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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