Yes, master
THE Nobel Prize in Biology for 1995 was awarded jointly to Edward B Lewis of the California Institute of Technology (US), Christiane Nusselein-Volhard of the Max Planck Institute for Developmental Biology, Tubingen (Germany), and Eric Wieschaus of Princeton University, US, for "...discovering how genes control the early structural development of the body".
While studying the genetic basis of development in the fruitfly Drosophila melanogaster, the three prizewinners found that there were genes that guided the anterior-to-posterior patterning of the fly's body into head, three thoracic segments and eight abdominal segments. The existence of such genes can be inferred from what happens in mutant flies which lack one or the other of the genes. The mutants suggest that new genes, with specific effects on major features of the body pattern, have arisen when the fly evolved from its worm-like ancestors. As one consequence of the action of these 'pattern genes', the symmetry of an ancestral body plan has been 'broken' to give rise to a body which is less symmetrical. The study of these genes is concerned with a fundamental question in science: why are things different from one another?
In the fly, metameric design (basic body plan consisting of paired repeated segments) - obvious in the larval worm-like stage - also exists in the adult. Larval segments resemble each other markedly, but the segments in the adult are different from one another. Why are all segments not the same?
The starting point of E B Lewis's work was a mutation known as bithorax. Flies with two copies of the mutant bithorax gene (bx/bx) developed portions of an extra pair of wings. In these flies, the anterior (front) half of the third thoracic segment looked like a replica of the corresponding half of the second. In normal flies, the second segment carries a pair of wings while the third has a pair of balancers (halteres) attached to it. Bithorax flies had the normal pair of wings; but in addition, the front half of each haltere was replaced by a half-wing.
Lewis observed that in all mutants similar to bithorax, a segment, or a part of a segment, was replaced by another segment. The phenomenon is referred to as homeosis. These flies owed their appearance to a mutation. The mutated genes formed part of a co-ordinated group that Lewis named the Bithorax complex. The members of the complex are situated closer to each other than two different genes usually are, which led Lewis to infer that they must have arisen during the course of evolution through duplications of a single ancestral gene. For example, a combination bx pbx mutant has both anterior and posterior halves of the third thoracic segment transformed into the corresponding portions of the second, and so it displayed two pairs of entire wings.
In the bithorax complex, a body segment - when mutated - is replaced by the one immediately anterior to it. The body segments can be devoted by the symbols H (head), T1, T2, T3 (three segments of the thorax) and Al, A2 .... A8 (eight segments of the abdomen). The bithorax transformation can be denoted by T3(ant) --- T2(ant); postbithroax leads to T3(post) --- T2(post). If they occur together, the two cause a complete T3 --- T2 transformation, and the symbolic description of the doubly-mutant fly reads H-T1-T2-T2-A1-A2_...-A8.
As the bx and pbx mutations combine additively, so also do the other mutations in the complex. When Lewis generated embryos in which the entire complex was deleted, the mutation was too drastic to permit development until the adult stage. Luckily, the larvae succeeded in hatching, and their body plan carried the signature H-T1,-T2,-T2,-T2- ......-T2: all segments after T, looked like replicas Of T2.
This means it is mutation in genes (bx pbx) that causes a T3 ? T2 switch. Therefore, in the normal fly, the genes in question must be needed to make'13 develop differently from T2. The action of bx and pbx confers segmental identity to T3. One might say the wild-type gene breaks an underlying symmetry between T2 and T3; it is the mutant that reveals the existence of the symmetry. Similarly, other genes of the bithorax complex are responsible for breaking the symmetry between A, and T3, and so on. The deepest symmetry of all is unveiled when the entire complex is deleted. Lewis pointed out that both single gene mutations and the deletion of the complex evoked traces of the fly's evolutionary forebears: four-winged insects and worms.
However, mutants are not true throwbacks to an ancestral form. This means other genes must also have evolved in the course of the evolution from worms to flies. By virtue of the drastic - yet ordered - consequence of mutating the bithorax complex genes, they well deserve to be called 'master genes' or 'control genes'. Unlike Lewis, Nusslein - Volhard and Wieschaus did not embark on their investigations from a theoretical standpoint. Lewis, beginning with the assumption that new genes can arise by the duplication of old ones, concluded that a logical way to understand the roles played by genes in development would be to look for genes that had recently duplicated, newly diverged and affected similar parts of the body.
Nusslem-Volhard and Wieschaus decided to search for genes that act early in development and affect the body pattern. The two treated fly embryos with a chemical mutagen and set about looking for genes that could influence body patterning along the anterior-posterior axis. The results revealed that, firstly, the total number of candidate genes turned out to be only 15; 16 years later, the number still remains small. Secondly, the genes fell naturally into three families - gap genes, pair-rule genes and segment polarity genes; within each family mutations had striking but distinct effects.
in the case of gap genes, mutations gave rise to larvae with gaps of varying extent in the segmental pattern. Mutations in pair-rule genes caused the elimination of portions of the body pattern in a periodic fashion. Segment polarity genes, when mutated, led to the disappearance of portion of each segment and its replacement by the remaining portion. However, the replacement had its polarity inverted - the duplicated portion was a replica of the undisturbed part.
This illuminating report of Nusslein-Volhard and Wieschaus has helped build a model to show how genes specify the body plan of Drosophila. The basic idea is that there is a hierarchical order to genetic activity. Genes that are higher in the hierarchy specify gross features of the body plan, and genes that are lower down sharpen the specification further.
First in hierarchy are the maternal genes. These are active in the body of the mother, as also in the egg. The products encoded by them specify the body axes of the egg, especially the anteriorposterior (head-tail) and the dorsalventral (back-front) axes. In the absence of one of these genes, the egg resembles two mirror-imaged (posterior/posterior or dorsal/dorsal) halves and development is aborted early. Next in hierarchy come the gap genes, followed by the pair-rule and the segment polarity genes.
Research is going on in an attempt to decipher the mode of working of these master genes. One mind-boggler staring us in the face concerns the spatial concordance between the serial order of the bithorax complex genes along the chromosomes and the relative positions of body parts specified by them. The achievements of Lewis, Nusslein-Volhard and Wieschaus constitute a striking vindication of the power of formal genetic analysis in the study of development.