HAMBURG, Germany - Using 17 million zebrafish, Artemis Pharmaceuticals AG is preparing a major international effort to screen the genome of this small vertebrate to discover and evaluate gene function in vivo.

The collaboration involves two German Max Planck institutes - MPI for Developmental Biology, of T|bingen, and MPI for Immune Biology, of Freiburg - the University of Heidelberg, Germany; University College of London; and the Howard Hughes Medical Institute at Children's Hospital in Boston.

"To our knowledge, this is the largest ever vertebrate genetic screening project," Peter Stadler, CEO of Cologne-based Artemis, told BioWorld International. "Zebrafish and man have a similar number of genes, and, surprisingly, they have more than 90 percent of their genes in common."

Scientists hope the tiny transparent larvae not only will reveal fundamental processes in vertebrate organ and tissue development, but also will serve as a model for human biology and disease mechanisms.

During the year-long project, called "T|bingen 2000 screen," mutations will be induced in zebrafish, which then will be bred according to a predefined breeding scheme. The resulting 17 million third-generation zebrafish larvae will be screened for mutations using 17 different assays to identify abnormal phenotypes in relation to bone and cartilage formation, heart and circulation properties, ear malformations, primordial germ cells, etc. From the parents of the abnormal phenotypes the scientists then will breed strains to map and finally clone the genes.

"Screening the fish is quite a task," Paul Rounding, head of Artemis' business development, told BioWorld International. "The larvae have to be inspected by eye and, in two days, our scientists will inspect about 5,000 larvae each. Due to the complicated logistics, we will have a limit of 20,000 to 25,000 larvae per week. He added that per assay the scientists hoped to find about 200 mutations, which might lead to the identification of 60 to 70 genes in each disease assay.

The methodology for the large-scale screen was developed by German Nobel Laureate and Artemis co-founder Christiane N|sslein-Volhard, who said she was pleased to have been able to attract an international consortium of world-class scientists to make optimal use of the scientific and technical infrastructure that had been established in T|bingen.

Stadler said the huge amount of gene sequence data from genome projects had created a mismatch between the generation of data and of knowledge. "The challenge now is to understand gene function and to determine the role of gene regulation and modulation in diseases. As this cannot be inferred from DNA sequences directly, Artemis has based the project on the approach to uncover the function of relevant genes before the sequence is identified."

The 15-month screen will cost Artemis about US$6 million to US$9 million. The company will retain certain exclusive commercial rights to all discoveries made during the project. "Findings will be published in the appropriate scientific journals," Stadler said.

He said he hoped the project would result in a great leap forward to identify screening targets and to develop innovative small-molecule therapeutics or therapeutic proteins to treat a number of diseases.

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