Resource Sharing in Biomedical Research (1996)

For more than 60 years, The Jackson Laboratory (TJL), a private, nonprofit, research institution on Mount Desert Island off the coast of Maine, has been the major repository for genetically defined mice. TJL is internationally recognized as the preeminent source of laboratory mice. The laboratory describes its mission as

1. providing new information to the scientific community through basic genetic research using mice;
2. providing the essential genetic resources for other scientists to do that research throughout the world; and
3. educating the next generation of scientists to carry out this work.

TJL is governed by a Board of Trustees that includes both scientists and nonscientists; a Board of Scientific Overseers; and a Director, who is also provided advice in different areas by staff scientists on four standing committees. Support for the laboratory's activities comes from a combination of federal agencies (National Institutes of Health [NIH] and National Science Foundation [NSF]), other health organizations (Howard Hughes Medical Institute, American Cancer Society, American Health Association, Cystic Fibrosis Society, Multiple Sclerosis Society, March of Dimes, and others), and fees from services or sales of laboratory mice. The total operating budget for TJL for 1995 was approximately $45 million, and about half of that is related to maintaining and distributing animal resources (mice) and related services, that is, production and sale of specific mouse mutants, maintenance of selected

breeding stocks, derivation of selected strains or congenic production, surgical manipulations, embryo conservation, and bioinformatics.

TJL develops mutant strains of mice as well as accepting mice from scientists who wish to make them available to other scientists. These mice from external sources may be spontaneous mutations, or they may be induced mutations. The laboratory also maintains pedigreed stocks of mouse strains using breeding programs that are designed to ensure their genetically unique qualities. Mice that are accepted by TJL must all be cesarean rederived to ensure that they are disease free. At this point they become Jackson Laboratory (JAX) mice and are distributed as such according to TJL policies. Internally, TJL has divided its 1,800 or so strains of mice into seven categories, each managed in a separate subunit known as a resource (instead of a department or division):

1. Induced Mutants—these include transgenics, induced and targeted mutations;
2. Mouse Mutants—spontaneous mutations;
3. Special Mouse Stocks—congenic and recombinant inbred strains;
4. Foundation Stocks—pedigreed source colonies for inbred strains;
5. Individual Research Colonies—these include all of the above types;
6. Animal Resources—the expansion and production of colonies of inbred, mutant, and special strains in high demand; and
7. Frozen Embryos—all of the above types.

The largest numbers of mice are distributed from the production colonies (Animal Resources) (1.6 million annually); the Induced Mutant, Mouse Mutant, and Special Mouse Stocks Resources each distribute 10,000–12,000 mice annually.

The newest and fastest-growing resource is the Induced Mutant Resource (IMR), which may include about 235 strains at any one time. Until this resource was initiated in 1992, TJL distributed only mice developed by its in-house research staff. Almost all mice in the IMR originate outside TJL. The original plan for this resource was that approximately 50 percent of the strains included would be requested from authors of published papers and about 50 percent would be offered by external scientists. The interest in entering externally produced mutants into TJL has been so great, however, that a review panel has been established to select those to be included. During 1995,

100 strains were added to the Induced Mutant Resource. TJL recognizes that this constitutes only a small proportion of these rapidly proliferating strains, and it is actively soliciting funds with which to expand the IMR.

Financially, the various units have some interdependence, because proceeds from the sale of animals by Animal Resources help to offset the costs of less financially viable resources (the philosophy of the laboratory is to provide mice to researchers as close to cost as possible). Although the distinction among these various resources is transparent to the users of TJL, the division of responsibility provides more focused management and encourages long-range planning.

TJL believes that a major reason for its continuing success is that each resource is supervised by a scientist with special expertise in the specific area; quality control is a major part of the supervisor's responsibility. The scientist supervises a manager who is responsible for day-to-day activities.

Several features of the TJL structure are important to the users of the resource. First, all mice that are obtained from the facility will be of known health status and genetic quality. Any mouse stock acquired by TJL is rederived by cesarean section to eliminate the burden of infectious agents that might interfere with research, and the mutation is established on an inbred line. This importation policy reduces intercurrent disease, reduces mortality and morbidity, and enhances reproductive efficiency while decreasing the costs of monitoring for disease. The second important feature of TJL mice is that the strain will be genetically defined before it is released for use. This ensures that individuals who obtain mice will continue to receive genetically defined animals.

A major function of TJL is the preservation of murine germ plasm via embryo freezing. If no orders are received for a particular stock for six months, the stock is usually taken out of production and maintained via cryopreservation. The laboratory also conducts research to develop additional or better methods for preserving germ plasm (e.g., sperm freezing, improving reproductive technologies).

TJL will, on request, rederive mice, develop congenic strains by customized breeding, or maintain stocks of animals for individual scientists. Charges for these services reflect the costs involved.

On request, TJL will provide mice that have been surgically prepared for example, by hysterectomy, vasectomy, adrenalectomy. Charges for these services reflect the costs involved.

As part of its goal to educate scientists in research, TJL issues price lists, lists of stocks with genetic information, a quarterly newsletter, data sheets on individual strains, and special newsletters devoted to specific topics. The laboratory also publishes a handbook (updated every five years) and has a World Wide Web site where most materials are available electronically. In addition, TJL is the location of the Mouse Genome Database, which provides genetic mapping and descriptive information to the worldwide scientific community.

Ownership of mice sent to TJL is transferred to the laboratory as a condition of entry into TJL. Contributors may not attach any reach-through rights to subsequent production and distribution of stocks by recipient scientists. Mice are not accepted with a condition that they must be licensed to individual academic scientists. If contributors require licensing agreements to cover for-profit use, TJL will place a label on shipping containers for mice from these strains, making the recipient aware that a license agreement is required if the mice or research is to be used for commercial purposes. TJL does not assume any responsibility for enforcing licensing agreements. If the originator of a strain requests royalties, he or she must bear the costs of rederiving the strain, putting it on an inbred background, and cryopreservation.

One of the reasons this approach works at TJL is that individuals have an incentive to contribute their genetically modified animals to the laboratory because is assumes responsibility for the distribution of animals; gives credit to the contributors in all TJL publications, including a reference to the investigator's work; and sees that the animals are shared with fellow scientists.

The increasing ties between individuals or academia and the pharmaceutical and biotechnology industries may raise some issues that would complicate this approach to ownership. In certain cases, deposits of new stocks are being severely delayed by intellectual property concerns. Occasionally these delays are attributable to investigators, but the primary problem has been

with the technical transfer offices at universities hoping to benefit financially from licensing or royalties. In fact, to date, there has been little monetary return from mice or other materials. This delay at the university level has also penalized investigators who want to share their mice and get replication or extension of results, forge collaborations, and so forth, because the investigators are then forced to use their technician and laboratory time to produce the mice for sharing with colleagues. A better understanding of university policies and what works or does not work to encourage and enable sharing of resources was identified as a major gap in the system.

Although most problems to date have been resolved satisfactorily, Jackson Laboratory administrators are nevertheless working on approaches to codify a research exemption in patent law, so that even if biologic materials are restricted or licensed, they could still be used for research purposes.

Jackson Laboratory mice are available to any scientist, regardless of employer, who wants to use them for research, with the restrictions only that they not be bred for redistribution or redistributed outside the recipient's institution. Scientists are, however, asked to come back to TJL for new breeders after 10 generations or to put their own laboratory registration code on the strain so it is no longer perceived as a JAX mouse. These restrictions serve principally to protect the genetic purity and pedigree of the animals. No mice are distributed to non-research institutions without a guaranty that there is a veterinarian to take care of the mice.

As a research institute, TJL derives considerable grant support from federal and private nonprofit agencies. This goes in large measure to the portions of the laboratory that are conducting basic genetic research, but even those units focused primarily on providing mice and related services to other scientists benefit from funding from NIH, NSF, the Howard Hughes Medical Institute, and a number of voluntary health organizations. The last of these are organizations such as the American Cancer Society, the Cystic Fibrosis Society, and the Multiple Sclerosis Society, which typically contribute amounts in the $10,000–$25,000 range for maintenance and production of mouse strains that are important to research on their own diseases. Because of this external support, the costs of mice to outside purchasers are less than they would be if all costs had to be recovered through sales of mice. TJL does distribute mice for a fee, so users pay part of the cost. Because of the grant support however, TJL can provide mice from the small specialized resources at a lower cost than would be necessary to make them self supporting. Animal Resources, which distributes high-demand strains such as C57BL/6J and other standard inbred strains, also helps cover the cost of more specialized strains so that these

strains do not have to provide full cost recovery for maintenance. This maintenance and distribution of special stocks at less than full cost may not be possible in the future, as federal money becomes tighter and Animal Resources is expected to cover more of the laboratory's research costs.

Like ATCC, The Jackson Laboratory puts institutional dollars into capital investments such as buildings, renovations, and equipment, as well as nonmonetary costs involved in providing resources for others. Muriel Davisson told the workshop that TJL is spending an incredible amount of institutional time negotiating agreements to obtain specific scientifically valuable mouse strains, despite the fact that these strains generate very little monetary return, either to TJL or to the people who contribute the mice. In-house scientists also personally provide a great deal of information about the resources that they share. Even though there is a technical support crew of two, which soon will be increased to three, the scientists themselves spend a considerable amount of time with customers and prospective customers. Finally, because it is the culture at the laboratory to share anything once it has been published, TJL scientists often find their own competitively funded research programs compromised by sharing information with potential competitors.

Problems that TJL has encountered include the fact that very few mouse strains are commercially viable. This has led other suppliers to develop their own mouse stocks of the most favored strains, which undermines the financial vitality of TJL. With the new importations into the Induced Mutant Resource, there are typically about 2,000 strains on campus, which is probably 100 times more than most commercial breeders would distribute. Without this additional overhead, commercial concerns do not find it difficult to undercut TJL prices on the popular strains.

Licensing requests, particularly by the contributor's institution, delay the release of new and interesting strains and add to the costs of the process. This aspect is enhanced by the increasing alliances between nonprofit institutions and for-profit biotechnology firms.

Initiation of the Induced Mutant Resource, and especially the attempt to open it to the maintenance of ''knockout'' mice developed elsewhere, have made it plain that a very large infusion of funds and personnel will be required if the TJL collection is ever to approach the status of a comprehensive national repository.