UP Natural Science Research Institute email account nsri at NICOLE.UPD.EDU.PH
Tue Oct 10 22:29:20 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 Nüsslein-Volhard and Eric F. Wieschaus 
   for their discoveries concerning
   "the genetic control of early embryonic development"
   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 Nüsslein-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 Nüsslein-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.
   Fig. 1. Regions of activity in the embryo for the genes belonging to
   the gap, pair-rule, and segment-polarity groups. The gap genes start
   to act in the very early embryo (A) to specify an initial segmentation
   (B). The pair-rule genes specify the 14 final segments (C) of the
   embryo under the influence of the gap genes. These segments later
   acquire a head-to-tail polarity due to the segment polarity genes.
   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 (Fig 1) 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 Nüsslein-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 (Fig. 2). 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
   Fig. 2. Comparison of a normal and a four-winged fruit fly. The third
   thoractic segment has developed as a duplicate of the second due to a
   defectic homeotic gene. In the normal fly only the second segment
   develops wings.
   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 (Fig. 3). 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 (Fig 3). 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.
   Fig. 3. The principle of colinearity in Drosophila (A-C) and mouse
   (Mus musculus, D-F) embryos. The horizontal bars indicate in which
   areas the homeotic genes 1-9 are active along the body axis. Gene 1 is
   active in the head region (left in A and F, respectively); gene 9 is
   active in the tail region (right). Gene 7 of the bithorax complex was
   inactive in the fly with four wings. The bar showing its normal range
   of activity is indicated with an asterisk.
   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 (Fig 3 D-F) 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 Nüsslein-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
   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.
   Lewis, E.B. (1978) A Gene Complex Controlling Segmentation in
   Nature 276, 565-570
   Nüsslein-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
   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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