At this point, it should be evident that we have a remarkable team effort that is integrated and focused on the key issues -- In order to engineer cells in ecosystems of energy relevance (and protect them from pollution), we need to model whole systems with explicit recognition of the central role of "optimality". In order to do that modeling, we need detailed and comprehensive data on the actual metabolism of individual cells, including cells, which do not replicate rapidly. We need to escape the "model organisms" including ways to genomically manipulate and measure whole populations of cells without the restrictions of colony purification. For some methods we also need populations of nearly identical (synchronized) cell states. To determine the constraints on each cell we need models and measures integrating the full metabolism and replication of the cells. The technologies described here are novel, cutting through previous impasses, yet down-to-earth in terms of feasibility and rapid start. We have tried to be frugal in numerous ways, focusing most of the costs on the most abundant, and initially the smallest genomes as well as employing novel, cost-effective technologies.

"The responsibility of and relationship between all participating institutions and investigators, a strategy for maximizing communication and exchange of information between investigators, a data and information management plan, and project milestones."

The ultimate responsibility for milestones, communication, coordination, and budgets lies with the Harvard Center for Computational Genetics (HCCG) and the PI, George Church. HCCG has been operational since 1997 with origin earlier in the first extramural DOE HGP technology center in 1987. Since then it has participated in over 50 academic collaborations including initiating three of the original HGP sequencing centers, co-managing several Boston functional genomics resources. It has over a dozen technology transfers and successful distribution of hundreds of strain and software requests. It has one of the first Internet sites in biology (FTP in 1987, HTTP in 1993) on which scientific and organizational communications are updated daily. These days some of the most challenging management issues deal with rapidly changing information technologies and the diverse set of highly intellectual talents required for true integration. This is a very different management task than running a technician-based sequencing center or large relational database maintenance. Our center focus has always been technology development and data-model integration. In recognition of this we have just been awarded the only PhRMA-Foundation. Center for Excellence in Integration of Genomics and Informatics (CEIGI).

We are very fortunate to be able to have a team of experts on each of these organisms and technologies all within walking distance (more typically shuttle bus or car), at five world-class institutions (Harvard Medical School, Harvard CGR, MIT, BWH, and MGH). So communication has been and will continue to be efficient and frequent. In addition to the twice-weekly HCCG meetings to which all collaborators are invited, we will hold monthly meetings specifically dedicated to integrating GTL components. We also will integrate our GTL project with other GTL centers and the potentially relevant (but so far non-overlapping) DARPA BioSPICE project by way of annual meetings organized by DOE and DARPA. Our group will be one of the few participating in both programs and would thus help bridge and coordinate.

We have established an external advisory committee consisting of Andrew Link (Vanderbilt, Goal 1), Saeed Tavazoie (Princeton, Goal 2), Colleen Cavanaugh (Harvard Goal 3), Bernard Palsson (UCSD, Goal 4). These four are chosen as people who, based on our past experience, are sufficiently motivated to look deeply into our project progress and plan adjustments. We expect that the oversight will be by phone, email and at international meetings so as to minimize the impact on the valued time of these four experts. Obviously our advisors will not be not limited to this set of four, but this set agree in advance to be more proactive and critical on this project than our other colleagues.

The details of the tasks behind the milestones are mentioned in main text for each of the goals.

4= Diverse genera, 5= Technology development

(1a) Proteogenomic Mapping 1 1 2 3 1,2,3

(1b) Quantitative Interaction Proteomics 5 1 2 3 1,2,3

(1c) Proteomic Cellular Deconvolution 5 1 2 3 1,2,3

(2a) RNA network in controlled conditions 1 2,3 1,2,3 - -

(2b) Regulatory motif combinations 1 2,3 - 1,2,3 -

(3a) Study the in situ microdiversity 5 1,4 1,4 4 4,5

(3b.i) Functional Diversity Arrays 5 5,4 5,4 5,4 5,4

(3b.ii) Single Cell Activity Multiplexing 5 5,4 5,4 5,4 5,4

(3c) RNA in situ 5 5,3 3 5 3,4

(3d) Transposon arrays 5,3 1 1 5 4

(4a) MPA for Goal 2. 5 1 2 3 1,2,3

(4b) Adding genes with MPA (3a) 5 - 3 2 1

(4c) Ecosystem FBA (3b) - 5,1,3 - 4 5

(4d) Compartmental FBA & MPA (3c) 5 1 1 3 2,4

(4e) 4D cell division model 5 1 5 2 1,2,3

There are relatively few crucial dependencies, but there are many beneficial interconnections. For example, goal 4c will greatly benefit from goals 3a,b so goal 4c is delayed correspondingly. Goal 4e will benefit from goal 1c. Based on past experience, we anticipate that significant changes will occur due the the positive effects of technology development in our group and others. The milestones will typically entail peer-reviewed publications, patents, and web-delivered data/software.

BIBLIOGRAPHY Names of PIs for this grant are in bold; asterisks (*) in the text refer to these papers, some of which are included in the appendices rather than repeat their detailed content and protocols in the main text of this proposal.

Prochlorococcus MED4: 1.658 Mbp

Prochlorococcus MIT9313: 2.4 Mb

Pseudomonas fluorescens Pf0-1: 5.5 Mbp

Pseudomonas putida KT2440: 6.1 Mbp

Pseudomonas putida PRS1: 6.1 Mbp

Pseudomonas aeruginosa PA01 *: 6.264 Mbp (Stover et al. 2000)

Pseudomonas aeruginosa PA14: 6 Mbp

Caulobacter crescentus: 4.016 Mbp (Nierman 2001)

Methanobacterium thermoautropicum * 1.751 Mbp (Smith et al. 1997)

Mycoplasma pneumoniae: 0.816 Mbp (Dandekar et al. 2000)

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1997 Graduated Magna Cum Laude, Highest Honors in Biology, UCSD

1996 Phi Beta Kappa

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Laub, M. T., and Loomis, W. F. (1998) "A molecular network that produces spontaneous oscillations in excitable cells of Dictyostelium" Molecular Biology of the Cell 9, 3521-32.

Laub, M. T., and Smith, D. W. (1998) "Finding intron/exon splice junctions using INFO, INterruption Finder and Organizer" J. Computational Biology 5, 307-21.