Associate Professor, Department of Cancer Biology
Director, Center for Cancer Systems Biology
Dana-Farber Cancer Institute
Associate Professor of Genetics, Harvard Medical School

Despite the considerable success of molecular biology to understand diseases such as cancer, many fundamental questions remain unanswered. Most importantly, since the majority of gene products in the cell mediate their function together with other gene products, biological processes should be considered as complex networks of interconnected components. In other words, for any normal biological process, or any disease mechanism, such as cancer, one might consider a “systems approach” in which the behavior and function of such networks are studied as a whole, in addition to studying some of its components individually. The draft of the human genome sequence is likely to help such a transition from molecular biology to systems biology.

Our laboratory uses a model organism, the nematode C. elegans , to study the role of protein networks in development and, doing so, develop the concepts and technologies needed for a transition to systems biology. Our goals are to:

i) generate protein-protein interaction, or 'interactome', maps for C. elegans networks involved in development,

ii) develop new concepts to integrate such interactome maps with other functional maps such as expression profiles (transcriptome), global phenotypic analysis (phenome), localization of expression projects (localizome), etc…. and

Our questions are: In the context of tens of thousands of different proteins present in each of our cells, many of them interacting with each other, how is the resulting complex network of physical protein-protein interactions organized? Moreover, are there functional and dynamic features of such protein interaction, or “interactome”, networks that relate to basic biology, evolution and human diseases?

Using C. elegans as a model to understand the global organization of the proteome of multicellular organisms, we have mapped a significant portion of its interactome: in all ~5,500 interactions. This interactome map suggests a higher level of interconnectivity between proteins than was originally anticipated. Particularly, our work points to an unprecedented level of connectivity between seemingly different biological processes. These global properties might relate to the robustness and plasticity exhibited by cells in general and might be used to understand basic questions of evolution.

Our most recent contributions are:

• a genome-wide description of the C. elegans complete set of protein-encoding open reading frames, or “ORFeome”

• the generation of a first draft of the C. elegans interactome map (Li et al, Science , 2004)

• the use of this interactome map together with systematic RNAi analyses to start modelling a developmental decision in C. elegans (Tewari et al, Molecular Cell , 2004)

• the study of organizational principles in the yeast interactome network (Han et al, Nature , 2004; Han et al, Nature Biotechnology , 2005).

References:

Li S., C. M. Armstrong, N. Bertin, H. Ge, S. Milstein, M. Boxem, P.-O. Vidalain, J. D. J. Han, A. Chesneau, T. Hao, D. S. Goldberg, N. Li, M. Martinez, J.-F. Rual, P. Lamesch, L. Xu, M. Tewari, S. L. Wong, L. V. Zhang, G. F. Berriz, L. Jacotot, P. Vaglio, J. Reboul, T. Hirozane-Kishikawa, Q. Li, H. W. Gabel, A. Elewa, B. Baumgartner, D. J. Rose, H. Yu, S. Bosak, R. Sequerra, A. Fraser, S. E. Mango, W. M. Saxton, S. Strome, S. van den Heuvel, F. Piano, J. Vandenhaute, C. Sardet, M. Gerstein, L. Doucette-Stamm, K. C. Gunsalus, J. W. Harper, M. E. Cusick, F. P. Roth, D. E. Hill and M. Vidal (2004). A map of the interactome network of the metazoan C. elegans . Science , 303, 540-543.

Tewari M., P. Hu, J. S. Ahn, N. Ayivi-Guedehoussou, P.-O. Vidalain, S. Li, S. Milstein, C. Armstrong, M. Boxem, M. Butler, S. Busiguina, J.-F. Rual, N. Ibarrola, S. Chaklos, N. Bertin, P. Vaglio, M. Edgley, K. King, P. Albert, J. Vandenhaute, A. Pandey, D. Riddle, G. Ruvkun and M. Vidal (2004). Systematic interactome mapping and genetic perturbation analysis of a C. elegans TGF- b signaling network. Molecular Cell , 13, 469-482.

Han JD, Bertin N, Hao T, Goldberg DS, Berriz GF, Zhang LV, Dupuy D, Walhout AJ, Cusick M, Roth FP and Vidal M (2004). Evidence for dynamically organized modularity in the yeast protein-protein interaction network. Nature , 430, 88-93.

Han JD, Dupuy D, Bertin N, Cusick M, and Vidal M (2005). Effects of sampling on the predicted topology of interactome networks. Nature Biotechnology , In press.