HMS LINCS

The Harvard Medical School LINCS Center studies how normal and diseased human cells respond at the molecular level to perturbation by drugs, mutations, and the local environment.

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Goals

The overall goal of the HMS LINCS Center is to delineate the fundamental principles of cellular response to perturbagens – in particular, small molecule kinase inhibitors, epigenome-modifying agents, and naturally occurring ligands such as growth factors and inflammatory cytokines – at the level of both cell populations and single cells. Current research is focused on understanding the relationship between dose and response, the origin and significance of cell-to-cell variation, and the molecular basis of drug sensitivity and resistance in both normal and disease contexts. At the same time, the Center commits substantial resources toward the development of improved analytical tools, metadata standards, and informatics systems to promote data analysis, accessibility, and reuse.

Approaches

The HMS LINCS Center collects multiplex perturbagen-response data across a number of complementary experimental platforms including live- and fixed-cell imaging, sandwich immunoassays, protein mass spectrometry, and mRNA profiling as a means to measure the levels, localization, and states of modification of key signaling proteins and the networks in which these proteins are embedded. From these diverse data types, perturbagen-response signatures are constructed using existing and novel statistical modeling, network inference, and machine learning tools, and these signatures enable predictive modeling of the responses of genetically diverse cells to specific perturbations.

All data and tools developed by the HMS LINCS Center are released to the public in a timely manner. Information about these resources is available through the HMS LINCS website. In addition, customized query, browse, and explore tools grounded in established ontologies and standards developed in collaboration with the BD2K-LINCS Data Coordination and Integration Center make it possible to access and interrogate HMS LINCS data programmatically through the HMS LINCS Database and the LINCS Data Portal.

Outcomes

The Center’s research will provide a comprehensive picture at the molecular level of the responses of cells and tissues to some of the most important classes of therapeutic molecules and of the extent to which these responses vary with genetic and epigenetic context. By comparing perturbagen response across tissue types and disease states, this research will not only uncover fundamental properties of cell signaling networks but also will identify opportunities for drug repurposing and for reducing drug toxicity. Finally, by creating predictive models of drug response for different tissue niches this work aims to improve our ability to personalize therapies to the needs of individual patients and to increase the durability of existing treatments.