Glenn Foundation Lures Scientists And Funders To Biology Of Aging

In just over a decade, genetically engineered mice have brought dramatic changes to the biomedical sciences, offering basic researchers ways to detect the influences of single genes and more clinically oriented investigators compellingly close models of human disease. Of Aging A small California foundation that does not accept grant applications has nonetheless gained ground as an unusually flexible seed funder and advocate for research in the biology of aging. Researchers and officials in this field say the Glenn Foundation for Medical Research, endowed and run by venture capitalist Paul Glenn, is helping to crack the door on a broad area of biological investigation that still commands only a portion of the federal budget for medical research. Glenn "does fill some holes we can't handle," says Huber Warner, deputy associate director of the program on the biology of aging at the National Institute on Aging (NIA). That program had just $44 million for research grants in fiscal 1993, enough to fund only about 15 percent of proposals that cleared its peer-review process, he says. Glenn's Santa Barbara, Calif.-based philanthropy is one of a small cadre of private donors that are known for stepping into the breach, in part by supporting junior investigators, students, and projects that "lay the groundwork for what might become important research," says Stephanie Lederman, executive director of the American Federation for Aging Research (AFAR) in New York. "We feel that aging is an under-recognized field," says the 64- year-old Glenn. He contends that more research could delay and shorten terminal illnesses, which often consume the final decade of life and account for as much as half of the United States' health care bill, according to the Alliance for Aging Research in Washington D.C. Glenn's foundation, which currently has $7 million in assets, is due to mushroom in size upon his death, when Glenn says the rest of his estate will pour into its coffers. In the meantime, he and the foundation's executive vice president, Mark R. Collins, are concentrating on ways of leveraging limited grants to attract more resources and researchers to the field. Glenn says his foundation, which lacks staffers to sift through research proposals in-house, picks grant recipients primarily by relying on three sources: other organizations, such as AFAR, which administers Glenn Foundation award programs; members of the aging-research community, who propose other sci-entists' projects for funding; and a rotating committee of scientists, which recommends investigators for fellowships. Award Programs The Washington, D.C.-based Gerontological Society of America (GSA) and AFAR administer several awards for the Glenn Foundation. On November 21, Earl Stadtman, a biochemist at the National Heart, Lung, and Blood Institute, is scheduled to receive the $20,000 Glenn Foundation Award from GSA. The award recognizes outstanding contributions in biological research on aging. Stadtman is the second investigator in two years honored for research focusing on oxidative damage from free radicals, which Glenn regards as potentially "the chief villain in the aging process." Last year the award went to Bruce Ames, a professor of biochemistry and molecular biology at the University of California, Berkeley. Ames's work on new methods of detecting oxidative DNA damage affirmed that simple dietary changes can retard aging and some degenerative diseases. GSA accepts nominations for this annual award until September 1. Through AFAR, the Glenn Foundation now funds two grants of $25,000 to $50,000 per year (but limited to $25,000 per scientist) specifically to help investigators develop data they can use to seek larger grants from the National Institutes of Health. The federation makes 35 to 40 such grants annually. AFAR's deadline for applications is January 15. The two organizations are launching a new Glenn Foundation/AFAR Scholarship in Biomedical Research. This program will provide $8,000 or $10,000 each for research projects that pair a medical student with an established faculty mentor, says Lederman. For the first round of scholarships, intended for the summer of 1994, proposals are due at AFAR's office by February 15. Seed Funding Glenn and Collins also scout for grantworthy projects through an informal network of investigators and colleagues in aging research. This occasionally leads to novel funding arrangements. For example, J. Fred Dice, a physiologist at Tufts University School of Medicine, encountered Glenn and Collins at scientific meetings, an acquaintance that led recently to the foundation's first corporate-style research agreement with a university laboratory. Under the agreement, the foundation is providing one-year "bridge" funding, enabling the lab to prepare enough data on age- related changes in protein degradation to seek major support from NIH, says Dice. In return, he says, the foundation has right of first refusal on any patents that might result, splitting potential commercial returns with the university and Dice. "We really needed this extra year, and the Glenn Foundation came through for us," says Dice. He and his colleague Lois Isenman think they are finding evidence that aging alters the way peptides calve off of proteins and migrate to the surface of cells. If so, the change might reveal a "fundamental" mechanism in the decline of immune recognition with advancing age, says Dice. Dice says he considers this work unlikely to lead to viable drugs to combat the aging process. But Collins, who works with Glenn in the venture capital business as well as at the foundation, says the agreement represents a model for how research foundations could recycle their investments in a time of declining funding from conventional sources. Recently, the foundation's involvement in research on certain anti-oxidant compounds led Glenn and Collins to help launch a biotechnology startup, Centaur Pharmaceuticals. "Paul and I got very deeply involved," says Collins, noting that they helped to form the company, raise venture capital, secure patent licenses, and recruit a chief executive. The Sunnyvale, Calif., firm aims to commercialize patents stemming from research the foundation honored by giving a $50,000 Glenn Fellowship Award to Robert A. Floyd, head of the free radical biology and aging unit at the Oklahoma Medical Research Foundation, Oklahoma City, who shared the prize money with a colleague, John M. Carney, an associate professor of pharmacology and psychiatry at the University of Kentucky in Lexington, says Collins. Fellowship Grants The Glenn Fellowship Award process represents the foundation's third major avenue for grant selection. An annually appointed, rotating committee of leading scientists nominates recipients for the prize. The latest recipient was Dean Ornish, president and director of the Preventive Medicine Research Institute in Sausalito, Calif. Using positron emission technology to scrutinize blood vessel walls, Ornish demonstrated that atherosclerosis can be reversed through diet, exercise, and stress reduction, without the need for costly drugs and surgery. The Mutual of Omaha Companies followed up by announcing a pilot project in six cities to reimburse customers who opt for the "lifestyle-modification program" recommended by Ornish. Glenn has proposed fattening the funding pool for medical research by asking NIH to share its files of grant applications with interested corporations. He also is urging insurance companies, in particular, to support biomedical research, arguing that its fruits could reduce the enormous medical claims of elderly patients. Apart from research grants and awards, the Glenn Foundation cosponsors scientific meetings with NIA, which rarely receives nongovernment support, and with professional scientific organizations such as GSA. For more information, contact the Glenn Foundation for Medical Research, 1250 Coast Village Rd., Suite K, Santa Barbara, Calif. 93108; (805) 565-3363. The American Federation for Aging Research can be contacted at 1414 Avenue of the Americas, New York, N.Y. 10019; (212) 752-2327. The Gerontological Society of America can be contacted at 1275 K St., N.W., Suite 350, Washington, D.C. 20005-4006; (202) 842-1275. "These mice are, quite simply, extraordinary," says Joseph Perpich, vice president for grants and special programs at the Howard Hughes Medical Institute (HHMI) in Chevy Chase, Md., many of whose investigators use the new mice. Unlike the laboratory mice that have long been a staple of biology, genetically engineered mice carry genes specifically selected and imported into their genomes through a complex process involving DNA delivery, embryo manipulation, and classic genetics. And the technological challenges and labor necessary to create each line of mice have led to a problem--how to supply these custom-designed animals to the growing numbers of researchers requesting them, while keeping costs down. When companies began licensing rights to market these mice and then charging scientists stiff fees and imposing difficult restrictions on their use, researchers protested (C. Anderson, Science, 260:23, 1993; J. Travis, Science, 256:1393, 1992). Now, however, a new program at the Jackson Laboratory in Bar Harbor, Maine, as well as a breeding center there backed by the National Institutes of Health, should increase the availability and affordability of genetically engineered mice. In addition, researchers can choose among several commercial vendors or develop their own mice. There are two kinds of new laboratory mouse models: Transgenic mice bear a foreign gene inserted randomly into their genome; so- called knockout animals carry an inactivated form of a gene that replaces a functional version. Both technologies begin with identifying and isolating a gene of interest. The gene is then delivered, usually by microinjection, into a target cell. In transgenic technology, the target cell, a fertilized ovum, is implanted into a foster mother. The investigator then selects and breeds to each other the heterozygous offspring--those with one copy of the inserted, recessive gene, the transgene--to produce homozygotes that express the recessive trait the gene encodes. Transgenic organisms often are used for what has been called "pharming"--producing a pharmaceutical substance such as human clotting factor in their milk, for example. They also serve as models of human disease. Perhaps the best-known transgenic is the OncoMouse, also known as the Harvard Mouse, developed by Philip Leder at Harvard Medical School in 1988 (E. Sinn, et al., Cell, 49:465, 1987). The breast-cancer-prone rodent was licensed to E.I. Du Pont de Nemours and Co. Inc., Wilmington, Del., and distributed by Charles River Laboratories, Wilmington, Mass. Along with its innovative genetic programming, the mouse was delivered to researchers with problematic restrictions, including a so-called reach-through clause claiming royalties for Du Pont on any products or inventions using the mice. Gene targeting, to create the knockout mice, is a bit trickier than transgenic technology. It relies on a natural process called homologous recombination, in which a DNA sequence seeks its complement on a chromosome, and then switches places with it. The targets are mouse embryonic stem cells, taken from four-day-old mouse embryos. At this stage, the cells will take up foreign DNA, and they can then be introduced into another embryo to continue developing as part of it, still capable of differentiating into any tissue (M.J. Evans, M.H. Kaufman, Nature, 292:154, 1981; G. Martin, Proceedings of the National Academy of Sciences, 78:7634, 1981). To engineer a knockout mouse, a researcher transfers an inactivated gene into an embryonic stem cell, cultures that cell, then adds single cells to embryos from mice of a different color. The hybrid embryos complete development in a foster mother. Progeny containing some cells with the targeted gene are easy to spot--after birth, they have splotches of the color of the manipulated mouse in the background color of the recipient embryo. The bi-colored mice are next bred to albino mice. Completely pigmented progeny have the targeted gene in each cell--but only one copy. These pigmented mice must then be bred to each other. According to Mendel's laws, each offspring has a one-in-four chance of being a sought-after homozygote--a mouse with two copies of the targeted gene. Knockout mice model the most severe forms of human inherited disorders because they express a complete lack of gene function (J.N. Snouwaert, et al., Science, 257:1083, 1992). Particularly intriguing are knockout mice that bear inactivated genes thought to be essential for life--and yet survive (K.L. Philpott, et al., Science, 256:1448, 1992). This was the case for the p53 knockout mice developed in the laboratory of Allan Bradley at the Baylor College of Medicine in Houston (L.A. Donehower, et al., Nature, 356:215, 1992). Lack of p53, a tumor suppressor gene, can cause a variety of cancers in humans. So, researchers were surprised that mice with a double dose of knocked-out p53 appear quite healthy. The mice do develop malignancies as they age--but not more often than do humans. Now, the possibility that the mice might possess some undiscovered genetic factor able to compensate for lack of p53 function is stimulating a new set of research questions. The p53 knockout mouse was the cause of the recent controversy over mouse pricing. Bradley's lab, unable to meet requests from colleagues for the p53 knockouts, licensed the mouse to GenPharm International in Mountain View, Calif. Because of high licensing fees and the considerable cost of maintaining the animals, GenPharm's p53 knockouts sold, in 1992, for $100 per mouse. And at first, researchers were not permitted to breed the mice other than to produce a few offspring to test the mice for birth defects. Anger over GenPharm's pricing and restrictions coalesced at the Mouse Molecular Genetics meeting at Cold Spring Harbor Laboratory, Long Island, N.Y., in August 1992, in an impromptu session attended by more than 300 researchers and chaired by NIH director-designate and Nobel Prize-winning University of California, San Francisco, geneticist Harold Varmus. "The Cold Spring Harbor meeting was critical," says HHMI's Perpich. "There had been ad hoc meetings of scientists all over the country [to protest GenPharm's policies], but nothing had been crystallizing." One alternative to GenPharm brought up at the meeting was to involve the Jackson Laboratory, a nonprofit facility founded in 1929 to supply inbred strains of "Jax" mice for research, in producing supplies of genetically engineered mice. "At Cold Spring Harbor, Harold Varmus spoke to Howard Hughes Medical Institute's president and vice president about making a [financial] contribution" to the Jackson Laboratory to develop the mice, Perpich says. "It would be important for our own investigators and for the broader scientific community." With HHMI willing to provide funding to set up a program to supply the mice and researchers becoming more vocal in their objections to mouse prices, by the spring of this year GenPharm was already bowing to the pressure. Company president David Winter announced that, for a $1,000 annual fee, researchers could freely breed their GenPharm mice. "We no longer limit the number of offspring a researcher can breed, and [scientists] don't have to disclose the nature of the work. We let researchers do what they want with the animals," says Anthony P. Cruz, product manager of the transgenic laboratory at GenPharm, pointing out, too, that the company never had a reach-through clause similar to Du Pont's. Meanwhile, HHMI was rushing through a $1.2 million grant to the Jackson Laboratory to implement a mouse-supply program. "By May, it was all set, and the check, in full, was sent out three weeks later," says Perpich. Unexpectedly, support for the Jackson program from other sources took off. Organizations funding research into specific human disorders, from orphan genetic diseases to major killers, began to recognize the power of these mice as disease models. Dollars poured in, first from the March of Dimes, and soon after from the American Cancer Society, the American Heart Association, the Multiple Sclerosis Society, the Cystic Fibrosis Foundation, and others. The Maine facility got to work immediately. "The Jackson lab is making a concerted effort to start acquiring these mice, maintain them, and make them available," says Mario R. Capecchi, the HHMI investigator and professor of human genetics at the University of Utah, Salt Lake City, who pioneered gene targeting (M.R. Capecchi, Science, 244:1288, 1989; S.L. Mansour, K.R. Thomas, M.R. Capecchi, Nature, 336:348, 1988). "An important function will be to cryopreserve embryos, so that breeding need not be repeated over and over," he adds. "Some mice are available now," says John Sharp, superintendent of the induced mutant resource at the Jackson lab. "A researcher would order them like any Jax mice. We are trying to base prices on the amount of genetic typing that has to be done. Most range from $65 to $75 for a breeding pair of heterozygotes. And, as with all our mice, the researcher can keep the progeny." The "Jaxp53" strain, for example, knocked out for the p53 gene, sells for $60 per breeding pair. It was developed in the laboratory of cancer geneticist Tyler Jacks at the Massachusetts Institute of Technology. Soon there will be even more support for genetically engineered mice. NIH's National Center for Research Resources awarded a grant to the Jackson Laboratory earlier this fall to create a National Resource for Transgenic Animals. This program will provide transgenic and knockout mice at cost to basic researchers. Researchers seeking genetically altered mice have alternatives to commercial suppliers and the Jackson Laboratory. DNA Biotherapeutics Inc. in Princeton, N.J., offers contract services in developing transgenic mice. "Injecting DNA, screening the progeny, and identifying progeny costs $7,250 to $8,000," says Mark E. Swanson, associate scientific director for transgenic animal development. "But we find that most academic labs can't afford this. So we offer, for $4,000, to inject the gene and send progeny of injected embryos, and the researchers screen to identify the transgenics." DNX, also based in Princeton, offers yet another option--a $2,000 program underwritten by the National Institute of Child Health and Human Development (NICHD). Researchers with proposals accepted by NICHD may send DNA to the NICHD Transgenic Mouse Development Facility operated by DNX. Some companies developing strains of transgenic or knockout mice have entered into collaborations with research institutions as they move toward making the mice commercially available. This is the case at Exemplar Corp., Worcester, Mass. Exemplar's proprietary transgenic mice currently are being used in research on AIDS, cancer, and Alzheimer's disease, although they are not yet available for purchase. "We have given them to institutions with whom we've entered into a relationship," says Paul Leibowitz, Exemplar's senior vice president of research and development. "They can't give them to a third party, but they are free to publish on anything." For those laboratories with the combination of expertise and technology necessary to engineer their own mice, that too will get easier, Capecchi says, as people become more adept at the manipulations of creating transgenics and knockouts. "And the price will continue to go down as people become better at it," he adds. The diverse suppliers of genetically engineered mice are likely to complement each other rather than compete, experts in and users of the technologies agree. Sharp of the Jackson Laboratory predicts a stratification of the market, with commercial vendors focusing on mice needed for research on such prevalent disorders as cancer and heart disease, and subsidized sources pursuing the rarer genetic conditions. Brad Warren is a Seattle-based freelance writer.

Glenn Foundation Lures Scientists And Funders To Biology Of Aging

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