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Software for the Genome Created by Scientists
at The Scripps Research Institute

La Jolla, CA. January 28, 2000 -- Scientists at The Scripps Research Institute (TSRI) have developed a method of producing and combining proteins as modular building blocks capable of functioning as genetic switches to turn on or off genes on demand. According to Carlos F. Barbas, III, Ph.D., Associate Professor, Department of Molecular Biology, Janet and W. Keith Kellogg II Chair in Molecular Biology, and Member of The Skaggs Institute for Chemical Biology, "In essence, we have created an operating system for genomes. This approach allows scientists for the first time to be able to turn endogenous genes both on and off in a very controlled way. It is very much like installing new software on a computer. You can now get the computer or in this case, the genome to do interesting new things, like fighting disease."

The study, "Positive and Negative Regulation of Endogenous Genes by Designed Transcription Factors," by Drs. Roger R. Beerli, Birgit Dreier, and Carlos F. Barbas, III, appears in the January 28th on-line edition of The Proceedings of the National Academy of Sciences.

TSRI President Richard A. Lerner, M.D., commented, "The importance of this work cannot be overestimated. Its goal is to develop a new class of therapeutic proteins that can inhibit or enhance the synthesis of proteins, providing a new strategy for fighting diseases of either somatic or viral origin. The Barbas lab is currently developing proteins that may inhibit the growth of tumors, halt HIV, and even make healthier corn. They have demonstrated that they can use their alphabet of proteins to specifically turn on or turn off genes at will."

In all organisms, proteins that bind nucleic acids control the expression of genes. The nucleic acids DNA and RNA are the molecules that store the recipes of all life forms. The coordinated expression or reading of the recipes for life allows cells containing the same genetic information to perform different functions and to have different physical characteristics. Proteins that bind nucleic acids enable this coordinated control of the genetic code. Lack of coordination, due to genetic defects or to viral seizure of control of the cell, results in disease.

Barbas continued, "The ability to manipulate gene expression has wide-ranging application in medicine and biology. Nature's control mechanisms center around transcription factors that function to direct the localization of enzymes to specific DNA addresses. This is predicated on the availability of sequence-specific DNA-binding domains, of which zinc finger DNA binding domains have shown the most promise for the development of a universal system for gene regulation. We have shown that this motif is adaptable to the recognition of a wide variety of DNA sequences, often with exquisite specificity."

In this study, two endogenous genes, shown to be involved in human cancers, were targeted for regulation. Experiments revealed that transcription factors designed to bind to the transcribed regions of the genes were capable of selectively switching on or off the specified target genes.

The research group has shown that the building blocks are functionally modular and may be recombined with one another -- just like a child's Lego set -- to create proteins capable of binding 18 base-pair sequences. They now have at hand a family of zinc finger domains sufficient for the construction of 17 million novel gene switches.

Ongoing work includes building a protein that binds to the DNA sequence known to cause Huntington's Disease, a methodology for correcting sickle cell anemia, and constructing modular proteins to inhibit the spread of HIV. Other implications of the technology include controlling genes, either on a permanent or temporary basis, by an antibiotic which acts as a genetic on-off switch. Insulin production, for example, could potentially be controlled in this fashion.

The work was funded by the National Institutes of Health and The Skaggs Institute for Research.

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