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New Frontiers in Characterizing Biological Systems

Report from the May 2009 Workshop

To promote development of a new generation of characterization technologies,the U.S. Department of Energy's (DOE) Office of Science Office of Biological and Environmental Research (BER) hosted the New Frontiers in Characterizing Biological Systems workshop in May 2009. Experts from scientific disciplines relevant to DOE missions and from the enabling technologies (e.g., optical spectroscopy, genomic sequencing technology, electrochemistry, electron microscopy, and mass spectrometry) met to determine the opportunities and requirements for identifying and developing new tools and analytical approaches for characterizing cellular- and multicellularlevel functions and processes that are essential to develop solutions for DOE missions in biofuels, carbon cycling and biosequestration, low dose radiation, and environmental stewardship. The intent of the workshop was to broadly explore future technology capabilities that are needed, not current technologies and their development.

Publication date: December 2009

Suggested citation for this report: U.S. DOE. 2009. New Frontiers in Characterizing Biological systems: Report from the May 2009 Workshop, DOE/SC-0121, U.S. Department of Energy Office of Science (http://genomicscience.energy.gov/characterization/).

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Executive Summary

Understanding the relationship between the genome and functional processes is the most significant challenge and potentially enabling advancement that faces modern biology. Elucidating this connection presents opportunities for realizing sustainable energy solutions and responsible management of natural resources. Understanding the function of the genome is at the core of the Department of Energy’s (DOE) Genomic Science program and is central to realizing DOE’s mission goals in bioenergy research, carbon management, and environmental stewardship. Just as genomic science is central to these mission goals, technology advancements are central to genomic science and to unlocking the connections between the genome and functional processes occurring at cellular to global environmental scales. New developments in characterization technologies will be essential for driving advances in genomic science and in our understanding of the genomic bases of natural processes.

In May 2009, DOE’s Office of Biological and Environmental Research (BER) held the New Frontiers in Characterizing Biological Systems workshop to address the next generation of challenges in genomic science and its connection to functional systems. The workshop included a diverse array of scientists and engineers with expertise in the mission-relevant biological and environmental sciences and in the analytical and physical sciences. Working groups were focused on defining the challenges associated with studies at the cellular, multicellular, and interfacial levels. Common themes and priorities emerged from the different groups. There was universal agreement that appropriate advances in characterization technologies will first depend on articulation of the major challenges that face the biological and environmental science communities. To that end, this report— rather than comprehensively discussing currently available technologies—highlights the major challenges and outlines the future technological capabilities required to meet them. Workshop participants identified numerous knowledge gaps that inhibit the understanding of biological systems, and these can be distilled into three major challenges:

• Understand the Cell and Its Response to Chemical and Physical Perturbations. The characterization of genome sequences and their products has highlighted the need for identifying and characterizing the other parts that comprise the cell. Many of these components are difficult to identify or quantify. Completing the “parts list” of the cell and determining how cellular networks composed of these parts respond to local physical and chemical changes are priorities.
• Understand the Interactions Between Cells. Many cellular interactions are poorly understood, such as how cells communicate, regulate their genetic information in response to other cells, and combine their capabilities for higher-order functions. A needed advance involves routinely interpreting how multiple cells, with similar or different genetic content, combine to process information, energy, and materials.
• Understand the Functioning of Biological Systems Across Multiple Scales of Time and Distance. A connection between the genome and biological function at physical scales as diverse as an individual cell and an ecosystem or at temporal scales as diverse as seconds and years can be apparent but difficult to define. The dynamic nature, spatial and temporal ordering, and nonlinearity of system responses confound interpretations at any level of inquiry. The ability to design experiments, identify and model appropriate system components, and predict function are challenges that must be addressed.

These primary knowledge gaps are relevant to understanding the processing of biomass into different chemical forms, the cycling of carbon, and the transformation of contaminants in the environment. They are fundamental challenges intrinsic to diverse biological and environmental concerns. Timely resolution of these problems will revolutionize our understanding of biological systems and significantly advance DOE mission science. Achieving these goals will depend on a transformation of current measurement capabilities. Numerous technological approaches can be considered.

Regardless of approach, the specific technical capabilities needed to fill these knowledge gaps include:

• Expand and Integrate Global Characterization Capabilities. Biological systems are composed of a wide array of differing molecular species. We need to “see it all” and be able to monitor dynamic changes at increased spatial resolution. Currently, we cannot probe many of the dynamic processes occurring within the cell at the required chemical, spatial, or temporal resolution nor can we measure the response of these processes to chemical and physical perturbations. A wide assortment of metabolites, lipids, carbohydrates, and other biochemicals simply cannot be identified or accurately measured. Understanding the interactions and fates of these materials is essential for understanding cell function. Combining global measurements and extending the ability to comprehensively characterize and manipulate any system component are needed advances. New technologies for completing the parts list of cellular components are essential.
• Identify and Measure Important Molecular Species, Events, and Cells. Biological systems are recognized as containing complex mixtures of different chemical and biological species. The relative importance of particular components to functional outcomes is difficult to assess. Even more difficult is associating rare events or minority components to functional outcomes. Current technologies have the ability to monitor single cells and detect single molecules. However, they are limited in their ability to do so in complex, heterogeneous environments, let alone in natural systems. Technologies are needed that can identify and detect single or small populations of molecules or cells amidst complex, heterogeneous backgrounds. These technologies will aid in understanding the effects of chemical and physical forces on the cell and the interactions among cells.
• Simultaneously Measure Many Chemical and Biological Species Across Broad Spatial and Temporal Ranges. Biological information is carried in a wide variety of molecules and is expressed across broad spatial and temporal ranges. Current tools often are appropriate for providing characterizations at only specific spatial and temporal scales, or they are limited in the number or type of species that can be measured. There is a strong need to bridge the discontinuities between different measurements and to address the gaps that occur as we span length and time scales. Multiple dimensions need to be added to biological measurements so that molecular events can be linked to cellular, multicellular, and environmental scales.
• Integrate and Interpret Diverse Information and Technology Platforms. Biological systems can be assessed at many levels ranging from the molecular to the cellular to the ecosystem scale. Beyond the challenges of how to measure and collect such biological information, critical challenges related to what to measure and how to interpret the information remain. Addressing these problems will depend on effective tools for integrating and interpreting the information. Useful databases and computational approaches are needed for integrating measurement information and for modeling systems at multiple scales. Currently, we do not know at which scale to measure or model biological system function. Effective focusing of measurement technologies will rely on an iterative relationship with computational modeling approaches. Models that are capable of dealing with the gradients and discontinuities of biological systems must be developed and integrated with experimental design.

Overcoming these technical challenges will facilitate basic understanding of biological processes, not just at a particular physical or temporal scale, but the linking and relating of such scales to genomic information. Focused advancements in characterization technologies will address critical knowledge gaps and support the realization of mission needs. These advancements will broadly impact the biological and environmental sciences in general and ultimately transform biology into a quantitative science.

Moving forward in these needed developments will require concerted efforts on several fronts. Key among these is investment in stimulating technology developments. These developments will need to proceed within the context of the primary biological challenges identified in this report. A priority should be the development of approaches for simultaneously assessing multiple species at appropriate spatial and temporal resolution. This likely will proceed through combinations of different measurement techniques. Technology advancements also must commence with developing high-throughput parallel approaches for making sensitive measurements in heterogeneous environments. Small molecules within single cells and small populations must be tracked. Measurement techniques alone will not be sufficient. Rather, what is required to reveal function is the ability to manipulate relevant biological, chemical, and physical variables while tracking their effects on biological systems.

A second key focus should be on promoting analysis of the biological systems most relevant to DOE missions. We must move past the study of relatively simple model organisms and toward the study of organisms within their natural environmental setting (e.g., in planta and in terra). Initially, organism systems that are representative of the technological and environmental problems we wish to understand must be identified. Capabilities for culturing or studying organisms at the single-cell level need to improve along with the tools for manipulating and studying these organisms at the molecular level. Systems research will need to progress past the study of individual organisms in isolation and toward systems of increasing biological complexity, replete with the structuring and heterogeneity found in natural systems. Interrogating natural systems in situ should be a long-term goal.

A third focus should be on integrating biological and technological developments through computational tools. Large, disparate datasets must be combined and analyzed to yield new insights into the function of biological systems across diverse scales. Iterative cycles of experimentation and modeling in concert with new theory will be needed to define the appropriate scales for measuring, modeling, and functionally understanding biological processes. This integration will need to capitalize on DOE BER traditions and success in integrating scientific disciplines and in solving grand challenge problems. Multidisciplinary teaming should be promoted and facilitated through integrative training opportunities, incentives for collaborative science, and facilitated access to high-end technologies.

Understanding the connections that link the genome to events at different scales promises to unravel many of the challenges facing the biological and environmental sciences. Such insight will enable effective routes to sustainable energy solutions and responsible stewardship of the environment. Analytical technology developments are key to sustaining progress toward these goals and addressing the challenges and knowledge gaps that emerge. The complexity, emergent properties, and multiple scales of biological systems present substantial obstacles. The tremendous progress in characterizing whole genomes, which only a few decades ago was considered a nearly intractable problem, was enabled by the focused integration of a biological problem with technological advances in analytical measurements and computation. Similarly, the seemingly daunting challenges that we now face can be addressed through focused developments and bold advances in characterization technologies.

*Note to readers: The following notice applies to the figure: "Expression of Lactose Permease in E. coli" p. 27, which is used with permission from Science and AAAS for the report New Frontiers in Characterizing Biological Systems.

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