APPENDIX A – PLENARY PRESENTATIONS A-1
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APPENDIX A – PLENARY PRESENTATIONS
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APPENDIX B – WORKING GROUP OUTBRIEFS
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APPENDIX C – MEETING AGENDA
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State of the Science Meeting: Systems Biology of Drug-Resistant Infectious Diseases Agenda
DAY ONE 03 OCTOBER
8:00 – 8:10 am Arrival and Registration
8:10 – 8:15 am Opening and Administrative Remarks
8:15 – 8:30 am Dr. George Ludwig, Acting Principal Assistant for Research & Technology, US Army Medical Research and Materiel Command (USAMRMC)
Purpose, Process and Desired Outcomes of the Review
8:30 – 8:50 am Dr. Lee Hood, President, Institute for Systems Biology
Keynote: Systems Biology Disease Pathways and Molecular Systems
8:50 – 9:00 am Dr. John Aitchison, Professor, Institute for Systems Biology
Network Biology & Infectious Disease
9:00 – 9:15 am Dr. Marti Jett, Chief Scientist, Systems Biology Enterprise, US Army Center for Environmental Health Research The Current State of Systems Biology at USAMRMC
9:15 – 9:30 am Dr. Joseph Palma, Systems Biology Consultant to the USAMRMC Principal Assistant for Research & Technology, Leidos USAMRMC
Systems Biology Enterprise –Early Challenges and Outcomes 9:30– 9:45 am LTC Kurt Schaecher, Chief, Infectious Disease Laboratory, Walter Reed
National Military Medical Center The Current State of Anti-Microbial Resistance in ESKAPE-E.coli
9:45 – 9:50 am Administrative Remarks
9:50 – 10:00 am Break
10:00 – 12:00 pm
Breakout Groups (Discussion of Key Questions):
· Group 1 – Mechanisms of Host Response to Infection· Group 2 – Mechanisms of Pathogen Invasiveness and
Immune Evasion· Group 3 – Development of Drug Resistance and Persisters· Group 4 – Computational Analysis Approaches
12:00 – 1:00 pm Lunch
12:30 – 1:00 pm Dr. Doug Lauffenburger, Head, Department of Biological Engineering, Massachusetts Institute of Technology
Keynote: Systems Engineering Principles for Analysis of Biological Regulatory Mechanisms
1:00 – 1:30 pm Report of Preliminary Findings by Breakout Group Chairs [Chairs provide 5’ talks to all participants summarizing focus areas within
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their respective groups]
1:30 – 5:00 pm Breakout Groups 1-3- Discussion of Key Questions – Begin Formulating Conclusions and Recommendations
5:00 pm Adjourn
6:00 pm Evening Group Dinner (optional)
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DAY TWO 04 OCTOBER
8:15 – 8:30 am Arrival
8:30 – 8:45 am Day 1 recap and Review of Goals for Day 2
8:45 – 9:15 am Dr. Frank Doyle, Dean, John A. Paulson School of Engineering and Applied Sciences, Harvard University
Integrating Network Biological Data into Diagnosis and Treatment of Disease
9:15 – 10:30 am Breakout Groups 1-4 – Completion of Recommendations/Outbriefs
10:30 – 10:45 am
Break
10:45 – 11:15 am
Finalize Recommendation Summaries
11:15 – 12:15 am
Outbriefs (15 min per group)
12:15 –12:30 pm
Closing
Questions for Breakout Groups: [Breakout Groups to focus on militarily relevant bacterial pathogens, recognizing however, that those characteristics are shared across the biota, and thus are not limited only to militarily relevant bacteria]
Group 1: Mechanisms of Host Response to Infection
· Morning Session: Key questions - What are the current state of knowledge and keyknowledge gaps related to:
a) Regulation of mechanisms and pathways involved in the host response toinfection – e.g., what are the common and unique features of the immuneresponse to bacterial pathogens? This would include: 1) the innate immuneresponse that serves as a common first line of defense against a variety ofpathogens and 2) the antigen-specific adaptive immune response that confersimmunological memory and protection from reinfection.
b) Cross-talk between these mechanisms/pathways during infectious diseaseinitiation and progression.
c) Understanding the heterogeneity in the host immune response to infection.· Afternoon Session (Continue discussion from Morning Session and also address the
following):
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FOR COMMENT DRAFT
a) What are significant barriers to leveraging the host response, utilizing insightsfrom systems analysis for rational design of host- or bacterial-based diagnostics,therapeutics and (as applicable) vaccines.
b) What are significant technology, informatics or other barriers to thecomputational integration of in vitro, animal model, and human data on hostresponse that would limit the ability to perform integrated analysis across thesedifferent biological systems?
c) What can USAMRMC do to enhance cooperation and coordination acrossorganizations? What new processes or policies would improve data sharing andcollaboration among partners?
Group 2: Mechanisms of Pathogen Invasiveness and Immune Evasion
· Morning Session: Key questions - What are the current state of knowledge and keyknowledge gaps related to:
a) Understanding the factors by which pathogens influence host response to promotepathogen survival and invasiveness.
b) Role of the host microbiome (microbiome-pathogen and microbiome-hostinteractions) in pathogenesis of bacterial infections.
c) Bacterial mechanisms and pathways involved in regulating invasiveness andimmune evasion (e.g. regulation of bacterial virulence factors).
d) Development of pathogen-based and host-based therapeutics.· Afternoon Session (Continue discussion from Morning Session and also address the
following):a) What are significant barriers to leveraging bacterial mechanisms of invasion and
immune evasion, utilizing insights from systems analysis for rational design ofhost- or bacterial-based diagnostics, therapeutics and (as applicable) vaccines?
b) What are significant technology, informatics or other barriers to thecomputational integration of in vitro, animal model, and human data on pathogenbiology that would limit the ability to perform integrated analysis across thesedifferent biological systems?
c) What can USAMRMC do to enhance cooperation and coordination acrossorganizations? What new processes or policies would improve data sharing andcollaboration among partners?
Group 3: Development of Drug Resistance and Persisters
· Morning Session: Key questions - What are the current state of knowledge and keyknowledge gaps related to:
a) Mechanisms (stochastic vs. induced) by which bacteria acquire a drug resistantphenotype (e.g., stress on bacteria due to the host immune response / host
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microenvironment during infection – such as host-induced cytokines or reactive oxygen species – which may lead to bet-hedging and heterogeneity).
b) The regulation of these mechanisms during the course of infection (both in theabsence of and during antibiotic treatment).
c) Understanding the mechanisms governing the origin of persisters.d) Patient-specific or personalized factors that influence the emergence of drug
resistant bacteria within a given patient.· Afternoon Session (Continue discussion from Morning Session and also address the
following):a) What are significant technology, informatics or other barriers to the
computational integration of in vitro, animal model, and human data on drug resistance that would limit the ability to perform integrated analysis across these different biological systems?
b) What can USAMRMC do to enhance cooperation and coordination acrossorganizations? What new processes or policies would improve data sharing andcollaboration among partners?
Group 4: Computational Analysis Approaches
· Morning Session:a) What are the significant technology, informatics or other barriers to the
computational integration of in vitro, animal model, and human data that wouldlimit the ability to perform integrated analysis across the different biologicalsystems? For instance:§ Barriers associated with integrating omics data from both the host and
pathogens§ Integrating data from single cell biology and omics approaches to
understand host and pathogen heterogeneity.§ Technology barriers associated with expanding the druggable space
through uncovering host-pathogen interactionsb) What can USAMRMC do to enhance cooperation and coordination across
organizations? What new processes or policies would improve data sharing andcollaboration among partners?
· Afternoon Session: Integrate into other 3 groups to assist in development ofrecommendations
· Morning Session Day 2 complete Outbrief: Computational and Integration Challengesand Solution Approaches
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APPENDIX D – PARTICIPANT LIST
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State of the Science Meeting: Systems Biology of Drug-Resistant Infectious Diseases Working Group Assignments
Group 1 – Mechanisms of Host Response to Infection- Beyster Training Lab
Group 2 – Mechanisms of Pathogen Invasiveness and Immune Evasion- Solutions Hall 1
Tim Burgess Danielle Clark* Nabarun Chakraborty Frank Doyle* Richard G. Jarman Doug Lauffenburger* Bruce McClain Nelson Michael Clinton K. Murray James Lawler George Ludwig Matthew R. Rosengart Jeff Shupp (Facilitator)
Leidos Scientific Support: Elizabeth Walsh
Andrew Camilli Blair Dancy Derese Getnet Audrey Glynn Chris Henry* Lee Hood* Marti Jett Michael Otto Kurt E. Schaecher (Facilitator) Patrick Schlievert Valerie Trabosh Kathryn Wuertz
Leidos Scientific Support: Anna DiPietrantonio
Group 3 – Development of Drug Resistance- Solutions Hall 2
Group 4 – Computational Analysis Approaches Tesla Room 6th Floor (Visitor Badge Required)
Mark D. Adams* John Aitchison Robert Clifford* Gautam Dantas* Michael Gilmore (Facilitator) Shannon Greene Aarti Gautam Mary Hinkle Michael Kozar Yousif Shamoo Eva Top Stuart Tyner Paige E. Waterman
Leidos Scientific Support: Jason Downey
Mark D. Adams Danielle Clark Robert Clifford Gautam Dantas Frank Doyle (Facilitator) Chris Henry Lee Hood Doug Lauffenburger
Leidos Scientific Support: Jeff Zalatoris
During the afternoon session on 3 October, members of WG4 will integrate into the other 3 groups to assist in development of recommendations.
*Afternoon of 3 October only
The following meeting participants rotated throughout the working groups:
Kenneth Bertram Alan Feister Rasha Hammamieh Joseph Palma
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