Yes, master

Christiane Nuesslein-Volhard ( (Credit: Photographs: AP / PTI)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.