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A. ORGANIZATIONAL CHART

Organizational Chart

B. COMPONENTS OF THE ORGANIZATIONAL STRUCTURE

The Steering Committee oversees all functions of the AfCS; included in this group are three representatives of our sponsors (NIGMS, NIAID, and one representative from the pharmaceutical industry). When the Alliance was first established, the Steering Committee was relatively large and consisted predominantly of people who were well positioned to provide global advice about goals, strategies, and organizational structure. However, it soon became obvious that many of the non-sponsor members of this group were unable to maintain close contact with our progress and problems (e.g., by regular visits to the web site); every-other monthly meetings quickly became progress reports. After the first year we decided that we would be better served by a hands-on "operations committee", and sweeping changes were made. A few particularly unengaged members of the group were terminated, while most willingly became members of the External Advisory Committee (see below). Thoroughly engaged "insiders" were added, and this trend has continued with the recent addition of Lew Cantley. Attendance and participation at now monthly meetings is excellent. Non-sponsor members of the Steering Committee also attend monthly meetings of the System Committee and the Analysis Group, as well as twice monthly lab meetings (see below).

While regularly scheduled meetings of the Steering Committee are reasonably formal – focused on discussions of broad issues regarding strategies, experimental platforms, progress, budgets, etc. – we stress that the non-sponsor members of this group interact very frequently, in parts or as a whole. Essentially everyone is present at the roughly 6-8 hours of monthly meetings of the groups just mentioned, as well as the 2.5-3 day annual meeting. Spontaneous conversations are also very frequent. The non-sponsor members of the Steering Committee have met extensively to plan this renewal application, and this group as a whole has written the non-laboratory-specific portions of this application.

It also became clear that day-to-day operation of the AfCS required an essentially full-time chief operating officer: an individual who could and would discover, track, and solve detailed problems – for example catalyzing or mandating communication between the individual laboratories, implementing decisions of the Steering Committee, translating between experimentalists and data managers, etc. We were most fortunate to recruit Ron Taussig, Ph.D., an Associate Professor of Biochemistry from the University of Michigan, to fill this role. Ron is now a UT Southwestern faculty member, the Associate Director of the AfCS, and a member of the Steering Committee.

Note that communication among all AfCS participants is achieved with a Polycom, Internet2-based videoconferencing system installed in the offices of all Participating Investigators; there is no charge for use of Internet2. Many use this system instead of the telephone or in addition to email for spontaneous conversations or impromptu meetings. Everyone connects to a common meeting room for regularly scheduled meetings. The system permits shared use of any Windows-based computer application; most prepare Powerpoint presentations for data sharing. There are occasional glitches, sometimes amusing, but overall the system is a spectacular success and is absolutely enabling for projects of this type.

Steering Committee: Gilman (Chair), Simon (Vice Chair), Bourne, Cantley, Harris (Aventis), Long (NIGMS), Mattia (NIAID), Ross, Stull, Taussig.

We started this journey with two System Committees: B lymphocyte and cardiac myocyte. The switch to the RAW 264.7 macrophage dictated dissolution of these committees and formation of a single Macrophage System Committee. This was accomplished by fusion of the most committed members of the original groups, loss of those who were most system-centric, and addition of macrophage experts (Aderem, Brown, Smith). This group meets monthly and reviews and interprets data, particularly from the point of view of system experts, and helps to set priorities. We originally believed that this group would play a major role in interpretation of data and provision of specific direction of the laboratories. This was effective for the first two years when systems were being established and tested but was inadequate as the pace of data acquisition quickened. A data analysis group has been and continues to be built to meet these needs. The Macrophage Committee now serves in a valuable advisory capacity as a more focused adjunct to the Steering Committee.

Macrophage Committee: Bourne (Chair), Stull (Vice Chair), Aderem, Berridge, Brown, Cantley, Devreotes, Gold, Smith.

Retrospectively, and perhaps explained by the fact that most of us have led our lives as proprietors of "mom and pop shop" research enterprises, our original plan was rather quiet on the subject of large-scale data analysis. It has become clear that a broad group, capable of analysis of disparate types of data, was a necessary supplement to our data management team. We also now believe that at least several members of this group function optimally in proximity to those laboratories that generate the data. This helps to create a rapid cycle between experiment, analysis, and the next experiment and is becoming critical as we move away from relatively stereotypical ligand screens and toward the more hypothesis-testing approach that characterizes the FXM project. We have now recruited several biologically savvy data analysts, trained in computational approaches and able to interact with local experimentalists, other data analysts, and the data management group in San Diego. These people are responsible for data analysis at a number of different levels, including data quality and statistical integrity as well as extraction of novel insights gleaned from the experiments.

At present we have six full-time scientists dedicated to analysis of AfCS data. They include Madhusudan Natarajan (UT Southwestern), ligand screen analysis; Dennis Mock and Stuart Johnson (UCSD), statistical and Boolean approaches; Xiaocui Zhu (Caltech), transcript analysis; Michal Ronen (Stanford), microscopy and Ca2+ modeling; and Jeff Forrester (Vanderbilt), lipid profiles. In addition, Gil Sambrano (UCSF) and Lily Jiang (UT Southwestern) are part-time participants in data analysis efforts, particularly with regard to the FXM project, and have also become prime contacts with Adam Arkin’s group at UC Berkeley as this interaction has blossomed over the past year. The activities of the Data Analysis Group are overseen and coordinated by a committee that includes Mel Simon (Chair), Elliott Ross, Rama Ranganathan, James Ferrell, Shankar Subramaniam, and Temple Smith. The entire Analysis Group meets monthly to discuss progress and plan new approaches.

The approach of placement of data analysts and interpreters in proximity to the experimental labs has worked well and is sustaining us at the present time. However, as the pace of generation of knockdown cell lines expands and the scope of experiments performed on them expands, we can imagine that expert analysis of data may again become rate limiting. We will likely need to expand this group. We also believe that we would profit greatly from recruitment of a senior person with a great deal of experience in data analysis and modeling to enhance leadership in this area and facilitate/coordinate effective interactions between data managers, analysts, and modelers. If the AfCS project is fully supported for the next five years, we plan to recruit such an individual – first to lead the Analysis Group and subsequently (if an effective individual is found) to join the Steering Committee.

The experimental work of the AfCS (with the exception of now completed Bridging Projects) is carried out in dedicated laboratories – not in the labs of the Participating Investigators. This permits faithful adherence to highly standardized protocols and establishment of state-of-the-art facilities for the most efficient use of expertise and shared cell lines and reagents. A skilled senior scientist directs the operations of each laboratory, and they are staffed with Ph.D. scientists and technical personnel (total number presently = ~ 100). Formal AfCS-wide lab meetings are held twice monthly for 90-120 minutes. Two labs present updates at each meeting. Extensive Powerpoint presentations are posted prior to each meeting (behind a firewall) for internal viewing and subsequent reference. Brief written monthly progress reports are also received from all laboratories, distributed by email, and posted for internal use. A list of AfCS laboratories and resources follows. Their mission statements and capabilities are described in Sections VII-XVI (see also AfCS.org/rev).

Administrative Core: Alfred G. Gilman, M.D., Ph.D., Director. University of Texas Southwestern Medical Center (Core A).

Data Management, Analysis, and Bioinformatics Laboratory: Shankar Subramaniam, Ph.D., Director. University of California, San Diego (Core B).

Cell Preparation and Analysis Laboratory: Paul C. Sternweis, Ph.D., Director. University of Texas Southwestern Medical Center (Core C).

Macrophage Biology Laboratory: William E. Seaman, M.D., Director. San Francisco VAMC and University of California, San Francisco. Formerly the Laboratory for Development of Signaling Assays (Core D).

Molecular Biology Laboratory: Melvin I. Simon, Ph.D., Director. California Institute of Technology (Core E).

Protein Chemistry Laboratory: Marc C. Mumby, Ph.D., Director. University of Texas Southwestern Medical Center (Core F).

Microscopy Laboratory: Tobias Meyer, Ph.D., Director. Stanford University (Core G).

Antibody Laboratory: Susanne Mumby, Ph.D., Director. University of Texas Southwestern Medical Center (Core H).

Lipidomics Laboratory: Alex Brown, Ph.D., Director. Vanderbilt University. This laboratory grew from the successes of a Bridging Project (Core I).

Data Modeling and Network Analysis Laboratory: Adam Arkin, Ph.D., Director. University of California, Berkeley. This laboratory grew from the successes of a Bridging Project (Core J).

We have recruited a large number (~ 800) of talented individuals to join the AfCS as members (receive no financial support). Members are chosen for their expertise about specific molecules, and their job is to be authors of Molecule Pages – the core elements of the Molecule Page database (see Sections I.C.5.b, II.C.4, and VIII.C.2; see also AfCS.org/rev). The role of the Membership and Editorial Committee, chaired by Pat Casey, is to identify and help recruit the membership and to provide support for peer review and publication of Molecule Pages by the Nature Publishing Group. The Editorial Board, now numbering 25 individuals (who also receive no financial support), provides first-level Molecule Page review (i.e., is the submission worthy of peer review?) and assists in identifying appropriate individuals for the peer review process. The Editorial Board office is also the home of a scientific editor (Ashley Butler), who copy edits the AfCS-contributed materials for the Signaling Gateway, including reports, protocols, and other written materials to be disseminated to the signaling research community.

This group, initially small and chaired by Harold Varmus, is now larger (as explained above) and chaired by Joan Brugge. Their major function is to attend the annual meeting of the AfCS, interact with Participating Investigators and laboratory staff, meet with the Steering Committee, and provide detailed feedback based on their observations. Members of the External Advisory Committee have insider access to the website and receive (by email) minutes of Steering and System Committee meetings, monthly progress reports, etc. All of the reports of the External Advisory Committee are reproduced in the Appendix. Tony Hunter will assume the Chair of the External Advisory Committee if the AfCS continues as a result of the review of this application.

External Advisory Committee: Joan Brugge (Chair), David Botstein, William Catterall, Jack Dixon, Tony Hunter, Robert Lefkowitz, Paul Sternberg.

The AfCS as a whole meets yearly in May; the four meetings held to date have been in Bethesda, Dallas, Pasadena, and Dallas. Special meetings are held on a Sunday afternoon, with full-scale meetings on the subsequent 2.5 days. Agendas are included in the Appendix. Attendance includes all Participating Investigators, AfCS Laboratory Ph.D. staff, External Advisory Committee, Editorial Board, sponsors, and collaborators (see below). Members are invited; some attend but their numbers are not large because we cannot pay expenses and this is very much of a working meeting.

We have established collaborations with several companies when advantageous. These include: Myriad Genetics, Agilent Technologies, and Isis Pharmaceuticals with the Molecular Biology Lab; Cell Signaling Technology and Bio-Rad Laboratories with the Antibody Lab, and the Nature Publishing Group with the AfCS as a whole. These relationships are described in more detail in other appropriate sections.