MCR-1 GENE ISOLATEDMCR-1 gene isolated from human for first time in Brazil.
A Working Document for Multi-Agency Consideration
The Unseen National Resource:
Microbial diversity is an unseen national resource that deserves greater attention. Too small to be seen no longer means too small to be studied or valued. Microbial diversity encompasses the spectrum of variability among all types of microorganisms (bacteria, fungi, viruses and many more) in the natural world and as altered by human intervention.
Microorganisms are essential for the earth to function. They play many roles both on land and in water, including being the first to colonize and ameliorate effects of naturally occurring and man-made disturbed environments. The nation has committed to protecting the environment, and has included ecological diversity in this goal (National Science and Technology Council, 1994).
Because microorganisms are small, they are least known, and this gap in knowledge is particularly apparent for bacteria and other procaryotic organisms. Current evidence suggests there exists perhaps 300,000 to 1 million species of procaryotes on earth yet only 3,100 bacteria are described in Bergey's Manual. Learning more about these microorganisms will be of value for the following reasons:
microorganisms are important sources of knowledge about the strategies and limits of life,
microorganisms are of critical importance to the sustainability of life on our planet,
the untapped diversity of microorganisms is a resource for new genes and organisms of value to biotechnology,
diversity patterns of microorganisms can be used for monitoring and predicting environmental change,
microorganisms play a role in conservation and restoration biology of higher organisms, and
microbial communities are excellent models for understanding biological interactions and evolutionary history.
Several initiatives are underway or are being proposed that seek to inventory blota of the world. Although microorganisms are known to make up the bulk of the blota in both natural and managed ecosystems, they are mentioned only in passing in these initiatives.
Proposals are also being made to restore the function and integrity of ecosystems. Multidisciplinary proposals have not generally acknowledged the need to understand the types and functions of microorganisms in soil, water, land and wastes, as well as in forest, crop and other ecosystems. Any interagency coordination for pilot studies on terrestrial and aquatic ecosystems, and management and restoration would be incomplete if microbial systems were not included.
Newly developed methods now enable information to be gained in relation to establishing types of microorganisms (diversity). Data bases are becoming more widely available as a source of molecular and macromolecular information on microorganisms. New technologies are being developed that are based on diverse organisms, from diagnostics to biosensors and to biocatalysts. Much more needs to be done, however, on how to understand better the microorganisms, inventory their diversity, maintain reference cultures of them, and find ways to exploit them beneficially.
RECOMMENDATIONS FOR MICROBIAL DIVERSITY RESEARCH
Microbial diversity includes a vast array of organisms and suggests a spectrum of studies that are of importance for many national purposes. The following recommendations attempt to formulate critical initial efforts for several potential lead agencies. Some initiatives are within the purview of several agencies and will benefit from an interagency approach. For example, the importance of culture collections is mentioned for five different agencies. The list and approaches are not inclusive. For example, the National Oceanic and Atmospheric Administration might consider a relevant program on marine microbial diversity. The Department of Commerce has ongoing programs to foster the development of biotechnology and the development of microbial biocatalysts for commercial use. The National Institutes of Health must continue to confront the diversity involved in emerging microbial pathogens. The American Society for Microbiology, the American Phytopathological Society and the American Institute of Biological Sciences would be very pleased to help in any way to contribute further to the discussion of microbial diversity.
National Institutes of Health/Department of Energy/National Science Foundation
Microbial Genome Studies
A number of important scientific opportunities exist in genome analysis related to microbiology. Current genome projects, however, do not adequately represent the full range of microorganisms. A microbial genome program based on rational priorities is needed to make strategic decisions about the appropriation and distribution of funding and resources.
An ASM ad hoc subcommittee on Microbial Genome Science has outlined preliminary concepts of (I) broad groups of microorganisms of importance; (ii) possible rationales for selecting representatives from the wide diversity of microbial groups; and (iii) what might be learned from microbial sequencing. A copy of the Subcommittee's recommendations is available from ASM.
Adapting genome mapping, sequencing and data base developments, already defined for model organisms as part of the National Genome Initiative, a microbial genome program will serve major interests, including the following:
determination of the course of evolution, e.g., the way in which elements of genes developed; the genetic basis of diversity; the mechanism by which microbial metabolic pathways overlap for different organisms; and access to the large and as yet untapped gene pool resident in the microbial world;
definition of the entire repertoire of organisms in specialized niches and, ultimately, the mechanisms by which they interact in the larger "organism," i.e., ecology, and
analysis of organisms responsible for bioremediation and geochemical cycles of the planet; these organisms may prove useful for special purposes in the future, possibly for global environmental protection or food production.
The genomes of pathogens can be analyzed as a dynamic fossil record of host-parasite interactions during evolution and computerized data bases can be used to organize and coordinate these studies. This exciting prospect is based on the adaptation to microbial pathogens of genome mapping and sequencing approaches and data base developments already defined for model organisms as part of the National Genome Initiative. Such a program could serve several major interests:
to determine the course of evolution of pathogens, and the way in which metabolism overlaps for different pathogens;
to define the repertoire of natural commensal microbes as well as their pathogenic relatives, and ultimately the way they interact in the ecology of health and disease in the human body; and
to analyze the capacities of pathogens to interact with environmental conditions and host genes at the level of specific virulence mechanisms and recognition signals and of metabolic routes.
The new initiative on microbial genomes undertaken by the Department of Energy's Health Effects and Life Sciences Research Division will provide critical scientific information on organisms that have not previously been adequately studied at the genetic level. The current budget of $3.3 million should provide adequate funding to initiate the microbial genome sequencing project. This level of funding will permit establishment of one or more core centers and allow the initiation of the project. It should permit a test of whether this collaborative approach with a central sequencing center is the most effective means of developing data on microbial genomes. It is likely to produce one or more complete genome sequences in the near future. Assuming the success of the initial phase of this program, funding for microbial genome sequencing should expand to about $10 million. This will allow determination of gene function relationships by improving data and information systems analysis. It will permit the ongoing development of a core understanding of microbial genomes that can be used for recombinant DNA technology and genetic engineering of organisms with environmental and energy related applications.
We recommend that the DOE, NSF and other federal research and development agencies, particularly the Department of Agriculture support the research required for sequencing of taxonomic groups of microorganisms which offer a range of microbial diversity for further exploration. The National Center for Human Genome Research deserves credit for its support of sequencing the microbial genomes of several model organisms. We recommend that other NIH institutes focus on microbial diversity related to emerging pathogens, which are becoming increasingly important as a threat to public health, and fund studies to analyze the genomes of pathogens.
Integral to studies in microbial genome research is the accumulation, analysis and communication of information about genomes, and the collection, definition and preservation of genetic stocks allowing comparison of genetic diversity to be made and subsequently utilized in applied research. It is also recommended that a grant program (this could be a component of a pilot program being recommended) be established to support innovative research into the methods for handling genetics stocks (strains, vectors, genetic material, etc.) and for collecting and using information derived from combined systematics and genome research (databases, information processing technology, information networks, etc.)
National Science Foundation/Department of the Interior
The following are priority areas of microbial research, which should include work on viruses, bacteria, fungi, protozoa and algae.
Training of scientists with expertise in phylogeny, taxonomy, and physiology of environmental microorganisms so that diversity can be more efficiently recognized and characterized. The nation has very little remaining expertise in the identification and characterization of microbial groups.
Create, maintain, and integrate databases of microbial information including molecular, phenotypic, chemical, taxonomic, metabolic, and ecological information. Such databases are essential if new biodiversity discoveries are to be efficiently compared to what is already known. This may require support of centers, systems or laboratories, whose function is to characterize new organisms rapidly, collect and curate diverse isolates and maintain and disseminate data on them.
Support research on new methods and strategies for cultivation and isolation of microorganisms, and for rapid characterization of the projected large number of undiscovered organisms.
Support research that will identify sites of new diversity. This will lead to an understanding of the pattern of microbial diversity on earth and of the ecological and evolutionary mechanisms that could have contributed to localized diversity.
Foster Multidisciplinary involvement in microbial biodiversity research. Scientists with expertise in molecular biology, computer science, chemistry, device engineering, optical sciences, and macroecology are expected to be particularly important contributors.
Culture collections are key repositories of biodiversity as microbiology moves into an ever more powerful era, integrating genome science with ecology, systematics, molecular evolution and microbial chemistry. Innovative research in information management (databases, information processing technology, information networks, etc.), rapid identification techniques, and large volume handling (strains, vector, genetic material, etc.), will be needed. Enhanced funding of stock centers and greater emphasis on education and research in microbial systematics will be essential for the continued evolution of these activities. Investment here will not only ensure preservation of past treasures, but will amplify across the broad base of research into microbial diversity and its future application. The NSF should foster international coordination and sharing among collections. It is recommended that NSF develop a specific program to support the transfer of collections in danger of being eliminated to working stock collections. It is also recommended that a training program in microbial systematics and taxonomy be established.
An expenditure that scales up from $3 million per year to $10 million per year is needed to make a substantive impact in these areas of need.
Department of Agriculture
To support microbial diversity research and education in agricultural systems, it is recommended that USDA initiate or expand programs in the following three critical areas:
Microbial Biocontrol An interagency, competitive program, perhaps modeled after the USDA Plant Genome Research Program, is needed to support research in microorganisms that promote plant growth by interfering with (controlling) pathogens and pests. For most weeds, insect pests, nematodes and microbial pathogens of plants, alternative control measures are either not known, not yet developed, or are less effective or not economically feasible than are currently available pesticides. There is a compelling need for discovery and identification of microbial biocontrol agents, an assessment of their efficacy, development of delivery systems, and policy analyses and changes to encourage their use in public and private sectors. The studies collectively would include new developments in molecular ecology in natural and managed environments, where it is now possible to identify and track specific genes or traits fulfilling a particular function without necessarily isolating or culturing source microorganisms. Additionally, studies are needed to discover and classify diverse insect as well as plant viruses. These could be useful respectively, as natural insecticides and in weed-control, cutting down on the release of organo-phosphates into the environment.
Microbial Genome Studies A competitive program is needed to study the molecular nature of genomes of at least representative microorganisms in order to understand and manage pathogenesis, biocontrol, and bioremediation (e.g. nitrate pollution), develop rapid detection and monitoring techniques, and identify candidate genes for transfer of desirable properties. Research should also focus on microbial diversity related to emerging pathogens, which are becoming increasingly important to plant health, food security and food safety. The program should include a combination of research and training to enable both fundamental research and application. Emphasis should be on increased understanding of interactions between agriculturally and environmentally important microbes and higher organisms, for example, crop, forest and urban systems. Although USDA has large programs on both plant and animal genomes, microbial genome studies are currently not funded in any of its programs. There should be a coordinated effort with other microbial genome programs in NIH, DOE and NSF.
Microbial Collections Within USDA, a variety of culture collections should receive support through direct appropriation of sustained, base funds. Culture collections, whether in the hands of individual investigators or in a dedicated, formal collection, are in need of support. These collections, although they may represent limited diversity, are critical as reference cultures for comparative analyses for both basic science and commerce. Individual organisms in such collections are potentially useful and may also provide a source of a useful gene sequence or product. Also, collections are a repository for cultures used in published literature or as commercial products (e.g. patent deposits). The USDA should evaluate the status of its support for microbial collections and their significance to its mission. New funds should be used to strengthen certain types of collections, either by USDA funds alone or in conjunction with other agencies.
This request can, in part, be justified to provide support for the current administrative and congressional goal of reducing agriculture's dependence on synthetic pesticides, and supporting the broad goals of sustainability. Microorganisms represent an enormous but still largely untapped biological and genetic resource available for use in agricultural systems or at the molecular level and collections of microorganisms (including bacteria, viruses and fungi) are in jeopardy.
An expenditure of $10 million ($7 million for research; $3 million for education) will enhance or initiate these areas of need. These programs will reap environmental, economic and human benefits. Agribusiness and the public needs the riches that microbial diversity offers.
Environmental Protection Agency
Given the leadership roles assumed by the Environmental Protection Agency for the maintenance of environmental quality, there is good reason for the agency to undertake a significant initiative on microbial biodiversity. Microorganisms are sensitive indicators of environmental quality. Their responsiveness to environmental change and their rapid reproductive capacities result in population changes that alter relative numbers and types of microorganisms; thus indices of microbial diversity are a sensitive measure for the environmental state of a given habitat or ecosystem. By determining the diversity of microorganisms at selected sites using conventional and modern molecular approaches the agency can establish baselines against which changes in environmental quality can be measured. Microbial diversity measurement can be a sensitive and suitable index of environmental status and trends. Measurement of microbial diversity could be predictive of changes in populations that have resulted in serious threats to human, plant and animal health such as the outbreak of Cryptosporidium infections in Milwaukee. They also would permit detection of impact from chemical pollution and recovery of impacted biological communities. A modest $3 million program could be initiated to validate methodologies for assessing measures of microbial diversity that would also begin to collect baseline data at several sentinel sites.
Department of Defense
The U.S. Department of Defense has two reasons to initiate and expand programs in microbial diversity. The first is an extension of health programs aimed at protecting American forces, including defending against potential uses of biological warfare. Since diverse microorganisms can cause disease and could potentially be used as biological weapons, establishing an inventory of organisms and their distributions can aid in protecting troops against infectious diseases. Knowing what is likely to be present can lead to rapid diagnosis and treatment as well. The second reason for interest in microbial diversity by the Department of Defense concerns the numerous sites that the military has polluted and must now clean up and the various ordinances that must be destroyed. Biodegradation and bioremediation are potentially attractive means of achieving cleanup and destructions of unwanted materials. Given the specific compounds, e.g. nitroaromatics, microorganisms will be needed if biodegradation is employed. Reallocation of several million dollars for environmental cleanup will permit greater efficiency and cost savings using microbial systems for clean up and destruction of munitions.
Department of Commerce
To support microbial diversity research and education in oceanographic, shellfish and aquaculture industries, it is recommended that the Department of Commerce through the National Oceanic and Atmospheric Administration and associated agencies, e.g. Food and Drug Administration, undertake the classification and study of diverse aquatic plants: microbe interactions, as well as virus-host relationships as they exist in natural environments. Specific examples of this involve blue-green algae and cyanophages, as well as Vibrio species including Vibrio vulnificus and their resident bacteriophages. Recent dangers associated with Vibrio vulnificus contaminated oysters have had a serious negative impact on the national shellfish industry, while algal blooms have been associated with massive fish kills in aquaculture ponds