The Ties That Break: University, Company Part Ways After Transomic Mouse Success

Research stalls as a commercial agreement on the technology's future eludes Cytogen and the University of Pennsylvania Last year, two University of Pennsylvania biologists crossed the species barrier in a big way. Little did they know that their feat would lead to crossfire between their institution and the company that sponsored the work. Nor did they anticipate that continued scientific progress would be a casualty of this skirmish. Last July, Jean Richa and Cecilia Lo announced in Science (245:175, 1989) that they had successfully introduced human chromosomes into mice by injecting chromosome fragments into developing mouse embryos. The work was sponsored by Cytogen Corp., a Princeton, N.J., biotechnology company that hopes to create animals capable of producing the whole repertoire of human antibodies. Since then the work has come to a virtual standstill. It is bogged down by disagreements over who - the university or Cytogen - owns the rights to the technology. Lo's lab has generated two dozen mice that may produce a major portion of the human antibody molecule. But the lab has no money for analyzing or breeding the animals to determine whether, in fact, the chromosome has become integrated into the mouse genome and whether it is being expressed. Meanwhile, Cytogen has stopped supporting Lo's lab and is gearing up to transfer the entire project in-house. But that move will force company scientists to repeat much of Lo's work, at a cost of perhaps two to three years. The university, which has filed a patent application on the chromosome-transfer technique, is very circumspect about the status of negotiations with Cytogen. "I think it's fair to say that we have not been able to work out an agreement satisfactory to both Dr. Lo and Cytogen," says Barry S. Cooperman, Penn's vice provost for academic research. Cooperman declined to elaborate on the areas of disagreement. But Lo and Richa agreed to talk, as did Thomas J. McKearn, Cytogen's senior vice president of scientific affairs. Lo and Richa began the project in 1986, working with the first of several grants from Cytogen. The transfer of genes into mice to create what are known as transgenic mice had, by that time, become almost routine. But Lo proposed something more radical: to transfer chromosome fragments that were least 100 times bigger than genes inserted via transgenic technology. Lo's method would transfer clusters of genes, such as those needed to generate antibodies. And the method would not require cloning of the genes first. Instead, chromosome pieces could be snipped out of a human cell and microinjected into a fertilized mouse egg, where they presumably would become stably integrated into the mouse's own DNA. Lo saw great potential in this approach. She theorized that this technique would enable scientists to create mice capable of producing the human antibodies. It could lead to new plants and animals with genetic codes for new, desirable traits. Also, she reasoned, the humanized animals might serve as models of disease even when the specific gene responsible for the disease had not yet been identified. For example, the familial form of Alzheimer's disease appears to involve a region of chromosome 21. By inserting this segment into a mouse's genome, researchers could get the mouse to show some of the same symptoms of the disease. "When I first proposed doing this, people were extremely skeptical," says Lo. "But I was approaching it from the point of view that, in the literature, there was not one piece of evidence that said it couldn't be done. It took a lot of faith. "We had a lot of trials and tribulations," she adds, "and a lot of times we were close to giving up - there were so many technical difficulties. But after a grueling two years, we finally managed to get it to go." By March 1988, the research was finally starting to show some promise. Lo and Richa demonstrated that human chromosome fragments could be microinjected into developing mouse eggs. They showed that some of these eggs would incorporate and replicate the fragment. Also, when the injected eggs were transferred to surrogate female mice, the resulting progeny showed evidence of having retained at least part of the injected chromosome fragment. Cecilia Lo wanted to be a scientist for as long as she can remember. As a child in Taiwan, she first leaned toward agriculture and botany. But after she came to the United States at the age of 10, she became excited about more analytical approaches to biology, particularly molecular biology. That interest was whetted at the Bronx (N.Y.) High School of Science. From there she continued her studies as a biology major at the Massachusetts Institute of Technology, and in 1979 earned a Ph.D. in biology from Rockefeller University. Following a short postdoctoral fellowship at Harvard Medical School, she moved to the University of Pennsylvania. At Penn, Lo studies not only chromosome transfer, but also more basic questions about chromosome structure and function and the regulation of gene expression. "I'm motivated by a desire to understand how this one thing works, how information in the genome can be translated into all the things necessary for normal cell function," says Lo. Her interest in biology is not confined to her lab. At home, she gardens and paints landscapes. She also enjoys figure skating, but says that science severely limits her time at the rink. "Gardening I have to do, but the other things get left in the dust," she says. "It's been hectic ever since graduate school. Worrying about money and grants takes a lot of time." --L.B. Only then did the university and Cytogen begin negotiating licensing arrangements. They also began to draw up a research contract, something that for some unexplained reason was not done at the start of the research. Lo says that it's this contract that has led to her current problems. Her attorney advised her that the agreement, drawn up by Cytogen, was unfair to both her and to the university, and recommended that they not sign it. But when Lo refused to sign, university officials simply crossed out her name. "They signed it, Cytogen signed it, and they left me sitting there," Lo recalls. "I was speechless." Another disagreement arose once the paper by Richa and Lo appeared in Science. Cytogen issued a press release that claimed the company had worldwide rights to commercial applications. The university countered with its own release that claimed Cytogen had a six-month option to negotiate with the university for commercial rights. More troubling to Lo, the Cytogen release hyped the research. "We're still at the very beginning of a long journey," she says. Ralph L. Brinster, a biologist at Penn's veterinary school and a pioneer in transgenic technology, agrees that it's too early to assess the value of Lo's technique. The advantages of being able to introduce gene clusters into mice, he says, will become known only after scientists have had a chance to explore its potential applications. "I think it will be valuable, but it's hard to say if it will be a breakthrough," he says. Lo thinks her technique could be useful in constructing a linkage map of the human genome, as well as for developing mice models for human diseases. But she has had trouble getting support to explore these applications. Negotiations had dragged on between the university and Cytogen until finally her grants from Cytogen, which totaled $344,000 from July 1986 to December 1989, ran out. In October, Lo applied for a National Institutes of Health grant, but she won't know the outcome of her application until next month. Lo has also talked to the university about starting a company, but that too has not yet come to pass. Meanwhile, the loss of Cytogen's support forced her to lay off the technician who was helping with the research. "It's really demoralized people in my lab that have been involved in this project because they've put in so much time," says Lo. Scientists in her lab continue work on other NIH-funded projects, however. Richa, as the primary researcher working on transomic mice, has felt the disappointment most acutely. "It was very hard. It took literally 3 1/2 years to bring the technique to where it is," he says. "I had to start from scratch, I had to test every little idea since there's no literature. And now sometimes I think back at it and maybe smile a little bit. But it still hurts." With limited funds and no technician for the transomic mouse project, Richa has had to shift his attention to other activities in the lab. And now, nearing the end of his postdoctoral fellowship in Lo's lab, he believes that he has fallen short of his research objectives. Richa's career isn't the only thing up in the air. Cytogen's McKearn says that negotiations about commercial rights to the technology have progressed after the company dropped its initial claim to commercial rights to all aspects of the work. It now says it is only interested in the mouse's ability to make antibodies. But McKearn says that Cytogen still has certain licensing options. Not so, says Frank Roth, general counsel for the university. "Our position is that the period of exclusive negotiation, the six-month option period, is over." Roth would not comment on whether negotiations on a potential license are under way with another company. Even so, McKearn remains optimistic that the differences can be resolved. He says that he expects Lo to assist in transferring the technology to Cytogen, even going so far as to teach Cytogen's in-house staff the technique. Lo, for her part, says that she has no such plans. Lo maintains that Cytogen's "antagonistic" position, including attempts to hire people away from her lab, has made a satisfactory solution to the disagreement nearly impossible. In addition, she says that Cytogen's offer of continued funding came with strings attached that were unacceptable to her. "They want us to become Cytogen employees," says Lo. "But I don't want to be an indentured servant. I want academic freedom." Lo's attitude has put the university in a difficult position, according to John Cebra, chairman of Penn's biology department. "It was my suggestion that she sort of bite her tongue," he says. "Cytogen wanted to use the invention for a very narrow purpose. It was my feeling that if [she would agree to that], she could be done with them. Dr. Lo has chosen not to want to deal with them at all. It leaves both the university and Dr. Lo open to being challenged for any other uses of the technology." All the while, Richa watches in frustration as the mice approach old age - and once they die, researchers will have to start all over again. "The point is that once you do something or you find a new technique, you want to push it further," he says. "You find yourself against the wall if you can't do anything." Lisa J. Bain is a freelance writer based in Philadelphia.

The Ties That Break: University, Company Part Ways After Transomic Mouse Success

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