The MIT Tumor Cell Networks Center devotes high priority to training students and postdocs at the interface engaging cancer biology with computational modeling approaches. While our current faculty members are active in this emerging field, the future of cancer biology more critically depends on educating a new generation of scientists to lead advances in this field.
Our strategy is to encourage student/postdoc trainees to have joint mentorship from supervisors whose core expertises straddle the computational-biological interface. We endeavor to attract students/postdocs from both molecular/cellular biology and computer-science/engineering and place them together in joint research projects with faculty members from these two broad areas. In the context of the current application, four MIT PhD programs are principally involved: Biology, Electrical Engineering & Computer Science (EECS), Biological Engineering (BE), and Computational & Systems Biology (CSB); the latter two are noteworthy by their intrinsic interdisciplinary nature, at the biology/engineering and biology/computer-science interfaces respectively. Significant overlap exists in faculty membership among the three programs, and students frequently take courses offered by one of the other programs.
As techniques and software are developed that are of general interest to the broader MIT & Boston systems biology communities, our TCNC has offered short tutorials meeting for two or three sessions. The first of these took place in August 2005. It was attended by new and continuing graduate students, postdocs, and research staff. This first version focused on analysis of publicly available microarray data sets from the Gene Expression Omnibus (GEO) project at the NIH. The second consisted of two 2-hour classes: Introduction to Genome Sequence Analysis and Introduction to Protein Sequence Analysis. The first class focused on usage of the UCSC genome informatics tools; the second class covered various aspects of protein sequence analysis including usage of public databases, domain and motif annotation and phylogenetic analysis. Due to demand, the sessions were both presented twice, in August and October 2006. A third tutorial was added in January 2008, entitled Introduction to Systems Biology Modeling using KroneckerBio: an Open Source MATLAB-based Modeling Toolbox, over three class sessions on a mass-action-based modeling framework. This framework provides a unified environment for the simulation, analysis, optimization, development and design of mechanistic models of complex biological systems. Attendees learned new advanced optimization and analysis techniques, as well as convenient mechanisms for interfacing new computational methods available through the KroneckerBio toolbox framework. A fourth tutorial offered in September 2008 was on DataRail: Handling and Analysis of Large Multivariate Datasets. All together, these various tutorials have drawn more than 200 participants, from within our TCNC community and more broadly.
Graduate Student Report
At MIT some departments, such as Biology and Chemistry, have centralized support of graduate students covering the early years of their studies, after which their support becomes the responsibility of their faculty supervisors. Other departments, particularly those involved in computational analyses, have little or no centralized support and scarce grant resources for support of graduate students. Since students from those disciplines are precisely those we wish to attract to the interface with cancer biology, we have provided a centralized funding mechanism for the projects under this ICBP program. The Steering Committee selects graduate students for support on a competitive basis based on applications solicited annually in the summer, mainly from the graduate programs in BE, CSB, and EECS; criteria include academic excellence along with commitment to an interdisciplinary thesis experience â€“ including joint mentorship as a priority and multi-departmental thesis committee membership as a requirement. Awards are made on an annual basis with the possibility of renewal to maintain continuity, but in competition with new applications to ensuring that the strongest students/projects receive support.
The ICBP grant has had a significant impact within the MIT campus community by catalyzing interactions between the systems biology and cancer biology communities.
One example of the new communication between these communities was the choice to focus the annual MIT Center for Cancer Research Symposium on the "Systems Biology of Cancer" in 2008. The program for this Symposium (with over 1,000 attendees) featured outstanding investigators from a number of institutions across the USA and Canada bringing integrative systems approaches to bear on basic and clinical science facets in fundamental understanding, diagnosis and treatment of cancer. A striking manifestation of our marrying the cancer and systems biology communities was the evolution of the MIT Center for Cancer Research into the new Koch Institute for Integrative Cancer Research - doubled in size, now including a roughly equal number of members from MIT science and engineering departments.
Outreach Activities withing the MIT Community
The MIT TCNC organizes numerous internal activities intended to develop a cadre of scientists and engineers committed to bringing integrative systems approaches to bear on basic and clinical research problems aimed at improving understanding, diagnosis and treatment of cancer. The TCNC meets at least once each semester to provide member laboratories a regular opportunity to meet and update each other on their work. These provide an excellent opportunity for students and postdoctoral associates to network with each other and with the faculty of the TCNC. In addition, we have established a periodic seminar program, which brings in outside experts for 1-2 day visits that include a public seminar as well as discussions with faculty and trainees.
For an especially intense interaction experience, the MIT ICBP holds an annual off-campus retreat. The one-day retreat is held at a site near Cambridge, yet far enough from campus to minimize "coming and going" - ensuring that people stay for the duration of the retreat. The program is a mix of research talks by faculty and trainees, poster sessions and time to relax and eat together.
The use of ICBP funds to support Pilot projects has represented a highly efficient investment to stimulate important new areas of research and collaborative interactions among investigators not already ICBP members. These are selected by the Steering Committee, in response to brief (2-3 page) proposals offered either in unsolicited manner or in response to a suggestion by current TCNC PIs who become aware of potentially relevant methods or systems being pursued by colleagues at MIT or on other campuses nearby. During the last grant period the following Pilots were funded, generally as two-year propositions: Jackie Lees (Biology) on 'E2F in Apoptosis'; David Sabatini (Biology) on 'High-Throughput Cell Imaging'; Ernest Fraenkel (Biol Eng) on 'Modeling Signaling Network Control of Gene Transcription'; Kevin Haigis (Harvard Pathology) on 'Mutations in Colon Inflammation'; and Mike Hemann (Biology) on 'Leukemia Responses to Chemotherapeutics'.
Outreach to the Broader Cancer Systems Biology Community
Our community-building efforts have taken place on the national as well as local level. In June 2007 we hosted a unique combined meeting of the NCI Integrative Cancer Biology Program and the NIGMS Cell Decision Process systems biology centers. Faculty and students from across the country presented their work, permitting members of these two parallel NIH programs to observe each other's progress. The MIT ICBP also had significant presence at the 2006 meeting of the Society for Advancement of Chicanos & Native Americans in Science (SACNAS) in Tampa FL, where we sponsored two sessions. The first was a technical symposium: Multi-disciplinary Approaches to Biological and Computational Systems Research, co-chaired by Bruce Tidor along with Profs Carlos Rios (Univ Puerto Rico Mayaguez) and Elba Serano (New Mexico State Univ), both of whom spent sabbaticals at MIT under the auspices of our CSB program. The second was a professional development workshop: Hands-On Bioinformatics Workshop for Postdoctoral Researchers and Advanced Graduate Students was co-chaired by Dr Mandana Sassanfar, the diversity outreach coordinator for the MIT Biology department and taught by Dr Charlie Whitaker from the MIT Center for Cancer Research. The materials for this session are located here. Richard Hynes ran an NCI workshop on Bridging the Technology Gap - Molecules to Cell Behavior, covering gaps between molecular data acquisition and modeling in Seattle WA in June 2009. Finally, Doug Lauffenburger organized and chaired a session on Cancer Systems Biology at the April 2009 AACR Annual Meeting.
Locally, but beyond our grant boundaries, TCNC co-hosts a joint open meeting with the MIT-Harvard NIGMS Cell Decision Processes group on a weekly (Wednesday mornings) basis. The meetings consist of student/postdoc presentations and ample discussion, and are typically attended by 30 members of the local systems biology communities. Topics range from cancer biology to microfluidic devices for experimental measurement to novel computational algorithms. We also participate in the weekly (Friday afternoons) KI cancer biology meetings. In both cases, the meetings are run by and feature presentations by students and postdocs, although a number of faculty commonly attend. More broadly, we actively participate in the Council for Systems Biology in Boston (CSB2), which organizes numerous events throughout the year to encourage inter-institution communication and collaboration in the greater Boston/Cambridge area (including Tufts Univ, Boston Univ, and Northeastern Univ along with MIT and Harvard Univ). Doug Lauffenburger is a co-founder and executive committee member of CSB2.
The results of MIT CCSB sponsored research will continue to be easily publicly available, centrally via the Data section of this website, through which all data and models can be accessed via the journal reference. We will continue to support and expand our website for validated siRNA and shRNA sequences (here) in connection to the NCBI Probe Database. Moreover, we in the process of developing a capability for making our computational models easily available to the external community, in close partnership with the CDP Center, via our recently established DataRail software. As is well appreciated, linking experimental data to computational models in biology is impeded by the lack of suitable software to manage and transform data. Model calibration and ongoing evolution is facilitated by preserving links to training data along with a formal record of all normalization, scaling, and fusion routines used to assemble the training data from primary results. Towards this goal, we have developed DataRail as an open-source MATLAB-based toolbox that stores experimental data in flexible multi-dimensional arrays, transforms arrays, and then constructs models using internal or external tools. Data integrity is maintained via a containment hierarchy for arrays and implementation of a procedure for storing the history of all transformations with the array. Specific features include: data import in a general data format (MIDAS, Minimum Information for Data Analysis in Systems Biology); visualization of large datasets in multiple forms (time-courses, heat-maps, etc.); statistical modeling algorithms (e.g., multiple linear regression, principal component analysis, partial least-squares regression); export to mechanistic physicochemical differential equation modeling (PottersWheel), logic-based modeling (CellNetOptimizer and CellNetAnalyzer), and soon Bayesian network inference (BayesNet toolbox); modeling results can be stored together with the data set they were generated from; raw and transformed data can be exchanged either via Matlab or MIDAS files. DataRail is distributed freely under the GNU General Public License and is available here; the only requirements are to have a computer and a MatLab license.