The experiment was so elementary, and the results so surprising, that researchers working with San Diego’s Vical Inc. couldn’t really believe what they were seeing. It all seemed too simple.

They had been injecting submicroscopic fatty globules containing DNA or RNA into mice to see what would happen. The idea was that the fat globules, called liposomes, would be taken up by cells. The cells would use the genetic material inside to make proteins they couldn’t otherwise make.

The researchers found moderate success with that, but the rigors of science demanded that the experiment have a “control” portion--injecting the raw DNA or RNA into the mice to show that the liposomes themselves were making it possible for the new genes to be incorporated into the cell’s processes.

It turned out the cells like the raw material even better and began making the new proteins for as long as six months.

“This was a big surprise, and that’s really what you’re looking for in this area,” said [Dr. Philip Louis Felgner (born 1950)], director of product development at Vical. Felgner worked on the experiment with [Dr. Jon Asher Wolff (born 1956)] and others at the University of Wisconsin at Madison.

Researchers spent several months longer trying to find flaws in their methods or their conclusions. The literature of science is littered with examples of experimental results that deserved the label of too good to be true, explained [Dr. Karl Yoder Hostetler (born 1939)], vice president for research and development at Vical.

“We didn’t want any fiascoes,” he said.

Vical hopes that the results of this checking and double-checking, reported in today’s issue of the journal Science, will convert the company from a bare-bones start-up to a major player in the ranks of San Diego’s biotechnology community.

The company, which was founded in 1987, hopes to find financing to more than double its scientific staff of 22 as a result of the study. It is talking with several large drug companies to see if any would like to buy into the follow-up studies on the new gene transfer method, said Vical President Wick Goodspeed.

Some familiar names in San Diego science and business have played a role in Vical. Among them:

[Dr. Karl Yoder Hostetler (born 1939)], who is on leave from his longtime post as professor of medicine in residence at UC San Diego. His specialties include investigating ways to use lipid chemistry to improve the effectiveness of drugs.

[Dr. Douglas Daniel Richman (born 1943)], a founder and scientific adviser to the firm. Richman is a professor in residence of medicine and pathology at UCSD, specializing in virology and clinical trials of AIDS treatments.

[Dr. Dennis A. Carson (born 1936) ], also a scientific adviser to the firm. Carson recently resigned as head of the division of clinical immunology at Scripps Clinic to become head of UCSD’s new institute for research on aging.

Timothy Wollaeger, chairman of the board. Wollaeger formerly was senior vice president in charge of finance and administration for Hybritech Inc., the monoclonal antibody firm whose success was capped in 1986 with its $485-million acquisition by Eli Lilly & Co.

Howard E. (Ted) Greene, a director of Vical. He formerly was chief executive officer for Hybritech. Greene and Wollaeger were the driving forces behind Biovest Partners, a venture capital firm that financed several San Diego biotech firms.

W. Larry Respess, a Vical director. A leader in biotech patent law, he formerly was general counsel of Gen-Probe and Hybritech.

Until now, the best combination of science and business for Vical has been the multi-year research contract it received last summer from Burroughs Wellcome Co. to develop new forms of AZT for AIDS therapy. The study is investigating the idea that encasing AZT in fat globules would make it more powerful within the body.

The gene-insertion technique reported in Science this week is being suggested as a way to cause the body to generate proteins that would block persistent viral infections, ranging from AIDS to herpes. It also is seen as having potential use as a way to trigger cells to immunize the body against diseases, researchers say.

Vical is calling the new method “gene therapeutics,” to distinguish it from the traditional goal of gene therapy, which uses viruses to insert missing genes into the genetic codes of people with genetic diseases.

The so-called retroviral method has proved difficult and slow, despite several years of intense effort by research groups around the country, including a group led by Dr. Theodore Friedmann at UCSD.

Because retroviruses insert their own genetic code into the cells of their host, the method is also expected to be problematic as a gene therapy technique--since some scientists worry that this could harm the patient irreversibly in some unforeseen way.

Inserting the genes themselves into muscle cells--without any retroviral carrier--avoids this stumbling block entirely, [Dr. Philip Louis Felgner (born 1950)] said. The genes do their work of producing proteins, called expression, but they don’t seem to affect the cell’s own genetic structure, he said.

“People have worked in the gene therapy area for years assuming that a rather complex viral delivery system would be required in order to get expression. And we have found that you can do it very simply,” Felgner said.

It was the slowness of the gene therapy field that led Felgner’s collaborator, of the University of Wisconsin, to decide less than two years ago to get out of it altogether, Wolff said in a telephone interview.

Wolff was an assistant professor and a researcher in Friedmann’s UCSD lab before going to Wisconsin as an assistant professor of pediatrics and medical genetics in 1988.

“I had pretty much planned to get out of the gene therapy field because I got discouraged with the retroviral approach. Scientifically, it wasn’t very challenging,” he said. “Everybody was doing the same thing, and nothing was working that well.”

The results of the research contract with Vical, begun in January, 1989, have rekindled his enthusiasm, [Dr. Jon Asher Wolff (born 1956)] said.

He believes that, in the end, genetic therapies will involve a variety of techniques, not just the Vical method. But he and [Dr. Philip Louis Felgner (born 1950)] acknowledge that they expect some resistance to their ideas from the traditional gene therapy community.

“You’re talking about somebody who has spent his life in this field, and who would like to make the real breakthroughs that are going to allow it to be used in patients with diseases,” Felgner said. “There’s quite a bit at stake.”

Other collaborators with Wolff and Felgner on the research were [Dr. Robert Wallace Malone (born 1959)] of Vical and Phillip Williams, Wang Chong, Gyula Acsadi and Agnes Jani in Wisconsin.

Vical is planning to try to patent the technique, even though it involves no novel or complex steps unfamiliar to molecular biologists. In essence, it involves preparing DNA or RNA with standard techniques and then injecting it in the conventional way into muscle.

“The reason why we have patent position is that it was such a total surprise. Some of those things are the best patents you can get,” Felgner said. “Nobody who was ‘skilled in the art’ would have ever thought that what we have accomplished here was even possible. Nobody would have even thought to do the experiment.”