In collaboration with Dr. Melissa Ashlock, a colleague in the Genetics and Molecular Biology Branch, lab members are constructing human artificial chromosomes (HAC) that may provide an ideal gene delivery system. The HAC vector would not integrate into endogenous chromosomes, eliminating the possibility of insertional mutagenesis. It can, in theory, accept unlimited sizes of DNA, so large genes and long stretches of surrounding regulatory sequences can be transferred. Design features of the vectors suchas centromeres, telomeres, and replication origins should facilitate the stable maintenance and correct segregation of the vector in human cells. They have engineered yeast strains with telomerases adding human telomere sequences to chromosome ends. Such yeast strains are expected to be good hosts to propagate the HAC vectors. We are now concentrating on the characterization of functional and manageable centromere and replication origin sequences for the HAC vectors.

Finally, in collaboration with groups around the world, they cloned the gene responsible for the autosomal recessive disease familial Mediterranean fever (FMF), a disease mainly affects people in the Mediterranean area and is characterized by periodic attacks of fever, elevated neutrophils in the circulation, and abdominal pain. Interestingly, the FMF gene may encode a nuclear protein and is expressed exclusively in mature neutrophils. We are generating transgenic mouse models to understand the role of this gene in the differentiation and function of neutrophils.