New Methods and Models for Genomic Systems Biology
George Church(email@example.com), Martin Steffen, Wayne Rindone, Matt Wright, Daniel Segre, Dennis Vitkup, Jake Jaffe, Rob Mitra, Jay Shendure, Greg Porreca, Vincent Butty, and Jun Zhu
Harvard Medical School, 200 Longwood Ave, Boston, MA 02115; and Washington University
Understanding biological experiments will increasingly benefit from system models, not just subsystems, but comprehensive, genome-wide analyses. Genotype + environment yields phenotype. New methods allow us to cost-effectively overdetermine each of these components enabling studies of mechanism, optimality and bioengineering. New technologies include single-molecule sequencing with polymerase colonies (polonies) to assess alternative RNA splicing and DNA haplotyping. Polonies may also offer a path toward a Mbp per $ sequencing goal conducive to expanded diagnostics and environmental monitoring. New computational approaches include expression coherence for combinations of transcription elements and Minimization of Metabolic Adjustment (MoMA) to model proliferation of mutants. See http://arep.med.harvard.edu/
Stepping up the Pace of Discovery
Office of Science, Office of Biological and Environmental Research, U.S. Department of Energy
The systems biology revolution is proceeding along multiple pathways as science agencies and the private sector adopt strategies suited to their particular needs and cultures. During the past 3 years, the DOE Office of Science held 15 workshops involving some 500 scientists to advise the department on how it should contribute to meeting the systems biology challenge and to determine related technological needs, potential applications, and societal considerations. The result was the development of the new DOE Genomes to Life (GTL) program. A central focus of GTL is environmental microbial biology, and its key goal over the next 10 to 20 years is to achieve a basic understanding of thousands of microbes and microbial systems in their native environments. This focus demands that we address huge gaps in knowledge, technology, computing, data storage and manipulation, and systems-level integration.
The GTL program has several distinguishing features, including (1) strategies for unprecedented levels of comprehensive data collection using emerging high-throughput technologies, tightly coupled with (2) advanced computing, mathematics, algorithms, and data-management technologies; (3) a unique focus on microbial organisms and systems possessing capabilities for possible solutions to energy and environmental challenges; and (4) implementation of new research and management models that link facilities dedicated to production-scale systems biology data generation and analysis in a teaming environment for a large community of individual investigators.
The DOE Office of Science Joint Genome Institute (JGI) has played and will continue to play a key role in GTL by sequencing microbial and other important genomes. Consistently, roughly half the genes found in diverse microbial species are of unknown function, and half of those have not been observed previously, suggesting that the number of essentially novel genes could eventually range into the tens of millions. From this perspective alone, DNA sequencing clearly is and will remain for some time the most economical method for gene discovery. Discovery of new and novel genes and pathways that can aid DOE in its missions of energy security, bioremediation, and carbon management remains an important aspect of GTL. JGI thus will remain a key component of the GTL program and OBER facilities portfolio. In addition, JGI has a broader role to play in a variety of projects that will push forward the frontiers of science. DNA sequencing should be used, for example, to help understand and characterize the diversity of life on our planet, to address fundamental questions in biology and the evolutionary processes, and to develop new methods for understanding how protein structure affects functionality and efficiency.
Knowledge is powerbut only if you use it. The vast amount of information contained in the hundreds of genomes sequenced and the thousands of future sequencing projects offers an unprecedented opportunity for understanding complex biological systems and our environment. This opens exciting new avenues to solve some of the most urgent problems in healthcare, national security, agriculture, energy, the environment, and industry. Addressing these challenges expeditiously demands that we take bold steps to achieve a new, much faster, and more efficient pace of biological discovery.