Hen’s Teeth and Horse’s Toes
The first set, called the bithorax complex and abbreviated BX-C, regulates the normal development and differentiation of the fly’s posterior body segments. The larval fly is already divided into a series of segments, initially quite similar, that will differentiate into specialized adult structures. The first five larval segments build the adult head (the first forms anterior parts of the head; the second, the eyes and antennae; and the third through fifth, the various parts of the mouth). The next three segments, T1, T2, and T3, form the thorax. Each will bear a pair of legs in the adult, building the normal insect complement of six. The single pair of wings will differentiate in T2.
The next eight segments (A1 through A8) form the adult’s abdomen, while the final, or caudal, segment (A9 and A10) will build the adult’s posterior end. The presence of normal BX-C genes appears to be a precondition for the ordinary development of all segments behind the second thoracic. If all the genes of BX-C are deleted from the third chromosome, all larval segments behind the second thoracic (T2) fail to differentiate along their normal route and seem to become second thoracic segments themselves. If the adult survived, it would be a wonder to behold, with (presumably) a pair of legs on each of its numerous posterior segments. But this deletion is, in geneticist’s jargon, “lethal,” and the fly dies while still a larva. We know that the posterior segments of such aberrant flies are slated to develop as second thoracics because incipient differentiation within the larval segments serves as a sure guide to their later fate.
The bithorax complex includes at least eight genes, all located in sequence right next to each other. Edward B. Lewis (see bibliography), the distinguished geneticist from CalTech who has spent twenty years probing the complexities of BX-C, believes that these eight genes arose as repetitions of a single ancestral gene and then evolved in different directions. Just as the entire deletion of BX-C produces the striking homeotic effect of converting all posterior segments to second thoracics, several mutations in the eight genes produce homeotic results as well. The most famous mutation, called bithorax and commandeered as a name for the entire complex, converts the third thoracic segment into a second thoracic. Thus, the adult fly develops with two second thoracics and two pairs of wings, instead of one pair and a pair of halteres behind. (It is misleading to state that halteres “turn into” wings. Rather, the entire segment normally destined to be a third thoracic, and to produce halteres, develops as a second thoracic and builds wings.) In another mutation, called bithoraxoid, the first abdominal segment develops as a third thoracic, builds a pair of legs, and produces a fly with more than the usual insect number of six.
Lewis has proposed an interesting hypothesis for the normal action of BX-C genes. He believes that they are initially repressed (turned off) in the larval fly. As the fly develops, BX-C genes are progressively derepressed (turned on). The BX-C genes act as regulators—that is, they do not build parts of the body themselves but are responsible for turning on the structural genes that do code for building blocks. Adult form reflects the amount of BX-C gene-product in an embryonic segment; the more BX-C, the more posterior in appearance the segment. Lewis then argues that BX-C genes are derepressed in sequence, from the anterior point of their action (the third thoracic segment) to the back end of the animal. When a BX-C gene turns on, its product accumulates in a given segment and, simultaneously, in all segments posterior to it. BX-C first turns on in the third thoracic, and its product accumulates in all segments from the third thoracic to the posterior end. The next BX-C gene turns on in the next posterior segment, the first abdominal, and its product accumulates in all segments from the first abdominal to the posterior end. The next gene turns on in the second abdominal, and so forth. Thus, a gradient of BX-C product forms, with lowest concentration in the second thoracic and increasing amounts in a posterior direction. The more gene product, the more posterior in appearance the form of a resultant segment.
This hypothesis is consistent with the known homeotic effects of BX-C mutations. If BX-C is deleted entirely, it supplies no gene product, and all segments behind the second thoracic differentiate as second thoracics. In a mutation with opposite effect, all the BX-C genes are turned on at the same time in all segments—and all segments affected by BX-C then differentiate as eighth abdominals.
The second outstanding set of homeotics is also named for its most famous mutation—the antennapedia complex, or ANT-C. The fine structure of this complex has recently been elucidated in a series of remarkable experiments by Thomas C. Kaufman, Ricki Lewis, Barbara Wakimoto, and Tulle Hazelrigg in Kaufman’s laboratory at the University of Indiana. (I thank Dr. Kaufman for introducing me to the literature of homeosis and for patient and lucid explanations of his own work.) The BX-C genes regulate the morphology of segmentation from the third thoracic to the posterior end; ANT-C also affects the third thoracic, but then regulates development in the five segments anterior to it (the other two thoracics and the three that produce parts of the mouth). If the entire complex is deleted, then all three thoracic segments begin to differentiate as first thoracics (while the abdominals, regulated by BX-C, develop normally). Apparently, the genes of ANT-C normally turn on in the second thoracic segment and trigger the proper development of the second and third thoracics.
Kaufman and his colleagues have found that ANT-C consists of at least seven genes, not all with known homeotic effects, lying right next to each other on the right arm of the third chromosome in D. melanogaster. The genes are not named for their normal effects (which, after all, just yield an ordinary fly bearing nothing special for recognition) but for their rare homeotic mutations. The first, the antennapedia gene, regulates differentiation of the second thoracic segment, and normally turns on there to accomplish its appointed function. A series of mutations has been detected at this locus, all with homeotic effects consistent with this interpretation of normal function.
One dominant mutation, antennapedia itself, has the bizarre effect (as its name implies) of producing a leg where an antenna ought to be. This wayward appendage is not any old leg, but clearly a second thoracic. The antennapedia mutation apparently works by turning on in the wrong place—the antennal segment—rather than in the second thoracic segment.
A fly with antennapedia mutation, in which legs form where the antenna should be. SCANNING ELECTRON MICROSCOPE PHOTO BY F. R. TURNER.
Another dominant mutation, called extra sex combs, leads to the appearance of sex combs on all three pairs of legs, not only on the first as in normal flies. This morphology is not simply the result of a gene that makes sex combs (contrary to popular belief, very few genes simply “make” individual parts without series of complex and coordinated effects). It is a homeotic mutation. All three thoracic segments differentiate as first thoracics, and the fly has, literally, three pairs of first legs with their attendant sex combs. (The entire deletion of ANT-C also causes the three thoracics to differentiate as first thoracics, but this deletion is lethal and the fly dies in its larval stage. Flies with the extra sex comb mutation do live to become adults.) The extra sex comb mutation probably operates by suppressing the normal action of its gene. Since normal action causes the second thoracic segment to differentiate properly, suppression induces all three thoracics to develop as first thoracics.
The second gene of ANT-C is named for its prominent mutation, reduced sex comb. This homeotic mutation, contrary to the effect of its neighbor extra sex comb, causes the first thoracic segment to differentiate as a second thoracic. Only first thoracic legs bear sex combs in D. melanogaster. The next three genes do not have known homeotic effects, and their inclusion within ANT-C is something of a puzzle. One deletes a number of embryonic segments in its most prominent mutation, another interferes with normal development of the maxilla and mandible of the mouth, while the third produces a curiously wrinkled embryo.
The sixth gene of ANT-C is named for the other famous homeotic mutant of this complex—proboscipedia, discovered in 1933 by two of the century’s most famous genet
icists, Calvin Bridges and Theodosius Dobzhansky. Six mutations have been detected at this locus; most, like proboscipedia itself, produce legs where parts of the mouth should develop. The seventh and last (known) gene of ANT-C lacks homeotic effects in its mutant form and produces severe constrictions at segment boundaries in the larva. It is lethal.
Homeosis is not peculiar to fruit flies, but seems to be a general phenomenon, at least in arthropods. A set of mutations analogous (or even homologous) with the bithorax homeotics of Drosophila occurs in the silk moth Bombyx (order Lepidoptera; flies belong to the order Diptera). Two species of Tribolium, the flour beetle (order Coleoptera), exhibit mutations with effects that mimic the ANT-C homeotics of Drosophila. One set, in Tribolium castaneum, acts like antennapedia and produces a graded series of partial replacements of antennae by legs, ranging from tarsal claws on the eleventh antennal segment to the virtual replacement of an entire antenna with a foreleg. Another, in T. confusum, acts like proboscipedia and substitutes legs of the first thoracic segment for mouth structures known as labial palps. In the cockroach Blatella germanica, a homeotic mutant produces rudimentary wings on the first thoracic segment. No modern insect normally bears wings on its first thoracic segment, but the earliest winged fossil insects did!
Homeosis is easiest to demonstrate in arthropods with their characteristic body plan of discrete segments with different and definite fates in normal development, but common embryological and evolutionary origins. Yet analogous phenomena have been noted again and again in other animals and plants with repeated parts. In fact, Bateson’s first example after defining the term cited vertebrae in the human backbone. All mammals (except sloths, but including giraffes) have seven cervical, or neck, vertebrae (they are awfully large in giraffes). These are followed by dorsal, or rib-bearing, vertebrae. Bateson noted numerous cases of humans with ribs on the seventh, and even a few with ribs on the sixth, cervical vertebra.
Homeotic mutants are gripping in their weirdness, but what do they teach us about evolution? We must avoid, I believe, the tempting but painfully naïve idea that they represent the long-sought “hopeful monsters” that might validate extreme saltationist views of major evolutionary transitions in single steps (a notion that I, despite my predilections for rapid change, regard as a fantasy born of insufficient appreciation for organisms as complex and integrated entities). First of all, most homeotic mutations produce hopeless creatures. The legs that extend from antennal sockets or surround mouths in afflicted flies are useless appendages without proper neural and muscular hookups. Even if they did work, what could they accomplish in such odd positions? Secondly, the viable homeotics mimicking ancestral forms are not really forebears reborn. A bithorax fly bears the ancestral complement of four wings, but it attains this state by growing two second thoraxes, not by recovering an ancient pattern.
I believe that the lessons of homeosis lie first in embryology and then cycle back to evolution. As Tom Kaufman pointed out to me, they demonstrate in a dramatic way how few genes are responsible for regulating the basic order of developing parts in a fruit fly’s body. Together, the ANT-C and BX-C complexes of D. melanogaster specify the normal development of all the mouth, thoracic, and abdominal segments—only the two anterior segments are not subject to their control. Each complex contains only a handful of genes and each handful may have evolved from a single ancestral gene that repeated itself several times. When these genes mutate or are deleted, peculiar homeotic effects arise that usually throw development awry and lead to death.
Most importantly perhaps, these homeotic complexes display the hierarchical way in which genetic programs regulate the immense complexity of embryonic development, recognized since Aristotle’s time as biology’s greatest mystery. The homeotic genes do not build the different structures of each body segment themselves. This is the role of so-called structural genes that direct the assembly of proteins. The homeotics are switches or regulators; they produce some signal (of utterly unknown nature) that turns on whole blocks of structural genes.
Yet, at a higher level, some master regulator must be responsible for turning on the homeotics at the right time and in the right place, for we know that many homeotic mutations are mistakes in placement and timing. Perhaps this master regulator is no more than a gradient of some substance running from the front to the back end of a larval fly; perhaps the homeotic regulators can “read” this gradient and turn on in the right place by assessing its concentration. In any case, we have three hierarchical levels of control: the structural genes that build different parts in each segment, the homeotic regulators that switch on the blocks of structural genes, and the higher regulators that turn on the homeotic regulators in the right place and at the right time.
If embryology is a hierarchical system with surprisingly few master switches at high levels, then we might draw an evolutionary message after all. If genetic programs were beanbags of independent genes, each responsible for building a single part of the body, then evolution would have to proceed bit by bit, and any major change would have to occur slowly and sequentially as thousands of parts achieved their independent modifications. But genetic programs are hierarchies with master switches, and small genetic changes that happen to affect the switches might engender cascading effects throughout the body. Homeotic mutants teach us that small genetic changes can affect the switches and produce remarkable changes in an adult fly. Major evolutionary transitions may be instigated (although not finished all at once as hopeful monster enthusiasts argue) by small genetic changes that translate into fundamentally altered bodies. If classical Darwinian gradualism is now under attack in evolutionary circles, the hierarchical structure of genetic programs forms a powerful argument for the critics.
In this context, we consider the hypothetical major steps in insect evolution and recognize that homeotic mutants may help to illuminate them. Insects, with their relatively few, differentiated segments, probably evolved from an ancestor with more numerous and less differentiated segments. Initially, these less differentiated segments each bore a pair of legs (the antennae and mouthparts of modern insects are modified legs). Insects evolved by suppressing legs on the posterior segments and modifying them to antennae and mouthparts on the anterior segments. The major homeotic complexes of Drosophila seem to regulate just these changes—and with a minimum of genetic information. BX-C controls the posterior appendages with their suppressed legs, and its deletion causes these segments to begin a differentiation as second thoracics with incipient legs. The major mutants of ANT-C replace structures that were once legs with legs. The nature of homeotic changes is not capricious, but follows evolutionary channels.
Even the bizarre homeotics may not be devoid of evolutionary information. When Bridges and Dobzhansky described proboscipedia in 1933, they noted that a large set of coordinated changes—quite apart from the spectacular appearance of legs—all brought the mouthparts closer to the standard form of biting insects from which flies presumably evolved. (Dobzhansky, who died just a few years ago, was the greatest evolutionary geneticist of our times. Fancy, quantitative lab work often wins all the kudos while field naturalists, with their detailed and specific knowledge, are unfairly dismissed as stamp collectors. Dobzhansky’s life proves how misguided this prejudice is. Geneticists had been describing homeotic mutants for years, but none had the knowledge to recognize the subtle morphological effects that require a trained taxonomist’s eye to comprehend. Dobzhansky, the finest geneticist of them all, was a trained taxonomist and field biologist who began his work by specializing on the systematics of the Coccinellidae, or lady beetles. There is no substitute for detailed knowledge of natural history and taxonomy.)
If anyone has wondered whether homeotic mutants must find their significance only in highfalutin realms of evolutionary speculation, I close with an arresting fact. A homeotic mutation has been found in the biting mosquito Aedes albopictus. Yes, you guessed it. This mutation converts part of the biting apparatus into a pair of legs! The
six stylets that actually pierce our skin are unaffected, but the labella, the structures that surround the stylets and contain tactile and chemosensory hairs, are converted to legs with tarsal claws at their tips. These mosquitos cannot pierce skin, both because they lack the tactile and chemosensory hairs that locate the right spot and because the stylets get entrapped in the misplaced legs.
What a wonderful and joyous idea in a world inundated with bad news—an ouchless mosquito with an extra pair of legs. Oh, don’t raise your hopes. They won’t replace the normal ones. First of all, they die because they cannot feed (although they can be artificially maintained on blood-soaked cotton balls). Even if they learned to feed by lapping instead of piercing, they would be no match for the normal kind because they have longer larval lives, increased pupal mortality, and a significant decrease in adult longevity. Still, these are the curious facts that nurture hope in parlous times—in this case, and with only a little poetic license, an enormous advantage (if only for another long-suffering creature) of putting a foot in one’s mouth.
4 | Teilhard and Piltdown
16 | The Piltdown Conspiracy1
Introduction and Background
OF CONSPIRACIES
IN HIS GREAT ARIA “La calunnia,” Don Basilio, the music master of Rossini’s Barber of Seville, graphically describes how evil whispers grow, with appropriate watering, into truly grand and injurious calumnies. For the less conniving among us, the same lesson may be read with opposite intent: in adversity, try to contain. The desire to pin evil deeds upon a single soul acting alone reflects this strategy; conspiracy theories have a terrible tendency to ramify like Basilio’s whispers until the runaway solution to “whodunit” becomes “everybodydunit.” But conspiracies do occur. Even the pros and pols now doubt that Lee Harvey Oswald acted alone; and everybody did do it on the Orient Express.2