Six research institutions awarded NIH grants to create database of human cellular responses

Building on a successful three-year pilot project, the National Institutes of Health 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. Dr. 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:

• Harvard Medical School, Boston, $12.87 million over six years
  Principal Investigator: Peter Sorger, Ph.D.

This center will develop new measurement methods and computer algorithms to detect and analyze perturbations induced by therapeutic drugs in healthy and diseased human cells.

Dr. Sorger hopes that future drug developers will be able to perform computations on LINCS data in much the same way that Google Maps makes use of GIS (geographic information system) data. The team hopes its efforts will shed light on the interrelationships of proteins in complex diseases, which is an important step in developing a rational approach to drug discovery and personalizing therapy.

• Oregon Health and Science University (OHSU), Portland, $10.29 million over six years
  Principal Investigator: Joe Gray, Ph.D.

The environment may influence the way cells move and proliferate, and may alter their state of differentiation. But identical cells behave differently in different microenvironments - the collection of surrounding cells and the soluble signals and insoluble proteins produced by these cells. Cancer cells, for example, respond to treatment differently in different microenvironments. This is one of the mechanisms by which cancer evades many treatments.

The OHSU team will study how both malignant and non-malignant cells are controlled by the microenvironments in which they live. The researchers will provide measurements of the impacts of thousands of different microenvironments on cellular phenotypes, protein make-up and gene expression readouts in cell lines.

• Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, $12.56 million over six years
  Principal Investigator: Todd Golub, M.D.

The Golub team will study up to 50 cell types perturbed by a large number of chemical compounds and genetic reagents that activate or deactivate genes. Each perturbation will produce about 1,000 gene-expression readouts. By the project's end, Dr. Golub expects to have generated more than 1 million profiles of how genes are expressed in different cells.

The ultimate aim is to create a genome-scale catalog of the consequences of cellular perturbation. This would enable researchers to simply query the database in order to learn the effect of blocking or overexpressing a particular gene.

• Icahn School of Medicine at Mount Sinai, New York City, $11.39 million over six years
  Principal Investigator: Srinivas (Ravi) Iyengar, Ph.D.

Dr. Iyengar's Drug Toxicity Signature Center aims 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. The researchers will leverage the U.S. Food and Drug Administration's (FDA) Adverse Event Reporting System database to identify drugs that produce adverse events in heart, liver and neuronal function, and to search for drugs that may mitigate these events.

The researchers will use these drugs and drug combinations to develop gene-plus-protein signatures, using human heart, liver and nerve cells from stem cells that have been derived from human skin cells. Such signatures may help repurpose FDA-approved drugs to lessen adverse events and help in preclinical drug discovery.

• Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, $8.9 million over six years
  Principal Investigator: Jacob D. Jaffe, Ph.D.

Dr. Jaffe's LINCS Center for Proteomic Characterization of Signaling and Epigenetics will study cell disruption at the most basic levels: phosphorylation-mediated signaling - that is, how cells communicate internally; and epigenetics, or how cells perpetuate non-genetic information as they grow. These latter signals are transmitted in part by modifications to histone proteins, around which the DNA in cells is wrapped.

As in other LINCS projects, the researchers will seek patterns from known causes of cell disruption, such as drugs, that can help identify the cause of other instances of cell damage. Dr. Jaffe's center will test more than 11,000 perturbational conditions in several cellular model systems. Cellular phosphor-signaling and epigenetic systems are involved in a growing number of environmental and developmental diseases, and Dr. Jaffe's project may help develop new treatments for these conditions as well as other diseases such as cancer.

• University of California, Irvine, $8 million over six years
  Principal Investigator: Leslie M. Thompson, Ph.D.

The Thompson team will concentrate on human brain cells, which are far less understood than other cells in the body. The researchers believe it will be necessary to study these cell types directly to understand the causes of neurological disease and to develop new therapies.

By applying LINCS-type perturbations to studying an array of human brain cells, the researchers hope to identify 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.