Background Microscale Life Sciences Center
The Microscale Life Sciences Center (MLSC) is an NIH Center of Excellence in Genomic Science (CEGS) comprising investigators at Arizona State University, the University of Washington (UW), the Fred Hutchinson Cancer Research Center (FHCRC) and Brandeis University. The administration of Center activities is directed by Deirdre Meldrum, PI, at Arizona State University. Co-PI’s Brian Reid, Brad Cookson, Lloyd Burgess and Larry Wang lead components of the MLSC at the FHCRC, UW Medical Center, UW, and Brandeis, respectively.
The MLSC is composed of over fifty people working in scientific groups at our four research and clinical institutions. We place a strong emphasis on intergroup collaboration, with open transfer and communication of technology, biological protocols and approaches. Recent years’ work in the MLSC has been marked by a transition from technology development to biological application, observation and discovery. With our ability to perform measurements on individual cells in heterogeneous populations with unprecedented detail, dozens of publications, a number of patents filed, new jobs created, students graduated and significant commercial opportunities developed, this has been by all accounts a most successful period for our CEGS.
About Our Research
The three major causes of mortality in the U.S. are heart disease, stroke and cancer. These diseases will not be cured until the pathways involving these disease states are understood. Understanding pathways leads to identification of targets for both early diagnosis and early intervention, the keys to improving health outcomes and driving down the cost of healthcare. The complex interplay between genomic predisposition and environmental factors comes together when core pathways to disease are elucidated. As shown in Figure 1, genome sequence data enable global, high throughput approaches that link genomic differences to the physiological outcomes that ultimately lead to disease. However, the Achilles heel of global approaches is reliance on measurements averaged over large numbers of cells: Even isogenic cell populations are highly heterogeneous in both gene expression and phenotype. In many disorders such as cancer and inflammatory response-linked diseases cellular heterogeneity underlies transitions to disease states. Cell population heterogeneity confounds interpretation of links among genome, phenotype, and disease, as well as the understanding of responses to therapeutic intervention. Heterogeneity underlies most failures of current therapies for cancer. To realize the promise of genomics for guiding patient management or curing major diseases it will be necessary to elucidate pathways involved in disease at the single-cell level, to understand and manipulate the inherent heterogeneity.
The goal of the MLSC is to develop cutting edge technology for multi-parameter analysis of single cells, and to apply this technology to the understanding of biological questions characterized by cellular heterogeneity. Our current focus is on disease pathways, and our vision is to address pathways to disease states directly at the individual cell level, at increasing levels of complexity that progressively move to an in vivo understanding of disease, as shown schematically in Figure 2. The MLSC has developed a microsystem-based platform (the Living Cell Array, LCA) with core capabilities for measuring physiological parameters in individual cells. We are applying this technology and related capabilities for single-cell gene expression analysis to questions that focus on the balance between cell proliferation and cell death. Cancer, heart disease and stroke all involve an imbalance in cellular decision-making processes. Because of intrinsic cellular heterogeneity in the live/die decision, this fundamental cell biology problem is an example of one for which analysis of individual cells is essential for developing the link between genomics, cell function and disease.