Building on a successful three-year pilot project, the NIH has awarded more than $64 million to six research institutions to create a database of human cellular responses, the Library of Integrated Network-based Cellular Signatures (LINCS).  Discovering such cell responses will improve scientists’ understanding of cell pathways and aid in the development of new therapies for many diseases.

The funding establishes six centers, collectively called the Data and Signature Generating Centers. The National Human Genome Research Institute (NHGRI) and the National Heart, Lung, and Blood Institute (NHLBI), both part of NIH, administer the program on behalf of the NIH Common Fund.

The LINCS program aims to catalog and analyze cellular function and molecular activity in response to perturbing agents—such as drugs and genetic factors—that are potentially disruptive to cells. LINCS researchers then will measure the cells’ tiniest molecular and biochemical responses, and use computer analyses to uncover common patterns in these responses—called “signatures.” LINCS data will be freely available to any scientist.

“The simplest way to think about signatures is essentially as broad common patterns, as well as uncommon behavior, in how cells respond to being exposed to various small molecules, genetic perturbations or genetic changes,” said Ajay Pillai, Ph.D., program director in NHGRI’s division of genome sciences. Pillai is co-coordinator of the LINCS program, along with Albert Lee, Ph.D., a program director in NHLBI’s division of cardiovascular sciences. “For example, you could figure out patterns of toxicity of potential new drug compounds by looking at cellular responses and finding common responses to other known toxic molecules.”

A major challenge that will be addressed in the second phase of LINCS is to optimize the combinations of cell types, perturbations and measurements of cellular responses to address a wider range of basic biological and disease-related problems than was possible in the program’s initial pilot stage, said Alan Michelson, M.D., Ph.D., senior investigator, Laboratory of Developmental Systems Biology, NHLBI, and co-chair of the NIH LINCS project implementation team.

Even in its prototype phase, LINCS has produced meaningful results that will aid in improving human health. For example, a research team last year used LINCS data to identify the role of a critical transcription regulator, heat shock factor 1 (HSF1), in cancer. Another team reported that the LINCS approach of measuring a wide range of cells’ responses to drugs was more accurate than conventional drug-potency tests. This recognition may point the way toward more effective therapeutics with fewer unexpected side effects.

Recipients of the new LINCS grants (pending available funds) are:

• Peter Sorger, Ph.D., at Harvard Medical School, Boston, Mass. This team will receive $12.87 million over six years for development of new measurement methods and computer algorithms to detect and analyze perturbations induced by therapeutic drugs in healthy and diseased human cells.
• Joe Gray, Ph.D., from Oregon Health and Science University (OHSU), for $10.29 million over six years to study how both malignant and non-malignant cells are controlled by the microenvironments in which they live. 
• Todd Golub, M.D., from the Broad Institute of the Massachusetts Institute of Technology and Harvard University. He will receive $12.56 million over six years to create a genome-scale catalog of the consequences of cellular perturbation. 
• Srinivas (Ravi) Iyengar, Ph.D., of Icahn School of Medicine at Mount Sinai, based in New York City. The team recieves $11.39 million over six years to develop cell signatures that will predict adverse events that might be caused by drugs and will identify other drugs that might lessen these side effects. 
• Jacob D. Jaffe, Ph.D., from the Broad Institute of the Massachusetts Institute of Technology and Harvard University. The $8.9 million over six years will be for seeking patterns from known causes of cell disruption, such as drugs, that can help identify the cause of other instances of cell damage. 
• Leslie M. Thompson, Ph.D., of the University of California, Irvine. The grant of $8 million over six years is for identifing targets for developing drugs against neurodegenerative diseases such as Parkinson’s disease, amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig’s disease), spinal muscular atrophy and Huntington’s disease. 

Total funding for the LINCS program is set at $64 million over six years. The NIH Common Fund is funding five of the new LINCS grants as part of its Big Data to Knowledge initiative. The National Institute of Neurological Disorders and Stroke (NINDS) is funding Thompson’s grant.