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Breakthrough In Transgenic Animal Technology

Research reported in the 24 November 1998 edition of the Proceedings of the National Academy of Sciences may herald a new era in biopharmaceutical production.

Work performed in the laboratory of former University of Wisconsin-Madison dairy science professor Robert Bremel, and by Gala Design LLC, a Sauk City, Wis. company, has resulted in breakthrough increases in the efficiency in the production of transgenic livestock.

Dairy livestock are seen as key players in the production of genetically engineered protein drugs, such as monoclonal antibodies, hormones, vaccine proteins and enzymes. Introducing new genes into the animals allows them to produce specific pharmaceutical proteins in their milk, from where it can be extracted as a drug component. Costs of producing proteins by this route are far lower than more traditional pharmaceutical production methods, using large culture vessels or bioreactors.

The PNAS article describes a new method of gene introduction that greatly increases the efficiency of production of transgenic cattle. The transgametic method inserts a gene into the unfertilized oocyte or egg, which stably incorporates the gene into the maternal germline. Once the egg is fertilized, all cells of the resulting embryo carry the new gene, and the calf is born with the capability to secrete a new protein in milk. Subsequent generations, offspring of each founder animal, will also carry the desired gene.

Older, less efficient production methods made transgenic livestock very costly. Cloning and pronuclear microinjection typically lead to only 1 percent of animals born carrying the new gene. The new technology also sidesteps problems of gene stability and mosaicism seen with microinjection. When DNA is microinjected into a fertilized embryo, the DNA is often not taken up until cell division has occurred. As a result, only some cell lineages carry the new gene. If the germ or sex cells don”t carry the new gene, then the gene isn”t reliably transferred to offspring.

The efficiency of the new technology could make cloning and pronuclear microinjection economically obsolete for many biopharmaceutical purposes. It also paves the way to applications of biotechnology in agricultural livestock, similar to those that have changed crop agriculture in recent years. The technology may also have applications in other mammals.

The scientists believe the technology described also points to a key process in evolution. Transposable elements, or transposons, are known to jump to new locations in the genome (the cell”s hereditary material) and bring about changes in the genome that confer selective advantage. The experimental introduction of genes by a vector – which is structurally very similar to a transposable element – into the exposed genome of the oocyte results in uptake of a new, fully heritable, genetic characteristic. The vectors used build on the work of the late Howard Temin, a UW-Madison researcher who won a Nobel Prize for his work in describing reverse transcription, in which RNA is used as a template for copying and inserting a DNA gene into a cell.

Early steps in the research were performed by Anthony Chan, then a graduate student in Bremel”s lab at the UW-Madison”s College of Agricultural and Life Sciences, and the work was completed by Bremel and colleagues at Gala Design. The technology is licensed through the Wisconsin Alumni Research Foundation, which returns royalty income from university inventions to the University of Wisconsin.