Over the next year, a mammoth project involving some 17 million tropical fish is expected to yield a treasure trove of data for researchers working on the genetics of vertebrate development.
Artemis Pharmaceuticals, a company based in Cologne, announced last week that it has joined forces with Christiane Nüsslein-Volhard of the Max Planck Institute for Developmental Biology in Tübingen to conduct a zebrafish ‘saturation mutagenesis screen’.
The project, dubbed the Tübingen 2000 Screen, is already under way, and will cost around US$10 million. Its goal is to apply chemical mutagens to zebrafish sperm to introduce point mutations randomly throughout the genome.
Researchers will breed fish using the treated sperm, and screen for those that show developmental abnormalities. From these animals, geneticists can then try to clone the mutated gene. Applying this technique on a sufficiently large scale should make it possible to mutate every important developmental gene — hence the term ‘saturation’ mutagenesis.
Nüsslein-Volhard shared a Nobel prize in 1995 for her work in developing saturation mutagenesis in the fruitfly Drosophila. By this time, she had also begun to apply the technique to the zebrafish (Danio rerio) to investigate the function of genes that control the development of vertebrates. This popular aquarium fish is ideal for developmental studies, as its embryos are transparent, making it easy to spot abnormalities in internal structures.
Nüsslein-Volhard's previous zebrafish screen produced more than 1,000 mutants. A parallel screen — conducted by a team led by Wolfgang Driever, now at the University of Freiburg — produced half as many mutants again. Mutants from both screens were described in a special issue of the journal Development (see Nature 384, 514; 1996). “A lot of interesting mutants were found, and it has been possible to start to characterize some of those molecularly,” says Phil Ingham, a developmental biologist at the University of Sheffield.
But the original screens failed to mutate every important zebrafish developmental gene. “We probably didn't get to saturation,” says Nüsslein-Volhard, who is a co-founder of Artemis. In addition, some interesting mutants may have been overlooked because researchers didn't spot subtle developmental abnormalities in every single organ and physiological system.
This time, researchers with different expertise will examine the same fish to ensure that fewer mutants get overlooked. The screen will be twice the scale of Nüsslein-Volhard's previous project. Peter Stadler, chief executive officer of Artemis, says the project will employ about 50 people.
Scientists at Artemis will mainly screen for abnormalities giving information on gene function that could provide leads for drug development. These include abnormalities in the production of cartilage and bone, and in the cardiovascular system.
Nüsslein-Volhard's team, together with researchers from elsewhere in Germany, Britain and the United States, will look for mutants yielding fundamental insights into the processes of development. These will include fish with abnormalities in the formation of the eyes and the neural crest — paired strips of cells that form early in development, which give rise to a variety of tissues including the central nervous system.
Artemis will have six weeks to patent any discoveries. After this period, results will be made available to other scientists in the normal way, says Stadler.