REHOVOT, Israel - December 3, 1997 - In the genes of an organism, as in real estate, location is key. The functioning of any gene is significantly affected by its exact placement on the chromosome.
However, scientists currently have no means of delivering a new gene to a predetermined location in a cell's chromosomes during genetic manipulation, such as gene therapy.
A method that may make it possible to control where new genes go has been developed by Prof. Ernest Winocour of the Molecular Genetics Department at the Weizmann Institute of Science together with post-doctoral fellow Dr. Joe Corsini and Prof. Jacov Tal of Ben-Gurion University of the Negev's School of Medicine.The approach, described in the December issue of the Journal of Virology, may significantly improve all types of genetic manipulation in which new genes are introduced into an organism.
"The ultimate goal is to target a gene to a position where it brings the most good and causes no harm," says Winocour.
To carry new genes to the cells of an organism, scientists often use viruses that serve as "delivery vehicles." Before such a "vehicle," called a vector, is dispatched, researchers equip it with the gene they want it to deliver - for example, a healthy "replacement" copy for a faulty, disease-causing gene.The vector inserts itself into the chromosomes and the newly delivered gene begins to replicate every time the cell divides.
However, all existing vectors insert themselves into chromosomes at random positions. As a result, scientists have poor control over the function of the new genes. When these genes make their home in certain positions, they will function poorly or not at all; in other positions they may be thrown out of the cell altogether. Moreover, there is the risk that, in some positions, the new genes will negatively affect the neighboring DNA.
"Knowing where the genes go on the chromosomes may make it possible to develop improved gene therapy with a long-lasting effect," says Prof. Winocour.
To attain this goal, Winocour and colleagues propose to use a family of viruses called parvoviruses. The striking feature of parvoviruses is their "single-mindedness": they are the only animal viruses that integrate themselves into the cell's chromosomes at unique sites. Knowing in advance where the virus is headed gives scientists greater control over what it will do once it has inserted itself into the organism's genome.
In the new study, Winocour and colleagues studied one type of parvovirus called minute virus of mice, or MVM. The scientists revealed the mechanism that allows MVM to zero in on a particular target site. They were then able to replicate this mechanism - which consists of signals exchanged by the virus and the chromosomes - in a model system.
"Further research needs to be done to see if our method works in laboratory animals," says Winocour., "If successful, it can have far-reaching applications in medicine and animal breeding." Winocour notes further that this research may be extended to other parvoviruses. There are about 50 known parvoviruses, each of which might be capable of inserting itself at a specific location.If the entire parvovirus family is harnessed, it may provide scientists with an extremely useful and versatile array of gene vectors.
A patent application for the new method has been filed by Yeda Research and Development Co., the Weizmann Institute's technology transfer arm, together with Ben-Gurion University of the Negev.
This research was supported by the German-Israeli Foundation for Scientific Research and Development (GIF). Dr. Corsini is the recipient of a postdoctoral fellowship from the Planning and Budgeting Committee of the Israel Council for Higher Education.
The Weizmann Institute of Science is a major center of scientific research and graduate study located in Rehovot, Israel.