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The fruit fly begins life as a simple fertilized egg. From that single cell a complete animal arises, equipped with arms, legs, eyes, a nervous system, and all the other accoutrements of the body.
But how does the process of development begin? How are cells in the embryo directed to organize themselves, execute a specific biological blueprint, and begin development of a complex organism from an egg?
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What I did not realize until late in my development as a scientist is that morphology and cell biology are actually the same scientific areas,
or at least that the latter provides
the molecular explanation of the former. ”
— Eric Wieschaus*
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At one time, gaining access to the molecular mechanisms that assign developing cells to their respective regions of the body seemed impossible. Even in the fruit fly — the workhorse of molecular biology and an animal that goes from egg to adult in only 9 days — ferreting out such mechanisms was viewed as a formidable challenge. But in the late 1970s, HHMI investigator Eric F. Wieschaus, collaborating with Christiane Nüsslein-Volhard at the European Molecular Biology Laboratory in Heidelberg, began searching for the master genes responsible for transforming the fertilized egg of the fruit fly into a developing embryo.
The genome of the fruit fly contains about 14,000 genes. For Wieschaus and Nüsslein-Volhard, sorting through those genes to discover which ones kick-start early development meant a tedious trial-and-error process. The team first created mutant flies, “knocking out” the functions of random genes by treating the flies with mutagenic chemicals. Breeding the mutant flies, Wieschaus and Nüsslein-Volhard created nearly 40,000 families of Drosophila with defective genes.
Wieschaus and Nüsslein-Volhard were searching for genes that, if mutated, would cause irregularities in the body axis or segmentation pattern of the developing embryo. For more than a year, they painstakingly sorted through their families of mutant flies to home in on the crucial genes involved in early development. Under a microscope, the scientists could observe malformations in the embryo caused by the mutations of various genes and were thus able to find a limited number of genes that seemed to govern the first stages of development. In particular, they identified 15 genes that, when mutated, caused defects in the embryo's ability to correctly form its characteristic segments. They eventually found 139 genes that proved essential to development.
Their work showed that it was possible to use a systematic approach to identify the genes that control development. It also showed that those genes were limited in number and could be sorted into functional groups. Finding those master genes earned Wieschaus, Nüsslein-Volhard, and the late Edward B. Lewis of Caltech the 1995 Nobel Prize in Physiology or Medicine.
Building on the work of Wieschaus, who is now at Princeton University, and Nüsslein-Volhard, scientists learned that similar genes are at work in higher animals, including humans, and that those genetic circuits play identical roles during development. Those insights provided powerful evidence for the idea that, instead of inventing new genes to accomplish the same developmental tasks in different organisms, nature is simply reusing genes to set up new body plans.
* From Les Prix Nobel, The Nobel Prizes 1995, Editor Tore Frängsmyr, Nobel Foundation, Stockholm, 1996.
Photo: David Graham
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