By Dennis St. Germaine

It took 12 years, an interdisciplinary collaboration between professors from physiology and pharmacology and the professional nurturing of a post-doctoral fellow to discover a way to cause premature ovarian failure in female mice without surgically removing their ovaries.

Making the results of their work broadly available took more time and effort. Aided in part by the University’s Office of Technology Transfer, not only have they created a series of research relationships stretching across the country, but they also have created a start-up company located in Flagstaff and formed a relationship through UA with a non-profit that makes research animal models available to laboratories throughout the world.

What the Physiology Department’s Patricia Hoyer has accomplished, along with a post-doctoral fellow, Loretta Mayer, is the creation of a mouse model that can be used to study postmenopausal conditions such as cardiovascular disease, Alzheimer’s disease, osteoporosis, and a number of other conditions that increase in women after menopause.

“This seems to be good for a variety of things,” says Hoyer. “We can set up studies related to disease states; Alzheimer’s and a number of other conditions known to be associated with menopause. For example, we’ve found changes in bone mineral density of these animals, which has implications for osteoporosis.”

Mayer developed the appropriate conditions to rapidly deplete the mouse ovaries of the egg-containing follicles. “That causes ovarian failure, so we have an animal that is follicle depleted, but ovary intact,” Hoyer says.

“This method can be applied to mice of any age, opening up new possibilities for research into diseases and conditions that affect women in menopause,” says Hoyer.

“Normally, mimicking menopause in rats and mice involves surgical removal of the ovaries. Whereas that removes normal physiological contributions of the ovaries; for example, estrogen. It also removes residual ovarian tissue that might be making a physiological contribution in post-menopausal women,” she says. “Using our approach is preferable because it mimics normal menopause. The mouse still has ovaries even though the follicles (structures on the ovaries that contain the eggs) are no longer present.”

The method developed by Hoyer and her team uses a chemical called 4-vinylcyclohexine diepoxide (VCD), an industrial solvent normally used in the manufacture of tires, plasticizers and insecticides. When administered to a female rat or mouse, “we found that it destroys oocytes (eggs) in their ovaries. Furthermore, it is selective for the smallest form of oocyte containing particles, so it does not produce extensive effects within the ovary.”

In a 13-year collaboration with Glenn Sipes of the College of Pharmacy, Hoyer has found that by destroying the eggs in mouse and rat ovaries, VCD accelerates a natural process called “atresia.” As a result, the ovaries become depleted of eggs and the animals go into a state of premature ovarian failure, similar to menopause in women.

She says that atresia occurs in ovaries of all female mammals, but most species do not actually experience a natural onset of ovarian failure because their lifespans are too short. “But today a woman can expect to live 30 years after menopause.”

Hoyer continues her studies on the mouse model at UA and has recently received a grant from the National Institutes of Health, specifically the National Institutes of Aging, based on a five-year proposal to develop and characterize the mouse model.

Technology Transfer

In thinking about her work, like many researchers Hoyer says, “We want other people to use it.”

In the tradition of universities since their founding, Hoyer has been making the results of her efforts available to others. She already has moved the new discovery to and beyond campus, through collaborations with Carol Banka at the La Jolla Institute of Molecular Medicine, Cheryl Dyer of Northern Arizona University, Mari Golub at the University of California at Davis, and Janet Funk, a UA scientist who is researching bone changes in arthritis.

Banka has been using a transgenic mouse strain to study aortic lesions, or plaque development, as a model for cardiovascular disease, but has begun working with the VCD mouse in her studies as a replacement for the model with surgically removed ovaries. “The usefulness of this is that you can give these mice back estrogen and see if it prevents plaque formation.”

Dyer and Golub are working on studies related to Alzheimer’s disease, also using the VCD mouse.

“Collectively, we already have a group of collaborators who are working on these diseases in part using our model,” Hoyer says.

Other uses of the VCD mouse model could include wild animal population control, and “neutering” of pets without surgery. Hoyer says she and her team determined early on that except for causing ovarian failure, VCD causes no other adverse effect in animals.

And use it they will. Another set of professionals from UA’s Office of Technology Transfer (OTT) and supported in part by Arizona’s Technology and Research Initiative Fund (TRIF), is making it their job to see that the VCD mouse, as well as other discoveries at the UA are patented, and then licensed, to other entities. That way, market forces may play a role in the dissemination of discoveries from UA and bring the benefit of expanded business relationships and support back to the university.

 “Universities,” says Patrick Jones, who has been director of the UA Office of Technology Transfer since September 2002, “ have always been engaged in technology transfer. Traditional technology transfer happened by graduating students, teaching and consulting and performing sponsored research, particularly with industry.” The major change is that universities have added a more formal system of technology transfer by licensing companies and incubating start-up companies.

Technology transfer in this form, simply stated, is the orderly movement of the results of university research, inventions and discoveries to the public marketplace. At the University of Arizona, before 2000, there was a sense that, despite world-class science leading to breakthroughs and inventions, technology transfer efforts needed to be stronger.

The University recognized this in 1999 and initiated changes including the expansion of personnel and infrastructure for technology transfer. Says UA Vice President for Research Richard C. Powell, “In the spring of 2000, we hired a consulting group to analyze tech transfer, asking ‘What should be done to make it better?’”

The consultants interviewed those involved in technology transfer, both in and out of the UA, and benchmarked the UA with peer institutions. They recommended changes in policy, procedure and personnel.

“We’ve reorganized offices and hired new people,” Powell says. “To do this costs money,” he says. “We needed a lot more resources to support tech transfer.”

“All this occurred before Proposition 301 money so we teamed with the city and county to get outside support. When 301 money became available we supported (the changes) with that,” Powell says. UA uses a portion of the money derived from Proposition 301 to improve the UA’s technology transfer infrastructure.

Proposition 301 was a state, voter-approved initiative that raised the state sales tax by .6 percent to pay for improvements in education. The UA’s portion was $16 million from the first round of allocations, approved by the Arizona Board of Regents in March 2001.

One TRIF hire was Licensing Associate Suzanne Dubuque whose doctorate in cell biology and anatomy uniquely qualifies her to manage a portion of the UA’s life sciences intellectual property portfolio, about one third of the total portfolio.

“The field of technology transfer is unique,” she says, “It is at the cusp of business, law and science and integrates the three.” In her work, she brings together patent law and intellectual property-based contracts with the science being done by UA scientists to create new relationships with external partners, particularly businesses. “Faculty and staff are doing scientific research all the time.” Out of that work comes new innovations that sometime have broad uses. Says Dubuque, AWe make contacts and try to make available what has value to our business community.”

Which brings the conversation back to Hoyer and the menopausal mouse. The research group disclosed the technology in October 2001. After joining with Dubuque, the expanded team laid plans on how best to move the Mouseopause™ mouse model into broader availability.

Dubuque examined the role intellectual property rights could play and with Hoyer and Mayer set up a strategy for moving forward. “We are now seeking a patent on this,” says Dubuque, “we have created a lot of opportunities to help the public, and business opportunities as well.”

One of the opportunities benefits the women’s health research community and the potential for new pharmaceuticals development. This opportunity arises from making the mouse model broadly available through a business partner that specializes in mouse production. Dubuque located a business partner for Hoyer and the UA, a large research organization, which she says leads the field in mouse model production. “Because there was no mouse model for perimenopausal research, they jumped on this.”

“What the UA gets out of the relationship is a partner that brings business expertise,” she says, along with a known name in providing high quality research mice. Part of that business expertise is a strong marketing force to increase the visibility of this mouse model and a legal/regulatory staff experienced in handling any government approvals or other hurdles required. “We are not in any position to do that without them,” Dubuque says. The UA also receives a royalty on the sale of the mice, part of which goes to support new research.

 In general, companies also get a return beyond the chance to sell or create a new product: access to the UA’s expertise in doing basic scientific research. “Most companies can’t afford really broad basic research; they have to focus it toward a product,” says Jones. By building a relationship with the University, it gives them a potential access to discoveries they would not be otherwise see. Oftentimes scientists stay involved and may continue to develop the technology in partnership with the company.

This certainly has been true in the case of Hoyer and her colleagues. The relationship created by Dubuque expanded the possibilities for the work of Hoyer and the others. One realization of the team was the need for a new company to ensure adequate quality control in the production of the mice. Intrigued by that possibility and the possibility of addressing some of the other areas to which the method could be applied, Mayer worked with the others to form a new start-up located in Flagstaff.

For his part, Jones, director of OTT, thinks this example demonstrates what good technology transfer activities should do B create new opportunities for the researchers and community, ones that wouldn’t be there without the kind of expertise OTT provides.

 “One of the things the TRIF money is focused on is to provide the infrastructure and enhance our activities there (in technology transfer),” says Powell. This has certainly enhanced the activities possible in bringing the world-class research of one group into broader use.