Fluorescent Mice Herald Gene-Transfer Breakthrough

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Some of the mice glowed more than others, depending on how many copies of the jellyfish gene they acquired. But 80 percent of the original mice (14 out of 17) that received the gene transfer carried at least one copy of the gene, and most of them, 90 percent, showed a high level of fluorescence.

Trojan Horses, Gene Promoters

Carlos Lois, the lead author of a paper on the work, said the researchers used a modified HIV virus for the experiments to exploit the qualities that make HIV particularly virulent. Known as a retrovirus, HIV acts like a Trojan horse—once the virus infects cells, it transfers its own genetic material into the chromosomes of the host animal.

"How many horses do you let inside the cells? You can get one or many," said Lois, explaining why the mice could acquire one or multiple copies of the foreign gene from the invader virus. The scientists were able to control the level by manipulating the concentration of individual viruses present in the transfer solution.

A factor that apparently influences the results, Lois said, is the nature of the DNA material that controls how well a gene is "expressed," or manifested in certain traits.

The strings of chemicals that comprise individual genes are basically divided into two segments. One sequence carries the coding for making the proteins that produce various traits, while an accompanying sequence acts to "promote" the gene expression.

"If you have a very good promoter, one copy of the virus may be sufficient" to produce an animal with the desired genetic trait, Lois said, adding that the identification of reliable promoters is critical for the successful application of transgenic technologies.

Toward Progress in Research

In the first experiments done to produce a transgenic animal, scientists used a different kind of virus to deliver the imported gene into mice. A major problem, however, was that the genes were "silenced" as the mice developed. "The approach was good and could have been used universally for many species, but there was no gene expression," said Lois.

In the 1980s, the research community adopted a technique called pronuclear injection—using tiny glass pipettes to insert genes from various organisms directly into DNA in the nucleus of mouse cells. Although it is now the most common method for producing transgenic animals, it is inefficient and limited mainly to mice, Lois noted, because 100 or more embryos may be required to achieve a single successful gene transfer.

"We have found that by using the modified virus we can combine the best of both these techniques because we can have expression of the gene and we are not limited by the number of embryos we have to obtain," Lois said.

The technique also holds much promise for inserting genes that regulate specific tissues of the body, Lois said. In one experiment, the researchers equipped the virus to carry, along with the jellyfish fluorescence gene, a gene and related promoter sequence that help regulate the development of muscles. When the researchers examined the mouse embryos at 11 days old, fluorescence was seen only in the nucleus of muscle cells and not other cells. In another experiment, the generation of mice carrying the jellyfish fluorescence gene under the activity of a promoter sequence that regulates the development of lymphocytes resulted in the expression of the green gene in blood cells. "These results indicate that with this technique it is possible to direct the expression of exogenous genes into specific organs or tissues of the body," Lois said.

The researchers also generated some transgenic rats that successfully acquired the jellyfish fluorscence gene. This is a huge advantage to researchers, Baltimore noted, because rats are preferred for use in many laboratory experiments.

It should be possible, the scientists said, to use the new technique to produce many other transgenic animal species, especially higher mammals and birds.

"There's no real need for a new technique for mice, but there are many areas of research for which [transgenic] mice are not helpful—for example, as a model for Alzheimer's," said Lois. "So it would be extremely useful to develop monkeys that could develop Alzheimer's, or a primate that could get AIDS, so we could use them to test vaccines and treatments."

The Caltech team tried two different methods of inserting the virus and the fish gene it carried into the mice cells. One method involved injecting the virus under the layer (called the zona pellucida) that protects recently fertilized eggs. A second method entailed removing the protective layer and incubating the denuded fertilized eggs in a concentrated solution of the virus. The researchers found that the latter method was easier, but less efficient. Like other methods of gene transfer, the viral-transmission technique has some limitations, the scientists noted. It may not work, for example, when transferring very large pieces of DNA.

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