Second 5-Year Plan (2004-2008)
March 2004
Metabolic Engineering Working Group
Subcommittee on Biotechnology
The Metabolic Engineering Working Group (MEWG) was originally
formed early in 1995 to foster one of the priority research
areas (Manufacturing/ Bioprocessing) identified in the
National Science and Technology Council (NSTC) Report:
"Biotechnology for the 21st Century: New Horizons." After
considerable deliberations, it was decided that the Metabolic
Engineering of microbial, plant, and animal cells, as
described in the Report, held the greatest promise of
advancing the productivity of Bioprocessing. Further support
for this research topic came from the recognition that
Metabolic Engineering is expected to play a major role in the
progress of the other three priority research areas mentioned
in the Report, i.e. Agriculture, Environmental Biotechnology,
and Marine Biotechnology and Aquaculture. With the recent
issuance of the White House Memorandum (June 5, 2003) on "FY
2005 Interagency Research and Development Priorities", MEWG
sees a continued opportunity for Metabolic Engineering to play
a key role in meeting those priorities, and wishes to renew
its original five-year plan.
MEWG GOALS
- Promote the Advancement of Metabolic Engineering
The MEWG has defined Metabolic Engineering (ME) as "the
targeted and purposeful alteration of metabolic pathways found
in an organism in order to better understand and utilize
cellular pathways for chemical transformation, energy
transduction, and supramolecular assembly." The MEWG believes
that this emerging technology will have a significant effect
on our nation's "quality-of-life" and international
competitiveness. Accordingly, it should be the responsibility
of the MEWG to promote and coordinate activities in this area.
- Coordinate Federal ME research activities for maximum
productivity.
It is a goal of the MEWG to see that the current Federal
expenditure for ME is coordinated for maximum efficiency and
effectiveness. Key to this coordination is the dissemination
of research program information among Federal Agencies with
active ME programs.
- Identify and address gaps in ME research activities.
LIST OF MEWG AGENCIES
- Department of Agriculture (USDA)
- Department of Commerce (DOC)
- Department of Defense (DOD)
- Department of Energy (DOE)
- Environmental Protection Agency (EPA)
- National Aeronautics and Space Administration (NASA)
- National Institutes of Health (NIGMS/NIH)
- National Science Foundation (NSF)
ACCOMPLISHMENTS (1997-2003)
MEWG has generated a Metabolic Engineering Web Site (http://www.metabolicengineering.gov)
that is providing a one-stop location for information on
Federal Government activities in Metabolic Engineering.
MEWG has held four Interagency Conferences where results of
funded ME projects have been shared with participating
Grantees and Agency Representatives.
MEWG has issued five Interagency Announcements of Opportunity
in Metabolic Engineering calling for research proposals that
would centrally employ and/or significantly advance the
techniques of ME. These proposals led to 45 research grants
from the MEWG participating agencies. Grants from the first
four competitions are listed on the MEWG web site.
While many of these grants are still in progress, examples of
some particularly noteworthy outcomes include:
- A grant to Jay Keasling on the “Metabolic Engineering of
Isoprenoid Production”, which was supported by the Office of
Naval Research (ONR) and NSF, has led to the publication in
Nature Biotechnology of “Engineering a Mevalonate Pathway in
Escherichia coli for Production of Terpenoids”. The technology
described in the paper has the potential for providing a
microbial means of producing the anti-malarial drug
Atremisinin, which is usually extracted from plants.
- A grant to Bernhard Palsson on the “in silico Analysis of
the Escherichia coli Metabolic Genotype and the Construction
of Selected Isogenic Strains” funded by ONR and NSF, and other
grants to Palsson funded by NIH, have lead to numerous
publications on this technology including a cover article in
Nature Biotechnology. In silico, or computational methods to
predict cellular responses to environmental stimuli based on
the genome for a cell are being experimentally verified, and
provide a powerful tool to understanding cellular behavior.
HOW THE PROPOSED ACTIVITY SUPPORTS THE MISSION OF EACH
AGENCY
Metabolic engineering, being a broad, enabling technology,
supports the missions of all of the current participating
Federal Agencies in MEWG.
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 draft
CSREES Strategic Plan, five goals are listed:
1. An agricultural production system that is highly
competitive in the global economy.
2. A safe, secure food and fiber system.
3. Healthy, well-nourished population.
4. Greater harmony between agriculture and the environment.
5. Enhanced economic opportunity and quality of life for
Americans.
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 National Institute of
Standards and Technology (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 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.
• Materials
• Processes
• Devices
• Fabrication Schemes
• Information Processing
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 DOE 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:
• 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.
• 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.
Environmental Protection Agency (EPA)
The mission of the EPA 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 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; and 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; and 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.
Thus, whether a shared or unique focus, ME research has a
broad based interest throughout the Federal research
establishment.
PLAN
While the Interagency activities have been very successful,
there remains much to be done.
MEWG proposes to continue to coordinate Federal ME research
activities using the following mechanisms:
- Maintain an up-to-date web site
- Hold regular meetings of MEWG
- Sponsor annual Interagency Conferences on Metabolic
Engineering
MEWG proposes to issue Interagency Announcements of
Opportunities in Metabolic Engineering over the next five
years calling for research proposals in Metabolic Engineering.
ANTICIPATED SYNERGIES OF THE MEWG EFFORTS
It is the intent of MEWG to provide a means for the
participating Agencies to support projects in ME that would
not normally be done by a single Agency. For example, a
project at a government laboratory supported by one Agency
could be complemented by a linkage to university participation
in the project supported by another Agency. Three way linkages
between industry, government laboratories, and academe are
another possibility.
MEWG anticipates continued member participation in national
and international conferences on Metabolic Engineering.
AVAILABILITY OF FUNDS TO SUPPORT THE INTERAGENCY
ANNOUNCEMENT OF OPPORTUNITIES IN METABOLIC ENGINEERING
For the five Interagency Announcements already carried out,
each Agency provided a letter of support for an Announcement
indicating the amount of funding that might be available for
proposals submitted in response to that Announcement. It is
anticipated that this will continue with new Interagency
Announcements. The actual amount each Agency commits to
proposals from a particular Announcement, which can range from
no support to support of multiple proposals, will depend on
the quality and subject matter of the proposals that the
Agency is willing to fund.
EVIDENCE OF THE TIMELINESS OF THE CONCEPT OF METABOLIC
ENGINEERING AND THAT THE RELEVANT COMMUNITIES ARE READY TO
RESPOND.
- All MEWG Agencies are interested in furthering the goals of
MEWG.
- The recent issuance of a White House Memo (June 5, 2003) on
"FY 2005 Interagency Research and Development Priorities"
highlights the need for "Molecular-Level Understanding of Life
Processes" where Metabolic Engineering has a far-reaching
opportunity to contribute.