Life & Medical Sciences Division Status Report

1. Life & Medical Sciences DivisionStatus Report David Thomassen Acting Division Director

2. U.S. Department of Energy Office of Science Life & Medical Sciences Division Who are we? Sharon Betson – Secretary Joanne Corcoran – Program Assistant Dean Cole – Artificial retina Dan Drell – GTL, JGI, ELSI Patrick Glynn – BRCs Joe Graber – AAAS Fellow, GTL Susan Gregurick – Computation, GTL, JGI Roland Hirsch – Structural Biology, GTL John Houghton – GTL, BRCs Arthur Katz – GTL, Low Dose Radiation Peter Kirchner – Human subjects, Imaging Noelle Metting – Low Dose Radiation Prem Srivastava – Radiochemistry Michael Teresinski – Laboratory Safety Marvin Stodolsky – GTL, Genomics, SBIR Sharlene Weatherwax – GTL, BRCs, JGI Libby White – Human Subjects

3. U.S. Department of Energy Office of Science Life & Medical Sciences Division What do we do? • Genomics:GTL (including ELSI) • Joint Genome Institute • Low Dose • Structural Biology • Radiopharmaceuticals, imaging, retina • Protection of Human Subjects

4. U.S. Department of Energy Office of Science Life & Medical Sciences – COV Update Dates: June 8-11, 2008 Location: Germantown, MD COV chair: Dr. Peg Riley, BERAC 22 COV members from academic institutions and other federal agencies. The COV is charged to assess the processes used to: solicit, review, and recommend proposal funding actions manage ongoing research programs respond to the recommendations of the previous COV in 2005. Specific program elements to be reviewed include: Genomics:GTL (including the Bioenergy Research Centers) Carbon Sequestration ELSI Low Dose Radiation Research Radiochemistry and Instrumentation Artificial Retina Joint Genome Institute Structural Biology (Medical Sciences programs were merged with Life Sciences Research programs in 2006 and will be undergoing their first COV review.) A report will be provided at the next BERAC meeting.

5. U.S. Department of Energy Office of Science Life & Medical Sciences - Solicitations • Low Dose (with NASA) – fundamental mechanisms • Low Dose - integrated program projects • Plant feedstock genomics with USDA • Radiochemistry & imaging instrumentation • Genomics:GTL for biohydrogen

6. U.S. Department of Energy Office of Science DOE Bioenergy Research Centers: Multi-Institutional Partnerships

7. U.S. Department of Energy Office of Science BioEnergy Science Center (BESC) • Strong central strategic focus on overcoming “recalcitrance” (resistance of plant fiber, or lignocellulose, to breakdown into sugars) as major route to cost savings and cost-effective biofuels production • Longer-term goal of “Consolidated Bioprocessing” (CBP) – one-microbe or microbial community approach going from plants to fuel • Working directly on energy crops – switchgrass and poplar • Nearly completed development new high-throughput pipeline to screen thousands of genetic variants of switchgrass and poplar for amenability to deconstruction • Performed bioprospecting in Yellowstone National Park for cellulases that operate more efficiently at very high temperatures – using metagenomics to find new, more effective cellulases • Pursuing synthetic biology to make Clostridium thermocellum (CBP microbe) more efficient at fermenting and to re-engineer the cellulosome • Strongly committed to achieving cost-saving, commercializable breakthroughs in five years • Will eventually have the opportunity to test discoveries in a demonstration biorefinery being constructed by the state of Tennessee 40 miles from BESC

8. U.S. Department of Energy Office of Science Joint BioEnergy Institute (JBEI) • Strong basic science-oriented approach, looking for fundamental transformational, game-changing breakthroughs in basic science • Focusing on model crops of Arabidopsis and rice (and on switchgrass) – with idea that basic science breakthroughs can be achieved more rapidly on model crops and then transferred to energy crops • Innovative approach to lignin – rather that treat lignin as a wall to be broken through, change the monomer composition of lignin to make it more cleavable and its byproducts less toxic to microbes used in fuel synthesis • Progress on pretreatment – success already using ionic liquids as an alternative pretreatment method—yields no toxic byproducts and de-crystallizes the cellulose – significantly accelerates enzymatic hydrolysis • Especially creative on the microbial side – using synthetic biology, looking beyond ethanol to synthesis of butanol, isopentanol, hexadecane, geranyl decanoate (toward gasoline, diesel, jet fuel) • All researchers will work together in a newly leased lab building near Berkeley – move to new quarters in Emeryville nearly completed • Fostering strong connections to larger S.F. Bay Area Biotech Community, which is becoming hub of bioenergy technology and venture investment

9. U.S. Department of Energy Office of Science Great Lakes Bioenergy Research Center (GLBRC) • Reflecting agronomic orientation of the two universities, focusing on a wide range of plants, including both “model” plants and potential bioenergy crops – also in some ways the most diverse research agenda • Alternative approach to plants – in addition to working to overcome “recalcitrance” of lignocellulose, GLBRC will be re-engineering plants to produce more starches and oils, which are more easily processed into fuels – oils for biodiesel • Alternative approaches to fuels: • Exploring chemical catalytic as well as enzymatic/microbial conversion – producing hydrocarbons – green gasoline, diesel, aviation fuel – new approach of “aqueous phase processing” yields hydrocarbons from sugars • Developing microbial biorefineries that can use sunlight and plant biomass to generate hydrogen, electricity, or high-energy chemicals • Includes major “thrust area” on sustainability of biofuels production, comprehensively studying the environmental and socioeconomic dimensions of moving to a biofuels economy (not requested in FOA, but widely praised by peer reviewers and important for moving toward President’s “20 in 10” goal) – of growing importance in new societal debate on biofuels – actively working to educate public, community

10. U.S. Department of Energy Office of Science ASCR-BER Joint EffortsAccelerating Progress Toward GTL Goals PAST: SciDAC and GTL Efforts: Current research within the SciDAC/GTL program includes new molecular dynamics codes for very large biological systems such as Cellulases, network analysis for hydrogen metabolism, and programs, such as BACTER, aimed at bridging the computational/experimental microbiology gap. PRESENT: Multiscale Modeling Efforts between GTL and ASCR: Proposals were solicitedfor joint activities to interface computational and mathematical efforts with biological mission relevant research directions. Areas under consideration include large scale genotyping and simulations of microbial communities, large scale network analysis and coarse graining of dynamical processes. FUTURE: GTL Systems Biology Knowledgebase Workshop: A workshop will outline the mechanism necessary to create a community driven resource for the archival, curation and integration of data and information that is relevant to the organisms of interest and mission areas of DOE. Particular emphasis is given to creating a computational and collaborative infrastructure. (Reported by Susan Gregurick yesterday.)

11. U.S. Department of Energy Office of Science Cellulose Hemicellulose Lignin Life & Medical Sciences DivisionGTL Update Continued Addressing Deficiencies in Genomic Annotation • More genomic sequences require more robust annotation • Experimental confirmation of annotation lags far behind • Investing in innovative experimental approaches Understanding Lignocellulose Degradation • Improving lignocellulose degradation key to using non food feedstocks • Investments focus on understanding degradation through imaging • Range of techniques with higher risk complement and support BRC needs

12. U.S. Department of Energy Office of Science Life & Medical Sciences DivisionRecent Sequencing Successes • Chlamydomonas reinhardtii – green alga, carbon processing machine • Trichoderma reeseii – champion biomass degrading fungus • Laccaria bicolor – symbiotic fungus of Poplar and others • Soybean – of bioenergy interests to many • Termite hind gut metagenome – enzymes for lignocellulose degradation • New tool for metagenome data management & analysis (http://img/jgi/doe/gov/m)

13. U.S. Department of Energy Office of Science Low dose data only Radiation Protection Standards: Development Sequence National Standards EPA NRC DOE Recommendations may be modified … If the risk is judged to be lower … Recommendations NCRP ICRP New studies of low dose human cohorts Research Reviews (Risk Estimates) UNSCEAR BEIR And standards may change. Radiation Epidemiology RERF JCCRER Low dose epidemiology High bkg areas Nuclear workers Radiation workers Low Dose Radiation Biology “better scientific understanding and consensus”

14. U.S. Department of Energy Office of Science Low Dose Radiation Research Program • Workshop planned to discuss epidemiology needs • Tentatively November 2008 • Research shows extrapolation from A-bomb survivors not optimal • Update, extend available studies of human cohorts • Modify study designs: ecological cohort • Appropriate comparison populations • Dose Ranges charts now translated into Spanish, Russian, Georgian, Chinese, and Latvian (PNNL Interdict/RADACAD)

16. U.S. Department of Energy Office of Science Structural BiologyStatus of major projects • NSLS protein crystallography program reviewed in 2003, renewed for five years; latest renewal reviewed jointly with NIH-NCRR in March, 2008 • SSRL structural molecular biology program reviewed in 2004; renewed for five years • ALS programs all now part of a single Science Focus Area, but with distinct budgets and review plans; x-ray microscopy renewal application due to nih this month • LANSCE protein crystallography station program renewed in 2005 • APS Structural Biology Center reviewed and renewed in 2006 • SANS station at Oak Ridge has completed a full year of operation; renewal review to take place in coming year • Competitive renewal of PDB in progress with NSF and NIH

17. U.S. Department of Energy Office of Science Structural Biology – Pending Issues • National Synchrotron Light Source to be replaced. How will life sciences access be developed and what new techniques will be enabled by the facility? • How important are neutron techniques and how much should BER invest in user stations for them? [This question from 2005 is still unanswered.] • To what extent should the structural biology facility access program focus on needs of the Genomics:GTL program? Several beamlines are being used in GTL technology development and/or research, will more, or new types, be needed? • Are there areas for which a program solicitation would be desirable, perhaps jointly with other agencies? • Other new national user facilities, such as the Linac Coherent Light Source (LCLS), and major facility upgrades. What is the potential impact on life sciences in general and on BER research programs?

18. U.S. Department of Energy Office of Science Radiochemistry & Imaging - Update • FY 2007 Program Funding ($6.05M): Supported radiotracer and advanced imaging instrumentation for medical research and technology development activities mainly at BNL, and some imaging instrumentation work at other DOE laboratories including LANL, LBNL, ORNL and T. J. Laboratory. • FY 2008 Omnibus Bill: Congress provided additional $17.5M for nuclear medicine research. Solicitation issued.Formal applications encouraged from the initial pre-application phase and submitted in response to Funding Opportunity Announcement in the area of Radiochemistry and Instrumentation Research will be reviewed for scientific merit, and making grant awards in FY 2008. track RNA movements report gene activation er report metabolite levels

19. Artificial Retina Argus I Update U.S. Department of Energy Office of Science • 16 microelectrode implant • Six blind patients implanted • No device failures • Implant still operating after over 6 yr of daily use • Demonstrated feasibility of artificial retina prosthesis • Patients can see large print

20. Next Generation Argus II Update U.S. Department of Energy Office of Science • Argus II • 60 microelectrode device • RF power and data transmission • Smaller implant • Reduced surgical time (2.5 hours) • Advanced image processing • Real time • Portable • Reliable • Designed to last a lifetime • Extensive in vivo and in vitro testing

21. Argus II Clinical Trials U.S. Department of Energy Office of Science www.clinicaltrials.gov/ct/show/NCT00407602 • Worldwide Testing • United States • FDA approval for 3 yr feasibility IDE • 10 patients implanted at multi-centers in US • No damaging effect after 8 months of daily use • Europe • 3 patients implanted in Geneva and the UK • Latin America • 2 patients implanted

22. U.S. Department of Energy Office of Science Protection of Human Research Subjects • New Program Manager – Libby White • 2007 site visits – LBNL, LLNL, Fermilab • Coordination with NNSA • DOE Human Subject Working Group • DOE resources – resource book, newsletter, resource group • DOE human subjects database • Coordination with Health & Human Services Office for Human Research Protections – 2008 site reviews planned for Sandia (+ 2 more) • Lab accreditations to date (BER will support initial and ongoing costs) – PNNL (2008), BNL (in process)