Plan for group integration and response to RFA

Plan for group integration and response to RFA

Plan for group integration and response to RFA November 21, 2006 John Aach, PhD, Lecturer Church Lab Department of Genetics Harvard Medical School [email protected] CONFIDENTIAL 1 What we are now Fantastic -- great science, stature, experience! We are a major force now. Not completely familiar with each other Projects unintegrated. Many individuals/groups with independent projects should connect and synergize Budget a bit too big with items still coming in. Need for prioritization and adjustments Currently ~$30.4M / year vs. $30M / year ( = $25 GTL-BRC + $5 GTL-SB) 2

Objectives for this meeting Operate as a Center Establish climate of open discussion Start process of Center-wide integration Look for opportunities for improvement and integration Understand our strengths & strengths of competing teams Establish focus on what it will take to have a winning proposal Bring merger and budget considerations within that focus Discuss how to align project repertoire with DOE expectations Provide food for thought on what projects, people, and groups need to do to fit into winning proposal

Call for preliminary management team; identify next steps 3 Things we will not do Completely resolve project integration or budget considerations Much will be left to preliminary management team Things we need to do Disclose contacts / collaborations with other proposal groups and BP effort 4 Purpose of this talk Describe on-going thinking about how to structure Center / proposal Identify key themes and issues that we need to think and talk about in todays area-specific sessions Identify some of the next steps 5

Plugging in + some next steps for everyone Contact me to get on Center email distribution list and to get access to the Center proposal wiki wiki address: http://karma.med.harvard.edu/gclab-gtl my email: [email protected] wiki GTL_grant_sections page has project write-up examples and standards. Get me information sufficient to render your project into this format by the end of November. ~60-65 pages for project narrative, currently >50 projects Deliverables, Time Line, Project Summary that is clear concerning proposed project activities We consider the wiki, this meeting, and all associated materials to be confidential. 6 DOE says a BRC must Basic attributes be a Center be a Genomics:GTL BRC have short, intermediate, and long term vision

respond to shifting research directions / promising opportunities Activities conduct basic, genomics-based research; fundamental science develop basic research to point of easy transition to applied science real steps to real solutions support range of high-risk, high-return approaches (high-payoff breakthroughs) top priority: improve production of liquid transportation fuels; cellulosic ethanol = most plausible near-term candidate Other vertical integration (?? two perspectives) develop & integrate needed core capabilities (Center) complete, integrated strategy for improving biofuel production (Process) understand current industry roadblocks; aim to resolve them quality assurance / information management strategy component collaborate with National Labs / companies 7

Resources relevant to DOE expectations for BRCs RFA 8/2006 White Paper 8/2006 6/2006 8 Resources relevant to DOE expectations for Genomics:GTL Centers 2005 NAS Report 3/2006 DOE Roadmap: 4 Centers which are user facilities, each dedicated to single capability Protein production, molecular machines, proteomics, modeling

Centers to support microbial research for 3 long-term goals Bioenergy, environmental remediation, carbon cycling/climate NAS: Better to have these capabilities vertically integrated in each Center & dedicate Centers to specific goals (Bioenergy = #1) DOE: accepted NAS recommendations (embodied in the RFA) 9 Two DOE offices have had input Office of Biomass Program Office of Science RFA comes from OBER Harvard/MIT GTL Center = Genomics:GTL Center 10 What we need to have for a winning RFA response

Draft Center Vision / Letter of Intent statement http://karma.med.harvard.edu/gclab-gtl/ Go to GTL_Grant_Sections and look at Center Vision item Centerhood Integrated project portfolio that addresses DOEs expectations Other attributes Short, intermediate, long term goals Required components (QAIMS) 11 Centerhood Geographical vs. conceptual No DOE requirement for geographical Centers but DOE makes allowances for them, suggesting possible preference We claim that conceptual center with best + most experienced minds is better than a geographical Center How to achieve Centerhood Unified vision, integrated plan, integrated management (see wiki)

We need to start today by setting up a preliminary management team Center composition Very desirable to include National Labs, companies 12 Project portfolio implicit in DOE documents Improve current practice Move mainstream research directions closer to practice real steps to real solutions systems biology enabling basic science and technology GTL:Genomics approach Explore alternative paradigms (e.g.,

biodiesel / alkanes ..) Explore new organisms, capabilities high-payoff breakthroughs Process and economic modeling, policy analysis environmental + ELSI Understand industry roadblocks 13 real step to real solution vs. high-payoff breakthrough Distinction 14 real step to real solutions vs. high-payoff breakthrough Fermentation real steps to real solutions high-payoff breakthrough

Organisms that take lignocellulose hydrolysatesEtOH on par/+ with organisms taking starch EtOH C5+C6 EtOH >95% theory yield Final EtOH titers 10-15% 2-5 g/L-h productivity Resistant to hydrolysate toxins Genomes and sys.bio on engineered, evolved, wt yeast, coli

Additional engineering, evolutions Process improvements: SSCF, less severe pretreatments, CBP Microbial communities vs. monocultures Predictive systems models of metabolism and regulation Direct production of alkanes, long chain alcohols, fatty acids Final EtOH titers of 40% Biocatalysts taking syngasEtOH 15 real step to real solutions vs. high-payoff breakthrough Feedstock deconstruction real steps to real solutions

high-payoff breakthrough Structure / chemistry analysis of cell walls Better ligninases, hemicellulases Better understanding / improvement of cellulases, cellulosomes Discovery of new enzymes / systems via metagenomics High-throughput characterization of cell walls

Express cell wall deconstruction enzymes in plants 16 real step to real solutions vs. high-payoff breakthrough Biofeedstocks real steps to real solutions high-payoff breakthrough Understand, optimize cell wall structure and composition (e.g., control lignin)

Understand type II (energy only) plants such as perennial grasses Understand / modify poplar Stress tolerance, productivity High-productivity biodiesel crops (other opportunity) 17 real step to real solutions vs. high-payoff breakthrough Bottom line real steps to real solutions Improve current practice mainstream research directions that have demonstrated at least a small improvement current systems biology / genomic / analytic tools on principal organisms, features, enzymes / structures extend modifications in one system to another similar one certain well-argued good ideas that have not been demonstrated

high-payoff breakthrough Good idea that has been tried / theoretically feasible but for which there is uncertainty regarding successful development Understand, develop, exploit currently uncharacterized phenomenon found in nature relevant to bioenergy 18 Enabling technology 19 Enabling technologies & expertise available in Center Low cost genome DNA resequencing e.g., for strains optimized by artificial evolution

low cost DNA or RNA tag sequencing low cost DNA synthesis from oligos e.g., synthesis of libraries of gene or promoter variants metagenomics artificial evolution single-cell sequencing membrane protein production and purification computational modeling e.g., reverse engineering of regulatory networks, metabolic network modeling forward engineering of artificial circuits (switches, counters, etc.)?Lowcost resequencing 20 Process modeling and economic and policy analysis

p. 181 21 Some of your answers PI Peters (UFL) Project Modify cell walls of woody feedstocks approach Biomass cost decrease (%) Southern pine $1.26 /grn MT growth+30% (6.3)

Southern pine >= 20% CH2O/lignin + increase / wood 20% unit (0) Southern pine >= 10% increse hemicellulose/ EtOH / wood cellulose + 10% unit (0) Poplar $1.50 /grn MT growth+30% (8) Poplar >= 15% CH2O/lignin + increase / wood 15% unit (0) Poplar >= 10%

hemicellulose/ increase EtOH / cellulose + 10% wood unit (0) EtOH cost basis EtOH cost decrease (%) $0.05/gal (3.3) $0.18/gal (12) $0.09/gal (6) $1.50/gal $0.07/gal (4.66) $0.13/gal (8.66) $0.09/gal (6) PI Project approach Cost basis

Production Reduction PSU various Pretreatment cost reduction 2G barrels Pretreatment recuced 25% Cosgrove (PSU) faster degrading Expansins biomass 2G barrels

Saccharification $5G cost reduced 30% Regan (PSU) MFC on waste water Pretreatment = 30% of cost; EtOH = $1/gal. Expansin / cellulase synergy = 1:10; saccharification = 20% cost; EtOH=$1/gal 2% 2005 USA electricity = $300G

Replace up to 5% electricity Cost savings (%) $6G Up to $15G (5) 22 Project universe by pathway steps Zea,Miscanthus,Poplar, Crambe, Algae Pretreat silage x (acid, NH4) AGRICULTURE Saccharify Trichoderma, Clostridia, Aspergillus, new x (soluble vs. cellulosome) Ferment

Saccharomyces, Escherichia, Zymomonas, Pichia, Klebsiella, new, communities x (sequential vs. cofermentation) Extract distill, gas strip, phase Process crack, blend, zeolite, Uses transportation, chemicals, power Separate vs. CBP Plants Enabling Tech: Modeling, Synthesis, Evolution,

Sequencing, 23 Process and economic modeling combined with field testing as a kind of high-level systems biology AGRICULTURE Process and economic modeling Field testing (Fields-toWheels?) AGRICULTURE AGRICULTURE Plants Pretreat PROJECTS

Plants Pretreat Plants Pretreat Saccharify Saccharify Ferment Saccharify Ferment Ferment Extract Extract Extract Process Uses

Process Uses Process Uses CENTER INDUSTRY 24 Our current project mix Project category Pathway step 25 Project category and pathway steps as management tools Should we set targets for fraction of budget or project number for project categories?

How about pathway steps? 26 Other attributes Short, intermediate, long term vision required by DOE, but time frames are not identified in RFA Cellulosic ethanol report: 5, 10, 15 year time frames GTL:Genomics Roadmap: 1-8, 9-15, >15 year time frames (1.3.6.1) Center is funded for 5 years, so could be 1-2, 2-4, 5 years. Quality Assurance and Information Management Strategy Assumption is that there will need to be a bioinformatics czar in the Center to help coordinate data and computational resources and guide them towards accepted standards 27 Questions to ask yourself for rest of day

Where does my project fit into the DOE scheme of things? What are the real steps vs breakthrough directions for each process category? (Is DOE right?) What is the likely economic benefit of my project? What are reasonable targets and priorities for project categories and pathway steps? How can my project synergize with others I am hearing about? What enabling technologies will help my project? Have we interpreted DOE expectations correctly? Should we argue with them vs. accept them? Budget issues Can the project category / pathway step framework help guide budget adjustments? Should there be special provisions for companies in the budget? Do we have a reasonable approach to Centerhood? What is a good name for our Center? 28 Next steps that will follow this meeting

Settle on preliminary management team Develop priorities and implement in project portfolio and budget Finalize Letter of Intent Get on the Center proposal mailing list Look at Center proposal wiki and revise, supplement your project write-ups by end of November. List of core services at your institution 29 Thank you! John Aach [email protected] 617-432-0061 http://karma.med.harvard.edu/gclab-gtl/

30 Things to consider in each session Does this project group have a different priority than others? Are there synergies between these projects or with projects in other groups? Are there overlaps which should be resolved? What enabling technologies can these make use of low cost DNA or RNA resequencing

low cost DNA synthesis from oligos artificial evolution metagenomics single-cell sequencing membrane protein production and purification computational modeling Can specific economic benefits be assigned to any of these projects? CONFIDENTIAL 31 Thank you for coming & Enjoy your Thanksgiving holiday! George and John 32

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