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Agency Activities in Metabolic Engineering
Department of Agriculture (USDA)
The Cooperative State Research, Education and Extension Service (CSREES) is
the USDA agency that participates in the Interagency Metabolic Engineering
Working Group. In the CSREES Strategic Plan, five goals are listed:
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An agricultural production system that is highly competitive in the
global economy.
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A safe, secure food and fiber system.
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Healthy, well-nourished population.
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Greater harmony between agriculture and the environment.
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Enhanced economic opportunity and quality of life for Americans.
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These goals reflect the goals of the overall USDA strategic plan (enhancing
economic opportunities for agricultural producers, supporting increased economic
opportunities and improved quality of life in rural America, enhancing
protection and safety of the nation’s agriculture and food supply, improving the
nation’s nutrition and health, and protecting and enhancing the nation’s natural
resource base and environment).
Metabolic Engineering (ME) can enhance competitiveness of the US agricultural
system through the production of commercially useful products such as chemicals,
biofuels, and biomolecules from agricultural commodities. Through modification
of plants, animals, and microorganisms, ME can also result in new uses for
existing crops and animals, added value to traditional agricultural products,
and improved quality of agriculturally derived foods and materials. It is also
possible through ME to produce plants with enhanced nutritional value or to
modify plants and microorganisms for remediation of polluted environments.
The participation in MEWG has allowed CSREES to leverage funding for support
of several research projects that address one or more of CSREES’ and USDA’s
goals. Funding is supporting research on metabolic engineering of biofuels that
may lead to maximized ethanol production as well as reduced costs. Another
funded project involves production of flavor compounds in microbes that may
eventually lead to improvements of metabolic function for processing of
agricultural biomass and manufacture of bio-based industrial products. Funded
metabolic engineering research projects in plants have the potential to produce
fruits and vegetables with increased nutritional value and extended shelf-lives,
to increase natural product-based disease and pest resistance, to enhance oil
production in oilseeds, and to modify plants for production of pharmaceuticals
and other economically important compounds. Thus, metabolic engineering, through
both basic and applied research, is of vital importance for achieving the
strategic goals of CSREES and USDA.
Department of Commerce (DOC)
The MEWG supports the DOC mission by advancing research and development of
new commercial and industrial processes. As an emerging technology whose
scientific basis is developing rapidly, ME is important to DOC’S NIST and
especially its Biotechnology Division. NIST is especially interested in ME
projects that support the development of biological and metabolic models,
measurement methods and standards.
Department of Defense (DOD)
The Department of Defense (DoD) currently supports a broad range of research
in the area of metabolic engineering through the Army Research Office (ARO) and
other Army research activities, the Office of Naval Research (ONR), and the
Defense Advanced Research Projects Agency (DARPA). The specific focus of the ARO,
ONR, and DARPA efforts will be summarized and future directions in metabolic
engineering research and technology development will be addressed.
The broad needs for the DoD that can be served through research efforts in
metabolic engineering are summarized below. These science and technology targets
will provide enhanced and expanded capabilities for the missions of the services
and provide greatly expanded capabilities for the civilian sector.
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Materials
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Processes
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Devices
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Fabrication Schemes
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Information Processing
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Current interests in metabolic engineering at ARO are focused on the
characterization of biochemical pathways, inter- and intra-cellular signaling,
and enzymatic mechanisms, and the genetic basis for manipulation of protein
expression, structure and function, and cell fate, in systems with potential
relevance to the Army. The goal is to develop a detailed understanding of how
macromolecules and cells execute their designated functions and how they
interact with other cells and macromolecules. With this information, it will be
possible to design and engineer particular sub-cellular elements and metabolic
pathways and cell systems to exhibit a set of specific functions and properties,
according to Army needs, and to identify and non-invasively correct molecular
deficiencies to optimize and maintain cognitive and physical performance under
normal and extreme conditions. ARO currently supports research in several areas,
including: how molecular transport, subcellular compartmentalization, and
reaction sequences are involved in enzymatic regulation and superstructure
formation; understanding and manipulating aminoacylation of tRNAs and genetic
code expansion to produce new polymeric peptides containing non-natural amino
acids; biologically based means for fabrication of functional nanostructures;
systems engineering of cell differentiation processes; the role and regulation
of classes of proteins differentially expressed in response to environmental or
external stimuli; molecular genetics and genomics of human cognition,
performance and function; and the design and implementation of unique
biomolecular and cell based strategies for economically and environmentally
favorable manufacturing, as well as the biodegradation of environmental
pollutants.
One of the metabolic engineering foci at ONR, currently, is the microbial
synthesis of energetic materials (EM) and EM precursors for the purposes of cost
and environmental impact. Practically all such materials are non-natural
products and their biosynthesis therefore requires the re-engineering of
existing pathways and/or the assembly of new or hybrid pathways in one or more
host organisms. An example of a simple EM precursor now under study is
1,2,4-butanetriol, which as its energetic trinitrate is used as a plasticizer in
propellant and explosives formulations. More advanced EM targets, such as RDX,
HMX and Cl20, involve high density fused ring cores with multiple nitramino
(C-N(NO2)) substituents. While these are very difficult targets, they suggest
worthwhile research goals such as the biosynthesis of highly electron
withdrawing substituents on carbon (as in C-nitramino) or the assembly of
strained heterocyclic rings. Clearly, a theoretical/experimental approach to the
prediction of the true scope of enzyme reaction specificity, with energetic
boundaries, would be particularly valuable in the design of pathways for EM
biosynthesis. Other non-polymeric targets, besides EM, would include novel
photonic/electronic/optical materials.
DARPA's metabolic engineering programs are driven by an interest in
protecting human assets against biological threats and using biology to maintain
human performance. The general concept of this thrust is to understand how
nature controls the metabolic rate of cells and organisms (e.g., extremophiles,
hibernation) and apply this understanding to problems of interest to DoD.
Examples of current investments in metabolic engineering include efforts to
develop technologies for engineering cells, tissues and organisms to survive in
the battlefield environment so they can be used as sensors. Related basic
research on biochemical circuit engineering in laboratory model organisms is
also supported. In addition, DARPA is developing technologies that permit the
long-term storage of cells including human blood. More complete descriptions of
current DARPA programs and solicitations in these areas can be viewed at http://www.darpa.mil/dso.
Department of Energy (DOE)
The Department of Energy is supporting research in metabolic engineering
research, largely through the Offices of Science (SC), Energy Efficiency and
Renewable Energy (EE), and Environmental Management (EM). The research falls in
two main categories: 1) basic research, which involves the advancement of
metabolic engineering fundamental knowledge and capabilities, and 2) applied
research, which employs metabolic engineering techniques in development of
target products. The basic research efforts of the Department reside within SC,
whereas most of the applied research in this area is conducted within EE. In
general, these research efforts are conducted by universities, national
laboratories, and industry.
The Department's goals related to metabolic engineering research are to:
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To expand the level of knowledge and understanding of metabolic pathways
and metabolic regulatory mechanisms related to the development of novel
bio-based systems for the production, conservation, and conversion of
energy.
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Apply metabolic engineering techniques to enhance and develop plants and
microorganisms for use in the production of chemicals and fuels or for
environmental remediation of waste sites.
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Environmental Protection Agency (EPA)
The mission of the Environmental Protection Agency is to protect human health
and the environment from adverse effects of anthropogenic activity. Included in
this mission are various elements for which metabolic engineering can play a
useful role.
One prominent concern is the introduction of chemicals to the environment,
which may have detrimental effects on humans and other biota. As mandated
by statute and implemented by rule, the Agency routinely conducts evaluation of
chemicals intended for use, currently in use, or determined to exist at
significant levels in the environment. From these evaluations, the Agency may
decide to implement management strategies designed to limit the potential for
adverse effects.
The application of novel technologies such as the use of biotechnology as a
substitute to conventional manufacturing and processing of raw materials into
final products is consistent with the mission of the Agency. EPA
implements this by supporting development of technologies which 1) use chemical
substitutes that are less toxic; 2) produce more efficient activity resulting in
decreased requirement for the chemical or; 3) develop engineering procedures
which produce little or no toxic end products. Finally, consistent with the
pollution prevention ethic is the reevaluation of chemical stewardship from one
of "cradle to grave" to a more multigenerational philosophy in which a chemical
may be utilized successively in different forms prior to final disposal.
Metabolic engineering has a role to play by enabling the development of
biological mechanisms for production or use that meet one or more of these
criteria.
While it is generally accepted that chemical-based technologies have evolved
to provide a higher standard of living for the general population, it is also
recognized that the use of some chemicals, either through the chemical
characteristics or the handling, synthesis or disposal, have produced negative
effects on human health and/or the environment. Advances in technology allow
scientists to better predict the potential for adverse effects from exposure to
chemicals as well as mechanisms to diminish the negative effects of chemical
production such as production of toxic byproducts and disposal of the chemical.
The approach, which strives to identify synthetic pathways that are less
polluting than existing pathways and that encourages the development of nontoxic
chemical products, is referred to as "Green Chemistry". The use of
metabolic engineering to evaluate the potential for increased risk from
chemicals, by allowing the study of responsible metabolic pathways and by
permitting modification of such pathways to reduce risk, is another way in which
metabolic engineering firs within the EPA mission.
Finally, basic research, which utilizes methods of metabolic engineering, can
provide longer-range approaches to assist EPA in its overall mission of
protecting human health and the environment. The EPA supports extramural
metabolic engineering research through the Technology for a Sustainable
Environment (TSE) program, which awards grants in the area of pollution
prevention. Since 1995, the TSE program has funded metabolic engineering
research related to methanol conversion, solvent tolerance, biopolymer
production and pesticide production-all focused on the elimination of pollution
at the source.
National Aeronautics and Space Administration (NASA)
One of NASA’s strategic goals is to extend the duration & boundaries of human
space flight to create new opportunities for exploration & discovery. To prepare
for and hasten the journey, the NASA Office of Biological and Physical Research
must address the following questions through its research:
| How can we assure the survival of humans traveling far from Earth? |
| What technology must we create to enable the next explorers to go beyond
where we have been? |
NASA’s efforts in the area of metabolic engineering are on approaches and
applications that will have a significant impact on the reduction of required
mass, power, volume, crew time, and on increased safety and reliability, beyond
the current baseline technologies. The targeted and purposeful alteration of
metabolic pathways found in an organism may play a key role in the development
of biological approaches and technologies that enable efficient use of
spacecraft resources for long-duration space missions.
National Institutes of Health (NIGMS/NIH)
The National Institute of General Medical Sciences (NIGMS) supports metabolic
engineering research, usually in the form of grants to investigators in
universities (R01s) or in small businesses (SBIRs). These grants support
basic research in two general areas: (1) the development of microbial or
plant-based metabolic routes to useful quantities of small molecules such as
polyketides; (2) the development of a much better understanding of the control
architecture that integrates the genetic and catalytic processes in normal and
aberrant cells.
National Science Foundation (NSF)
| The mission of NSF is to: |
| Promote the Progress of Science |
| Advance the National Health, Prosperity, and Welfare |
| Secure the National Defense |
| Provide for Other Purposes |
Support of ME research allows NSF to address specific goals within its
mission. These include, but are not limited to; development of technologies
integrating theoretical, computational, and experimental approaches to the study
of metabolic processes; the targeted and purposeful alteration of metabolic
pathways in living organisms in order to better understand and utilize these
pathways for chemical transformation, energy transduction, and supramolecular
assembly; providing a framework for studying the dynamics of interactions and
interconversions of biological molecules in order to understand how organisms
regulate specific physiological processes at the cellular and sub-cellular
levels and the "cross-talk" between pathways; measurement and control of in
vivo metabolic fluxes; metabolic control analysis of pathway groups or
networks; development of in vivo techniques to accomplish these goals.
Metabolic Engineering has been heavily supported in all five interagency
competitions by three Directorates within NSF. There is a recognition at NSF
that this Activity has been beneficial to NSF and that NSF would like to
continue with this Activity.
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