Report of the PSAB Committee on Culture Collections compiled for the March 26-27, 1995 meeting of the United States National Committee of the International Union of Microbiological Societies. The report answers questions raised by organizations on such topics as funding, consequences of under investment in collections, how collections priorities could change with no growth in funding and maintenance of collections.
The US National Committee of the International Union of Microbiological Societies (chaired by Anne Vidaver) will be addressing a request by the NRC at its meeting on March 26-27, 1995, to determine the need for a study on solutions to sustain microbial culture collections. A number of relevant questions concerning the culture collection issue have been raised by several organizations over the past few months, in advance of the USNC/IUMS meeting. The PSAB Committee on Culture Collections has prepared the following comments in response to these questions.
1. Are funding levels for collections declining relative to past support levels (have priorities shifted)?
Available information shows a consistent trend of declining funding for culture collections. However, there is currently insufficient information to conclude that these reductions are due to priority shifts by the Federal agencies. A sense of gravity for the situation does exist, but the concern is based on anecdotal observations. Discussions with academic and government researchers in the field suggest significant difficulty in retaining adequate funding for culture collections. For example, funding for the NRRL collection in Peoria and a joint project between the EPA and ATCC were seriously challenged, and the fundees at the NSF/Genetics Society workshop all reported funding shortages last year (workshop report attached). Two separate searches of on-line NIH, NSF and USDA grant databases, conducted via the Internet, suggest that funding has been fixed from past years, and remains flat, leading to an effective decrease in funds available to the collections because of growth in fixed costs due to inflation and salary increases. Comments from scientists at several government agencies suggest that internal funding for culture collections is viewed as discretionary and, therefore, extremely vulnerable to cutbacks or elimination.
The seriousness of the funding problem cannot be critically assessed until more complete and meaningful information is collected. This information is almost certainly available by formal request from funding agencies as well as from major collections. Such information would be necessary to make a credible argument for increased funding. If the problem is as severe as many perceive, then such a study should be initiated soon, since irreversible damage to collections could already be occurring.
Exacerbating the information deficit is the fact that the last effort to obtain information on culture collections in the United States was made almost 20 years ago by the ASM in collaboration with the American Phytopathological Society and the American Association of Veterinary Laboratory Diagnosticians. Thus, a reasonable first step toward defining the magnitude of the culture collection problem in the United States would be to create a registry of collections from which to gather information. One attempt to register culture collections in the United States, involving the WCC, is Larry Moore's Microbial Germplasm Database Network. In addition, the ASM has been working with the US Federation of Culture Collections to secure funds for the establishment of a Registry of US Culture Collections (see attachment). A consortium of 18 organizations has been formed to participate in the project, but the inability to raise supporting funds has stalled the effort.
Recent efforts have been undertaken in response to the funding problem for culture collections: the USDA report to Congress on genetic resources, the NSF workshop on culture collections, and efforts by USDA, EPA, NSF, NIH and other agencies to maintain their support for committed projects. However, a coordinated approach to evaluating the problem and developing appropriate solutions is required. It is the recommendation of the committee that a thorough culture collection study be undertaken, and include (1) a goal of defining potential funding sources for completion of the registry, (2) participation of funding agencies and collections in determining the current status and the history of culture collection funding, in relation to on-going needs, and (3) development of proposals for means to structure a coordinated response to funding needs.
2. What are the indicators that underinvestment in collections may eventually lead to negative long-term consequences such as the loss of important microorganisms?
Culture collections, herbaria, museums and libraries are all critical components of the scientific infrastructure. The consequences to the scientific community of inadequate funding for these resources should be obvious: inadequately characterized and documented biological materials, and inadequate specialized expertise in preservation, maintenance and characterization of biological materials. This could ultimately lead to an accumulation of unrecognized errors appearing in the work of many scientists, either directly or indirectly, and certainly would impinge upon independent verification of data and findings. Moreover, because science builds on other's work, including cultures, unnecessary duplication would occur, resulting in underutilization or squandering of public investment into biological research. Finally, inadequate support of such an important and dynamic scientific infracstructural element could lead to a loss in national technological and commercial competitiveness.
The long-term consequences of inadequate funding to the collections themselves should also be obvious: reduced services, decreased cost-effectiveness, lower quality of product, disgruntled and overworked staff, decline in training of qualified personnel, and finally organizational termination. Research in culture collection technology (information management, rapid identification techniques, large-volume handling, microbial systematics) and its integration with other fields of research (genome science, ecology, molecular evolution, microbial chemistry) has already reached a critically low level in the United States, and the lack of research training opportunities as well as emerging new technology will ultimately accelerate the rate of decline in quality and service that culture collections will be able to provide.
More specifically, if funding is not adequate, genuinely or potentially important strains of microorganisms will be lost. In a user-fee driven collection, important strains which generate few requests, and thus little income, would most likely be discarded, and the opportunity to capitalize on the recent surge of activity in microbial diversity could be missed. Also, we stand the real risk today of losing existing collections held by retiring scientists. One example of this situation is Ellen Simon's valuable and interesting Tetrahymena collection, threatened with extinction as she goes into retirement. Another example might be the Phaff yeast collection, which has provided very valuable key cultures to the brewing industry. This collection was threatened with extinction until Jennie Hunter-Cevera undertook a fund-raising effort to save it. As reported at the NSF/GSA workshop, as some collections must live on ever smaller budgets, they are able to afford only technicians, rather than scientists, to run the collections. Some collections, such as the Drosophila sp. collection, are threatened as there is no one with scientific expertise to oversee the operations. Culture collections could probably give many more significant examples.
It is the recommendation of the committee that a culture collection study be undertaken, with direct involvement of the culture collections, to get hard figures relating to the numbers of strains lost annually, the numbers of strain requests not filled, and the number and identity of collections threatened with extinction.
3. What should be the basic criteria for selecting certain organisms for public support? What justification can you provide for having Federal funding as a primary source of support for living stock collections?
Culture collections have been developed to provide one or more general functions: (1) to establish repositories of interesting, rare or useful organisms, (2) to provide the research community with a- taxonomic type strains, or b- control/reference strains for experimental use and standardized testing, or c- specialized genetic or clinical strains, and (3) to establish a repository of organisms necessary to permit enablement of patented inventions. Selection criteria for a particular collection thus depend upon the mix of these functions within the collection's intended mission. The basic decisions, though, are based on novelty, taxonomic and physiological significance (i.e., type strains) and anticipated use. Uniqueness is very important. Some collections have wild-type organisms which are unique, or are from special, extreme or endangered environments, which are all valuable. Other collections have genetic stock strains, which are well-characterized, and represent the end points of research which has been supported by Federal grants. These strains can also be very valuable, as their replacement cost is extremely high. The general collections should have an active user community which considers the deposits to be valuable. The collection should have a database or catalog. The collection should have quality control and characterization procedures in place, and the deposits should be well documented.
Federal support for culture collections is justified (1) because culture collections serve important national interests, i.e., technological and commercial competitiveness, (2) because they are necessary for advancing the missions of many Federal agencies, i.e. in health, education, agriculture, commerce, etc., (3) because they are an important national infrastructure for the biological sciences, (4) because they advance the protection of intellectual property rights and hence c ommercialization of new technologies, (5) because adequate revenues cannot be obtained from user fees or service charges, (6) because no other source of independent public funds are available, and (7) because the research community, both academic and industrial, is dependent upon open and equitable access to cultures, and their selection for archival.
Culture collections are not self-sustaining because large portions of most collections are rarely requested, even though they deserve preservation in the interests of science. A significant example is the recent establishment and failure of In Vitro International (IVI). Since culture characterization and preservation are a significant portion of the overall costs of maintaining a collection, total costs cannot be recovered solely from the cultures distributed.
4. Assuming no growth in funding, what are the priorities among activities and services from the user's standpoint?
Maintenance of useful existing collections should logically be a top priority. Also, the preservation of endangered collections emerging from academic and industrial institutions (cf. retiring experts) is a very major concern. A strategy which may need to be considered is to spend more of the money available on the preservation of novel organisms rather than distribution of cultures to protect against "loss" of cultures, as ecosystems are lost globally and expertise in microbial systematics vanishes, making these assets available to future researchers when funding for microbial research increases or funding priorities change.
It is fairly clear that enhanced funding of stock centers will be essential just for continuation of their current activities into the future (see question 5 below). Even now, top priorities are not being covered. Ironically, spending here could be catalytic, and amplified across the broad base of research in microbial diversity. Innovative research in information management, rapid identification techniques, and large-volume handling could greatly enable exploration of microbial diversity. Training in microbial systematics could be equally enabling at a time when experimental tools for understanding microbial systems offer powerful new approaches to problem solving. Training a new generation of researchers with broad skill-sets in these areas should be a funded priority.
The culture collections themselves, as well as users, perhaps through the ASM, should be asked for a prioritization of culture collection functions, and it is the recommendation of the committee that a culture collection study be undertaken, which includes this as a goal.
5. Is the maintenance of collections changing in fundamental ways? Are there new demands being placed on collections that have increased costs or services? Is culture maintenance changing in fundamental ways? Have the needs of academic scientists for access to cultures changed in any way over the last decade? Would it be more efficient and/or useful if the information system (genetic data, bibliography, etc.) was shared and consolidated with others?
New demands are being placed on collections in both the public and private sectors. As new technologies emerge, new methods of characterizing biologicals will be required for both scientific and legal purposes. Changes in the data processing environment have also had a positive yet costly effect on collections. There are also constant changes in the regulatory environment that could impact collections. For instance, the EPA has requested comments from the public regarding the deposit of new intergeneric strains covered under the Toxic Substances Control Act. Such demands could be viewed as an increased burden on existing collections. Alternatively, these new regulations could be viewed as a new source of revenue for the public collections that distribute to the public.
With regard to maintenance costs, increases are being experienced due to increasing reliance on liquid nitrogen storage. This practice is necessary since many types of organisms require this type of storage, and, further, the methodology does not require the same technical expertise as freeze-drying. Long-term costs for this type of storage are far higher than for lyophilized strains.
In looking at funded biodiversity grants, most propose to deposit novel microbes in reference collections such as ATCC or NRRL. If many biodiversity proposals of this type are funded, reference collection resources would be strained.
Another emerging trend is that academic scientists appear to now require more frequent access to recombinant and type strains and organisms. Also, increased strain documentation and increased access to strain information databases, particularly on the Internet, and access to germplasm cited in less accessible journals is requested.
With regard to data sharing, efforts have already been initiated via the World Data Center at Riken and through various Gopher, WAIS, and World Wide Web servers on the Internet. Much more sharing of strain information is necessary, and improved database tools and mechanisms are needed to increase sharing. It is the recommendation of the committee that a culture collection study be undertaken, and include a goal of exploring methods to expedite information flow and data sharing to and from and among collections.
Finally, one important and most disconcerting change in the way cultures are maintained is that lack of funding is encouraging some collections to make do with less trained personnel, endangering the future of these collections. Also, funding shortages are encouraging collections to discard organisms and information of potential future value in order to control costs.
6. What are some examples of the role the ATCC's Collections have played in advancing biological science? How important are the ATCC's collections to the biological research laboratory? What percentage of the research community is dependent on the ATCC's collections? Are there other possible sources of funds for the collections?
First, it is important to remember that there are many important culture collections in the US, most of which share the same problems as the ATCC. These collections have been of tremendous benefit to science and society in the past and hopefully will be so in the future. Countless contributions to basic and applied research have been made in agriculture, biotechnology, ecology, and medicine. In addition to maintaining and disseminating genetic material harvested from decades of research in microbiology, these centers preserve the knowledge gained and promote its advancement.
The ATCC's collections are indeed very important to the biological research community. Research on many pathogens is cyclical, with Mycobacterium tuberculosis being a good example. Much of the research on this organism had ended many years earlier when the incidence of MTB infection began to skyrocket in the past decade. ATCC was a ready source for strains to begin research efforts again. While many people have stopped studying Coxiella, when it was needed to test for reactivity with a Chlamydia probe, ATCC had the strains ready. With the FDA mandating extensive testing of large panels of organisms for reactivity with any new diagnostic test, ATCC's collection has become even more important. In most cases, the FDA strongly prefers (if not requires) that this testing be done with strains from ATCC.
A recent example of the impact of ATCC strains on the research community was the discovery by Cetus of Taq polymerase from Thermus aquaticus, made by screening ATCC cultures. The easy availability of Brock's characterized strain helped to accelerate the practical development of PCR. Enormous advances in genetics, forensics and diagnostics have been made quickly due to the availability of thermostable Taq polymerase.
The role of the ATCC and NRRL as Budapest Treaty Patent Repositories has been important to protect the United States biotechnology and pharmaceutical industries. The ARS Culture Collection (NRRL) received Budapest status on the same date as ATCC and represents a significant collection for this activity. ATCC's role as provider of standardized, characterized strains is also very important for quality control laboratories in pharmaceutical, health care and biotechnology companies. Most sterility testing in this country uses ATCC strains as standard controls. The same is true for bacterial identification and antibiotic susceptibility assays in industry in the United States. Availability of standardized ATCC strains therefore plays an important role in protecting public health.
7. What is the relative importance of "commercial" collections to industry versus the academic community, and how does this factor into the funding picture?
Only collection strain distribution records can determine if academia or industry is the heavier user of public collections. Clearly, industrial laboratories could more readily support collections through user fees for distribution of strains, while budget constraints in academic laboratories would favor generalized support of strain distribution (and thus reduction of user fees) from grants. Many collections have already adopted differential pricing policies. However, pricing suffers less from undercharging for the costs associated with strains used, but rather from the inability to finance the large portions of collections infrequently used. The more costly strains become to either industrial or academic researchers, the less they will be used for truly exploratory purposes, diminishing one of the key and most valuable attributes of these repositories. Practices such as screening panels of organisms for a desired biological property would be discouraged.
Collections such as the ATCC appear to be equally important to industry and to academia, and to high school (and earlier) science teachers, who can order specific educational strains from ATCC. Truly commercial collections, such as "Cultiloops", operate without any government funding and sell all cultures distributed. These commercial collections appear to be mostly unimportant to academia. Interestingly, most commercial collections sell subcultured ATCC strains.
Strain distribution records from culture collections will answer this question.
It is the recommendation of the committee that a culture collection study be undertaken, and include the goal of determining actual usage patterns and pricing structures, in relation to actual costs.
8. What is important, diversity per se or unique collections of closely related organisms, mutants and genetically engineered constructs? To what degree can genetic libraries replace culture collections? What is the relationship if any between ecological preserves and culture collections...the questions of biological diversity?
Both types of collections, those reflecting the range of microbial diversity and unique collections containing closely related organisms, mutants and genetically engineered constructs, are of equal importance to science, although they are used for different types of studies. Although the ATCC is quite large and holds a substantial number of strains of bacteria, fungi, yeasts, protozoa, cell-lines and viruses it is really not diverse in an ecological sense. It is generally thought that 1% of the microorganisms found in nature have been cultivated. The ATCC (along with the other large distributing collections) holds less than 10% of the named species. In reality, the holdings of the ATCC, as well as all other collections, represent areas of research that have been the focus of a selected number of individuals over the past 75 years. Some of the strains on deposit are vitally important to a wide range of investigators while other strains are nothing more than preserved specimens that were once of interest to a small number of investigators or a single scientist. Whether or not any strain will be important in the future is difficult to tell. It would have been very difficult indeed to predict the importance of the ATCC deposit of Thermus aquaticus 10 years ago. This also points out the importance of collections to commercial concerns as a source of strains for screening, especially as a source of carefully selected material that might not otherwise be available. In any case, without critically functioning culture collections, we will never be truly able to exploit biodiversity.
Genetic libraries are an important complement to organismal collections, but they cannot replace collections of organisms. In a way, a genetic library is like a herbarium collection. The deposits provide important information, but neither can answer questions of growth and physiology. They provide part of the picture; the folding of genomes, the regulatory elements, and the cellular milieu all contribute to the observable phenotype. Neither genetic libraries nor herbarium collections can reveal whether an organism might degrade toxic waste or produce a novel metabolite. Until it is feasible to successfully recreate viable cells of complex organisms (e.g., a bacterium, a yeast or a fungus) from preserved DNA by bench scientists of ordinary skill, there will be a need for collections. Moreover, the genetic library cannot be constructed until the organisms are isolated and differentiated, requiring both the resources and expertise of culture collections.
On the other hand, ecological preserves are an excellent complement to culture collections. It is most desirable to save endangered environments, but where that is impossible a culture collection can store many of the unique organisms. Today, with funding cuts, it is impractical to assume that any scientists will have the time and the support to identify and isolate every organism in an endangered environment. Evaluation of biological diversity within ecological preserves is fine, but without collections of isolated and characterized pure cultures this diversity will never be biotechnologically exploited.