Summary

The U.S. Department of Energy (DOE) is charged with promoting scientific and technological innovation in support of its overarching mission to advance the national, economic, and energy security of the United States (DOE, 2005a). Recognizing the potential of microorganisms to offer new energy alternatives and remediate environmental contamination, DOE initiated the Genomes to Life program, now called Genomics: GTL, in 2000. The Genomics: GTL program aims “to understand biological systems well enough to predict their behavior accurately with mechanistic computational models” so that such knowledge can be used to engineer systems for bioenergy production and environmental remediation and to understand carbon cycling and sequestration. Since the inception of the program, it has awarded funding for over 75 research projects to interdisciplinary teams of investigators. In the same period, DOE has been convening workshops to devise a plan for four user facilities for protein production and characterization, characterization and imaging of biomolecular machines, proteomic analysis of microorganisms, and modeling of microbial community cellular systems to facilitate genomic research relevant to its mission. The goals of the program and the plans for building the four user facilities are published in the 2005 Genomics: GTL roadmap (DOE, 2005b). The purpose of the present report, by the National Research Council Committee on Review of the Department of Energy’s Genomics: GTL Program, is to evaluate the design of the program and its infrastructure plan.

The committee comprises experts in comparative and structural genomics, computational biology, protein crystallography, molecular imaging, cellular systems, biophysics, biological and agricultural engineering, and economics and



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Review of the Department of Energy’s Genomics: GTL Program Summary The U.S. Department of Energy (DOE) is charged with promoting scientific and technological innovation in support of its overarching mission to advance the national, economic, and energy security of the United States (DOE, 2005a). Recognizing the potential of microorganisms to offer new energy alternatives and remediate environmental contamination, DOE initiated the Genomes to Life program, now called Genomics: GTL, in 2000. The Genomics: GTL program aims “to understand biological systems well enough to predict their behavior accurately with mechanistic computational models” so that such knowledge can be used to engineer systems for bioenergy production and environmental remediation and to understand carbon cycling and sequestration. Since the inception of the program, it has awarded funding for over 75 research projects to interdisciplinary teams of investigators. In the same period, DOE has been convening workshops to devise a plan for four user facilities for protein production and characterization, characterization and imaging of biomolecular machines, proteomic analysis of microorganisms, and modeling of microbial community cellular systems to facilitate genomic research relevant to its mission. The goals of the program and the plans for building the four user facilities are published in the 2005 Genomics: GTL roadmap (DOE, 2005b). The purpose of the present report, by the National Research Council Committee on Review of the Department of Energy’s Genomics: GTL Program, is to evaluate the design of the program and its infrastructure plan. The committee comprises experts in comparative and structural genomics, computational biology, protein crystallography, molecular imaging, cellular systems, biophysics, biological and agricultural engineering, and economics and

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Review of the Department of Energy’s Genomics: GTL Program science policy (see Appendix A). The committee was charged to address three specific questions that are highlighted below. In response to its charge, the committee reviewed the Genomics: GTL roadmap and heard from representatives of DOE, scientists who are involved in the program, scientists who conduct research relevant to DOE’s mission goals but are not involved in the program, and representatives of other federal agencies that have genomics programs (see Appendix B). This summary is structured as a response to the questions in the charge and includes the committee’s recommendations. Question 1: Is the Genomics: GTL program, as currently designed, scientifically and technically well tailored to the challenges faced by the DOE in energy technology development and environmental remediation? Answer 1: Yes, the use of systems and synthetic biology approaches in the Genomics: GTL program to address some of the most pressing issues in microbial genomics relevant to DOE’s mission in energy security, environmental remediation, and carbon cycling and sequestration is not only appropriate but necessary. The study of individual components only does not provide knowledge on systems integration at the level of pathways, organisms, and microbial consortia—for example, on the effects of introducing new metabolites or new or engineered organisms to a community or on organism or community responses. Systems biology research is needed to develop models for predicting the behavior of complex biological systems, to engineer microorganisms for bioremediation and energy-related needs, and to understand carbon cycling. Current and planned research of the Genomics: GTL program promises to provide the predictive understanding of microorganisms needed to Develop affordable and reliable carbon-neutral energy alternatives from plants and microorganisms. Develop biological solutions to the many recalcitrant problems of legacy wastes. Increase understanding of the role of microbial communities in global carbon cycling to enable the development of carbon-sequestration techniques for addressing climate change. The committee endorses DOE’s use of a systems approach to achieve its mission goals through Genomics: GTL and supports its plan to enlarge funding of the program to $200 million per year for basic research. The committee suggests

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Review of the Department of Energy’s Genomics: GTL Program that plant biology research be included in the Genomics: GTL program where appropriate because plants represent a major pathway to the production of bioenergy, play an important role in carbon sequestration and global nutrient cycles, and are potential sources of bioremediation. The committee’s suggestion is consistent with the Energy Basic and Applied Sciences Act of 2005, which calls for an emphasis on both plants and microorganisms in the program. Systems biology research on plants and microorganisms is not likely to be conducted on a large scale without DOE’s visionary thinking. (See Appendix D for a list of microbial genomics programs in other federal agencies.) Because the productive applications of new technologies to advance science will be hampered by the lack of appropriate tools, the committee finds that the concept of infrastructure for research and technology development offers a logical and even necessary pathway for achieving DOE’s research goals. Recommendation 1: The committee recommends that DOE and the nation give high priority to genomics research aimed at achieving DOE’s mission goals. Question 2: Does the proposed Genomics: GTL research and facility investment strategy leverage DOE scientific and technical expertise in the most cost-effective, efficient, and scientifically optimal manner? Specifically, does the business model (i.e. number, scope, scale, order, and user operations plan) for the proposed Genomics: GTL facilities follow directly from the science case—should one exist—for systems biology at DOE? Are there alternate models for some or all of the proposed effort that could more efficiently deliver the same scientific output? Answer 2: The committee enthusiastically endorses the goals of the Genomics: GTL program and acknowledges the need for infrastructure, but it believes that DOE’s current plan for building four independent facilities for protein production, molecular imaging, proteome analysis, and systems biology sequentially may not be the most cost-effective, efficient, and scientifically optimal way to provide this infrastructure. As an alternative, the committee suggests the construction of up to four institute-like facilities, each of which integrates the capabilities of all four of the originally planned facility types and focuses on one or two of DOE’s mission goals. Under the current implementation plan, DOE is to construct the facility of different types consecutively, each taking 6 years for design and construction. It would therefore take at least 24 years for the Genomics: GTL program to reach

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Review of the Department of Energy’s Genomics: GTL Program full capabilities. In the fast-changing era of genome-enabled science, DOE cannot afford to spend that many years in pulling together the tools needed to make progress if it wants to remain a leader in cutting-edge science. Irrespective of the timeline, building four single-purpose facilities may not be the most effective way to meet the multiscale and multidisciplinary challenges of systems biology. The properties of complex systems can best be studied by interdisciplinary teams of scientists who have access to state-of-the-art techniques and computational capacity. This collaborative environment will also facilitate removal of cultural barriers between experimentalists and theoreticians. The needs of the studies would be met not only by scaling up protein production, molecular imaging, proteome analysis, and modeling of cellular systems but also by integrating them so that a specific problem in systems biology (as related to the Genomics: GTL objectives), rather than only a technique, is the focus of each facility. Having four independent user facilities that merely provide services to researchers who have different research foci will reduce DOE to the role of enabler rather than leader. In addition, because the economies of scale that made large genome projects successful have not yet been obtained in work with proteins or in most aspects of systems and synthetic biology, the large-scale facilities envisioned by DOE may not be as cost-effective as expected. The committee strongly encourages DOE to rethink its user-facility construction plans and to consider the creation of up to four integrated facilities. Each facility will combine the capabilities of the original planned facility types in a vertically integrated manner so that it can tackle all aspects of a problem or small set of problems in parallel and potentially achieve goals more quickly. The first vertically integrated facility would focus on one or two of DOE’s mission goals, such as bioenergy. It would operate as an intellectual center concerned with how to provide affordable energy alternatives and become a leading institute in bioenergy. Technologies would be developed with a greater emphasis on the needs of bioenergy research than on the objective of serving the scientific community as a whole. The synergy between researchers and technology developers would also speed technology outcomes and keeps them at the cutting edge. Experience gained from the first facility would be used to refine approaches and improve planning and execution of the second facility, which would have a different theme (Box S-1). The committee feels that the revised strategy would greatly improve the cost effectiveness and efficiency of DOE’s investment while optimizing the achievement of useful scientific results. Recommendation 2: DOE should revise its plans for creating four single-purpose technology-driven facilities in sequence. Instead, DOE should create up to four institute-like facilities that each contain all the capabilities of the original planned facility types—protein production, molecular imaging, whole-proteome analysis, and systems biology—in a vertically integrated manner. Each facility should focus on one or two of the DOE mission objec-

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Review of the Department of Energy’s Genomics: GTL Program BOX S-1 Merits of vertically integrated facilities for Genomics: GTL program Vertically integrated facilities would establish the Genomics: GTL program in a leadership position to launch a world-class, comprehensive, integrated research and training program in systems and synthetic biology. They would create a paradigm shift in biological research that will integrate data from a broad spectrum of spatial and temporal scales to advance understanding of biological phenomena to be able to predict or alter capabilities for optimal performance under field conditions. The facility would provide an intellectual and physical environment for both multidisciplinary teams and individual-based research. The research programs of the facilities would be built on overarching biological themes relevant to the DOE missions in energy production, environmental remediation, and carbon sequestration. They would involve diverse disciplines, including genomics, genetics, physiology, biochemistry, structural and computational biology, nanoscience, and engineering. The facilities would provide an intellectual and physical environment for both multidisciplinary teams and individuals pursuing research in relevant missions. New technologies would be developed in the facilities on the basis of well-justified scientific problems. The technologies will be aimed at particular ends rather than being ends themselves. The successful development of the integrated facilities would attract investigators around the country to use them. The resulting scientific discoveries and technology development can be expected to benefit not only a subset of biologists but a broad spectrum of scientists and engineers in different disciplines. Because of the diverse disciplines of the investigators, the integrated facilities are likely to have complex organization charts. That will leverage the experience of DOE to administer this new research enterprise. Modeling plays a central role in studying and understanding complexity. New computational approaches and tools would be developed in the facility to promote synergy between modeling and experimentation at both bench and field level. The first facility constitutes a pilot to validate the hybrid systems approach and to identify roadblocks to be addressed in the later facilities. All facilities can be designed so that they will not be outdated by the rapid pace of scientific discovery and technological development. The vertically integrated facilities lend themselves to a staged investment with expandable bases, flexibility to shift directions without losing prior investments, leverage, and open-source positioning. tives and develop short-term, medium-term, and long-term goals to chart a course for the program. Short-term milestones should be used as a metric for independent evaluation. The committee believes that selection of appropriate contractors, timing, and location will be key factors in the success of the Genomics: GTL program.

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Review of the Department of Energy’s Genomics: GTL Program Contractors should be selected through an open and all-inclusive competitive process that provides adequate opportunities for universities and industry to partner with DOE and its national laboratories. Criteria for selection of contractors to implement the Genomics: GTL facilities should include innovations of the project plan relevant to DOE missions, management organization, educational outreach, technology dissemination, intellectual property management plan, proximity to a concentration of high-caliber participating scientists in diverse disciplines, and possibly provision of matching funds by the applicant institutions. The committee encourages DOE to consider cost sharing by applicant institutions for design and construction because timely establishment of the proposed facilities is crucial in the fast-moving field of systems biology. For example, allowing the successful applicant to fund new construction or renovation of an existing facility upfront could greatly speed up the process. As federal funds become available through the appropriations process, DOE could then “lease-purchase” the facility to eventually acquire it from the private-sector partner. To expedite the operation of the facility, DOE could also use vacant space in buildings in localities that were once targeted or are being considered for major development by the biotechnology industry. Reuse of existing space would not only reduce costs but also improve access to the facilities for academic and industry scientists. The committee feels that it would be a mistake to create new user facilities behind the fences of some of the remote existing DOE laboratories (for example, Hanford and Los Alamos) that are not close to major centers of biotechnology research. The Genomics: GTL program will not succeed in achieving DOE’s mission goals unless it is embedded in a culture of strong basic biology and innovative biotechnology. To ensure the program’s success, DOE should consider locating the facilities close to universities or federal or private research institutions that have established centers of excellence in biology and biotechnology. An open-access policy will also encourage the best scientists to conduct their research at the Genomics: GTL facilities. Recommendation 3: DOE should consider locating user facilities on private land off DOE reservations to allow an open-access policy and close to research institutions that have established programs or centers of excellence in biosciences and biotechnology. The locations for the user facilities should be selected in an open and all-inclusive competitive process that provides adequate opportunities for universities and industry to partner with DOE and its national laboratories. In addition to facilitating research and developing enabling technologies—bioinformatics, computational biology, mathematical modeling, protein production, molecular imaging, and proteome analysis—the Genomics: GTL program and its facilities can serve as training grounds for the next generation of scientists.

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Review of the Department of Energy’s Genomics: GTL Program This is an especially important aspect of a program that promises to deliver a high degree of interdisciplinary cooperation. The National Science Foundation’s (NSF) Integrative Graduate Education and Research Traineeship program is a model that DOE could consider adapting to its own purposes. Several agencies have programs in microbial genomics that complement research at DOE. DOE should also be strongly encouraged to partner with and leverage the programs of the other federal agencies with common interests in microbial biology (NSF), bioremediation (the Environmental Protection Agency), biofuels (the U.S. Department of Agriculture), and genomics (the National Institutes of Health) (DOE 2005d). Recommendation 4: DOE should consider partnering with universities and other federal agencies to develop programs that use Genomics: GTL institute-like facilities as training grounds for the next generation scientists. Question 3: In an era of flat or declining budgets, which aspects of the proposed Genomics: GTL program are the most meritorious? Which appear to have the highest ratio of scientific benefit to cost? Answer 3: The Genomics: GTL program’s research has resulted in and promises to deliver many more scientific advancements that contribute to the achievement of DOE mission goals. The committee proposes the initiation of facilities that integrate the four capabilities of protein production, molecular imaging, proteome analysis, and modeling and analysis of cellular systems because they are all necessary for achieving a predictive understanding of microbial systems through systems biology. Therefore, the question of which facility with a distinct capability is the most meritorious is irrelevant. If DOE were to set up vertically integrated facilities, it would have to select which of its mission foci should be the targets of the first integrated facility. The committee suggests that bioenergy be its first choice given the pressing concern of energy security. The committee believes that there are compelling reasons for DOE to give its highest priority to creation of a “bioenergy institute.” First, the U.S. (and global) economy is increasingly vulnerable to oil shocks caused by political unrest, terrorism, or natural disasters. A recent analysis conducted by Securing America’s Future Energy and the National Commission on Energy Policy concluded that even “small incidents” that reduced global oil supply by 4 percent would cause oil prices to increase dramatically to more than $161 per barrel. Second, as several National Research Council reports have concluded, we need to act now if we are to have any chance of stabilizing greenhouse-gas emissions; this is espe-

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Review of the Department of Energy’s Genomics: GTL Program cially true given the 100-year residence time of carbon dioxide in the atmosphere and the 30- to 50-year lifetime of capital stock in the energy industry. Because reduction of carbon dioxide in the atmosphere and carbon cycling are related to use of bioenergy, the bionergy institute should have a secondary focus on carbon sequestration. Finally, recent advances in biology (for example, rapid sequencing, directed evolution, and whole-genome synthesis) may enable us to design biological systems capable of generating affordable, carbon-free energy. CONCLUSION The committee finds that the systems biology focus of the Genomics: GTL program is essential to achieving DOE’s mission goals and other goals and objectives in biology in general and in sustainable development. The current research program is excellent, and the need for infrastructure for protein production, molecular imaging, proteome analysis and modeling and analysis of cellular systems is well justified. If the committee’s recommendation on reconfiguring the plans to construct vertically integrated facilities that operate as institutes were followed, they could have an especially high ratio of scientific benefit to cost because the need for new technology will be directly tied to the biology goals of the program.