IMPORTANT - 1995 Nobel Prize in Physiology or Medicine

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Mon Oct 9 05:42:50 EST 1995


Press Release October 9, 1995

The Nobel Assembly at the Karolinska Institute has today decided to award
the Nobel Prize in Physiology or Medicine for 1995 jointly to

Edward B. Lewis, Christiane Nsslein-Volhard and Eric F. Wieschaus

for their discoveries concerning

"the genetic control of early embryonic development"



Summary

The 1995 laureates in physiology or medicine are developmental biologists
who have discovered important genetic mechanisms which control early
embryonic development. They have used the fruit fly, Drosophila
melanogaster , as their experimental system. This organism is classical in
genetics. The principles found in the fruit fly, apply also to higher
organisms including man. Using Drosophila Nsslein-Volhard and Wieschaus
were able to identify and classify a small number of genes that are of key
importance in determining the body plan and the formation of body segments.
Lewis investigated how genes could control the further development of
individual body segments into specialized organs. He found that the genes
were arranged in the same order on the chromosomes as the body segments
they controlled. The first genes in a complex of developmental genes
controlled the head region, genes in the middle controlled abdominal
segments while the last genes controlled the posterior ("tail") region.
Together these three scientists have achieved a breakthrough that will help
explain congenital malformations in man.

What controls the development of the fertilized egg?

The fertilized egg is spherical. It divides rapidly to form 2, 4, 8 cells
and so on. Up until the 16-cell stage the early embryo is symmetrical and
all cells are equal. Beyond this point, cells begin to specialize and the
embryo becomes asymmetrical. Within a week it becomes clear what will form
the head and tail regions and what will become the ventral and dorsal sides
of the embryo. Somewhat later in development the body of the embryo forms
segments and the position of the vertebral column is fixed. The individual
segments undergo different development, depending on their position along
the "head-tail" axis. Which genes control these events? How many are they?
Do they cooperate or do they exert their controlling influence
independently of each other? This year' s laureates have answered several
of these questions by identifying a series of important genes and how they
function to control the formation of the body axis and body segments. They
have also discovered genes that determine which organs that will form in
individual segments. Although the fruit fly was used as an experimental
system, the principles apply also to higher animals and man. Furthermore,
genes analogous to those in the fruit fly have been found in man. An
important conclusion is that basic genetic mechanisms controlling early
development of multicellular organisms have been conserved during evolution
for millions of years.

Brave decision by two young scientists

Christiane Nsslein-Volhard and Eric Wieschaus both finished their basic
scientific training at the end of the seventies. They were offered their
first independent research positions at the European Molecular Biology
Laboratory (EMBL) in Heidelberg. They knew each other before they arrived
in Heidelberg because of their common interest: they both wanted to find
out how the newly fertilized Drosophila egg developed into a segmented
embryo. The reason they chose the fruit fly is that embryonic development
is very fast. Within 9 days from fertilization the egg develops into an
embryo, then a larvae and then into a complete fly.

They decided to join forces to identify the genes which control the early
phase of this process. It was a brave decision by two young scientists at
the beginning of their scientific careers. Nobody before had done anything
similar and the chances of success were very uncertain. For one, the number
of genes involved might be very great. But they got started. Their
experimental strategy was unique and well planned. They treated flies with
mutagenic substances so as to damage (mutate) approximately half of the
Drosophila genes at random (saturation mutagenesis). They then studied
genes which, if mutated would cause disturbances in the formation of a body
axis or in the segmentation pattern. Using a microscope where two persons
could simultaneously examine the same embryo they analyzed and classified a
large number of malformations caused by mutations in genes controlling
early embryonic development. For more than a year the two scientists sat
opposite each other examining Drosophila embryos resulting from genetic
crosses of mutant Drosophila strains. They were able to identify 15
different genes which, if mutated, would cause defects in segmentation. The
genes could be classified with respect to the order in which they were
important during development and how mutations affected segmentation. Gap
genes control the body plan along the head-tail axis. Loss of gap gene
function results in a reduced number of body segments. Pair rule genes
affect every second body segment: loss of a gene known as "even-skipped"
results in an embryo consisting only of odd numbered segments. A third
class of genes called segment polarity genes affect the head-to-tail
polarity of individual segments. The results of Nsslein-Volhard and
Wieschaus were first published in the English scientific journal Nature
during the fall of 1980. They received a lot of attention among
developmental biologists and for several reasons. The strategy used by the
two young scientists was novel. It established that genes controlling
development could be systematically identified. The number of genes
involved was limited and they could be classified into specific functional
groups. This encouraged a number of other scientists to look for
developmental genes in other species. In a fairly short time it was
possible to show that similar or identical genes existed also in higher
organisms and in man. It has also been demonstrated that they perform
similar functions during development.

The fly with the extra pair of wings

Already at the beginning of this century geneticists had noted occasional
malformations in Drosophila. In one type of mutation the organ that
controls balance (the halteres), was transformed into an extra pair of
wings. In this type of bizarre disturbance of the body plan, cells in one
region behave as though they were located in another. The Greek word
homeosis was used to describe this type of malformations and the mutations
were referred to as homeotic mutations.

The fly with the extra pair of wings interested Edward B. Lewis at the
California Institute of Technology in Los Angeles. He had, since the
beginning of the forties, been trying to analyze the genetic basis for
homeotic transformations. Lewis found that the extra pair of wings was due
to a duplication of an entire body segment. The mutated genes responsible
for this phenomenon were found to be members of a gene family
(bithorax-complex) that controls segmentation along the anterior-posterior
body axis. Genes at the beginning of the complex controlled anterior body
segments while genes further down the genetic map controlled more posterior
body segments (the colinearity principle). Furthermore, he found that the
regions controlled by the individual genes overlapped, and that several
genes interacted in a complex manner to specify the development of
individual body segments. The fly with the four wings was due to inactivity
of the first gene of the bithorax complex in a segment that normally would
have produced the halteres, the balancing organ of the fly. This caused
other homeotic genes to respecify this particular segment into one that
forms wings. Edward Lewis worked on these problems for decades and was far
ahead of his time. In 1978 he summarized his results in a review article
and formulated theories about how homeotic genes interact, how the gene
order corresponded to the segment order along the body axis, and how the
individual genes were expressed. His pioneering work on homeotic genes
induced other scientists to examine families of analogous genes in higher
organisms. In mammalians, the gene clusters first found in Drosophila have
been duplicated into four complexes known as the HOX genes. Human genes in
these complexes are sufficiently similar to their Drosophila analogues they
can restore some of the normal functions of mutant Drosophila genes.

The individual genes within the four HOX gene families in vertebrates occur
in the same order as they do in Drosophila , and they exert their influence
along the body axis in agreement with the colinearity principle first
discovered by Lewis in Drosophila. More recent research has suggested that
the segments where shoulders and the pelvis form is determined by homeotic
genes.

Congenital malformations in man

Most of the genes studied by Nsslein-Volhard, Wieschaus and Lewis have
important functions during the early development of the human embryo. The
functions include the formation of the body axis, i.e. the polarity of the
embryo, the segmentation of the body, and the specialization of individual
segments into different organs. It is likely that mutations in such
important genes are responsible for some of the early, spontaneous
abortions that occur in man, and for some of the about 40% of the
congenital malformations that develop due to unknown reasons. Environmental
factors such as very high doses of vitamin A during early pregnancy are
also known to disturb the regulation of HOX-genes, thus inducing severe
congenital malformations. In some cases have mutations been found in human
genes related to those described here for Drosophila. A human gene related
to the Drosophila gene paired will cause a condition known as
Waardenburg"'"s syndrome. It is a rare disease which involves deafness,
defects in the facial skeleton and altered pigmentation of the iris.
Another developmental gene mutation causes a complete loss of the iris, a
condition known as aniridia.

Literature

Lewis, E.B. (1978) A Gene Complex Controlling Segmentation in Drosophila.
Nature 276, 565-570

Nsslein-Volhard, C., Wieschaus, E. (1980). Mutations Affecting Segment
Number and Polarity in Drosophila. Nature 287, 795-801

McGinnis, W., Kuziora, M. (1994). The Molecular Architects of Body Design.
Scientific American 270, 36-42

Lawrence, P. The Making of a Fly. Blackwell Scientific Publications.
Oxford 1992.

The Molecular Biology of the Cell. Eds Alberts, B. et al, 3rd edition pp
1077-1107. Garland Publishing, New York 1994. 




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