’s not at all. This “innovation” results in a crippled insect that cannot fly because it lacks, among other things, a musculature to support the use of its new wings. Because the developmental mutation was not accompanied by the many other coordinated developmental changes that were needed to make the wings useful, the mutation is decidedly harmful.
FIGURE 13.2
Examples of deleterious macromutations produced by experiments on fruit flies, including the “short wings,” “curly wings,” “eyeless,” and Antennapedia mutants.
This problem has led to what Georgia Tech geneticist John F. McDonald has called a “great Darwinian paradox.”16 He notes that the genes that are obviously variable within natural populations seem to affect only minor aspects of form and function—while those genes that govern major changes, the very stuff of macroevolution, apparently do not vary or vary only to the detriment of the organism. As he puts it, “Those [genetic] loci that are obviously variable within natural populations do not seem to lie at the basis of many major adaptive changes, while those loci that seemingly do constitute the foundation of many if not most major adaptive changes are not variable within natural populations.”17 In other words, the kind of mutations the evolutionary process would need to produce new animal body plans—namely, beneficial regulatory changes expressed early in development—don’t occur. Whereas, the kind that it doesn’t need—viable genetic mutations in DNA generally expressed late in development—do occur. Or put more succinctly, the kind of mutations we need for major evolutionary change we don’t get; the kind we get we don’t need.
My Discovery Institute colleague Paul Nelson (see Fig. 13.3), a philosopher of biology who specializes in evolutionary theory and developmental biology, summarizes the challenge to neo-Darwinism posed by animal development as three premises:
1.Animal body plans are built in each generation by a stepwise process, from the fertilized egg to the many cells of the adult. The earliest stages in this process determine what follows.
2.Thus, to evolve any body plan, mutations expressed early in development must occur, must be viable, and must be stably transmitted to offspring.
3.Such early-acting mutations of global effect on animal development, however, are those least likely to be tolerated by the embryo and, in fact, never have been tolerated in any animals that developmental biologists have studied.
FIGURE 13.3
Paul Nelson. Courtesy Paul Nelson.
Nelson came to appreciate the depth of the problem posed by these facts after many years of discussion with two members of his University of Chicago Ph.D. committee, evolutionary biologist Leigh Van Valen (1935–2010) and evolutionary theorist and philosopher of biology William Wimsatt. Van Valen, famous for his “Red Queen hypothesis” about the need for organisms to continue to evolve in order to maintain fitness, was passionately interested in the mechanisms of macroevolution. Wimsatt originated the theory of “generative entrenchment,” an account of the “causal asymmetries” at work in complex systems, including those responsible for animal development.18 Both acknowledged to Nelson that the scientific literature offers no examples of viable mutations affecting early animal development and bodyplan formation (Premise 3, on previous page) and also that the macroevolution of novel animal form requires just such early-acting mutations (Premise 2, on previous page). Nevertheless, both Van Valen and Wimsatt remained committed to the descent of animal forms from a common ancestor via some kind of undirected mutations. Nelson argues, however, that those premises strongly imply that the neo-Darwinian mechanism does not—and indeed cannot—provide an adequate mechanism for producing new animal body plans. As he has told me: “If the only kind of mutations that can conceivably produce enough morphological change to alter whole body plans never causes beneficial and heritable changes, then it is difficult to see how mutation and selection could ever produce new body plans in the first place.”19
Thus, he concludes:
Research on animal development and macroevolution over the last thirty years—research done from within the neo-Darwinian framework—has shown that the neo-Darwinian explanation for the origin of new body plans is overwhelmingly likely to be false—and for reasons that Darwin himself would have understood.
Indeed, Darwin himself insisted that “nothing can be effected” by natural selection, “unless favorable variations occur.”20 Or as Swedish evolutionary biologist Søren Løvtrup succinctly explains: “Without variation, no selection; without selection, no evolution. This assertion is based on logic of the simplest kind… . Selection pressure as an evolutionary agent becomes void of sense unless the availability of the proper mutations is assumed.”21 Yet the “proper” kind of mutations—the mutations that produce favorable changes to early-acting, bodyplan�
�shaping, regulatory genes—do not occur.
Microevolutionary change is insufficient; macromutations—large-scale changes—are harmful. This paradox has beset Darwinism from its inception, but discoveries about the genetic regulation of development in animals have made this paradox more acute and cast serious doubt on the efficacy of the modern neo-Darwinian mechanism as an explanation for the new body plans that arise in the Cambrian period.
Developmental Gene Regulatory Networks
Another line of research in developmental biology has revealed a related challenge to the creative power of the neo-Darwinian mechanism. Developmental biologists have discovered that many gene products (proteins and RNAs) needed for the development of specific animal body plans transmit signals that influence the way individual cells develop and differentiate themselves. Additionally, these signals affect how cells are organized and interact with each other during embryological development. These signaling molecules influence each other to form circuits or networks of coordinated interaction, much like integrated circuits on a circuitboard. For example, exactly when a signaling molecule gets transmitted often depends upon when a signal from another molecule is received, which in turn affects the transmission of still others—all of which are coordinated and integrated to perform specific time-critical functions. The coordination and integration of these signaling molecules in cells ensures the proper differentiation and organization of distinct cell types during the development of an animal body plan. Consequently, just as mutating an individual regulatory gene early in the development of an animal will inevitably shut down development, so too will mutations or alterations in the whole network of interacting signaling molecules destroy a developing embryo.
Darwin's Doubt Page 29
