Moving Toward Designer Genes

By Anastasia Toufexis

DNA research steps up from the cell to the animal

Since scientists first began manipulating genes, they have been envisioning a brave new world in which diseases from Huntington's chorea to sickle-cell anemia to possibly diabetes could be cured simply by inserting the correct strip of DNA into the body's cells. So far, though, most of the genetic tinkering has been limited to transplanting genes into isolated cells in laboratory dishes or into bacteria.

But the dawn of designer genes is slowly moving closer. Researchers are now extending their experiments to living animals. In April, scientists at the University of California in Los Angeles reported they had inserted into intact adult mice a gene that makes cells resistant to a specific drug. Last week a team of Yale University scientists announced they had altered an animal's hereditary makeup at a more basic level: by injecting foreign genes into a mouse at its earliest stage of development, a fertilized egg.

In the Yale experiment, described by Biologist Francis Ruddle at an international conference on cell biology in West Berlin, he and Colleagues Jon Gordon and George Scangos isolated genes from two viruses and manufactured them in large quantities. Then, guided by a high-powered microscope and using tubes thinner than hairs, they delicately microinjected 1,000 to 20,000 copies of the genetic material directly into the nuclei of newly fertilized mouse eggs kept alive in laboratory dishes. The eggs were then carefully transferred to the wombs of female mice and eventually the foster mothers gave birth to 150 infants. The newborns were promptly killed, and the DNA was extracted from their tissues for study. Portions of the viral genes were found in two of the mice. Presumably the genes had been present in every cell of those animals.

While the experiment offers the possibility that by changing the genetic material in the human egg, doctors may one day be able to eliminate a host of inherited diseases--including hemophilia, Tay-Sachs disease and phenylketonuria, a metabolic disorder that may result in brain damage--many basic questions must first be answered. For example, will the transplanted genes actually work as they are supposed to or will they be modified or inactivated by the animal's own genetic machinery? Will the foreign genes free-float in the cells or will they latch on to the other genes arranged along the chromosomes? Will genes that normally are switched on only in specific types of cells function in the same way when they have been introduced into other types of cells through genetic engineering? Finally, will transplanted genes be inherited by the animal's descendants?

Last spring's U.C.L.A. development has prompted similar questions, but the medical payoff from it may come a bit sooner. In that experiment, a team of scienlists led by Martin Cline and Winston Salser isolated genes that help produce an enzyme resistant to methotrexate, a drug used to treat cancer. The researchers added the genes to cell cultures of mouse bone marrow. The cells that picked up the foreign material, along with cells that had been incubated with genes that do not confer resistance, were then injected into mice whose own bone marrow had been destroyed. To see if the drug-resistance genes were working, the animals were given methotrexate. Tests after two months showed that cells that carried the resistance genes made up most of the bone marrow.

The U.C.L.A. findings may eventually help patients undergoing cancer chemotherapy. Methotrexate, used to treat leukemia and other cancers, is like most antitumor drugs: potent but harsh. It indiscriminately destroys rapidly proliferating cells, malignant and healthy alike. Among the healthy ones are those of bone marrow, which produce blood cells. The damage that methotrexate does to bone marrow effectively limits how much of it can be given to patients. Making the cells resistant to the drug's assault might give patients the ability to withstand more intensive therapy.

Researchers also speculate that doctors might use the technique to correct blood diseases that result from defects in single genes, including sickle-cell anemia and thalassemia. The therapeutic gene could be transferred into bone marrow cells along with a gene for drug resistance. Exposure to the drug would kill off marrow that produces defective blood cells and allow a population of "cured" cells to take over.

A5 more experiments with living animals get under way, the longstanding debate over genetic engineering's ethical implications and potential dangers is sure to intensify. Some scientists, like Rockefeller University's Norton Zinder, maintain that experimentation with humans is still a long way off and the concern is thus premature: "No one's going to diddle with human embryos in a time frame we can understand. Maybe in a thousand years."

Others are not so sure. Notes Harvard's Jonathan Beckwith: "What's happened in this field is a series of advances. When each happens, most people go around saying, 'The idea of genetically engineering embryos is so far off.' And then the next advance occurs. We may be moving faster than we think."

Reported by Suzanne Wymelenberg/New Haven and Rosemary George/West Berlin

With reporting by Suzanne Wymelenberg, Rosemary George

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