The Microscale Life Sciences Center is an NIH Center for Excellence in Genome Science (CEGS) comprising investigators at Arizona State University, University of Washington, Fred Hutchinson Cancer Research Center and Brandeis University. The administration of center activities is centrally located at Arizona State University under codirection of Principal Investigator Professor Deirdre Meldrum. Guidance of MLSC research initiatives is performed under codirection of Professor Meldrum, ASU, and Professor Mary Lidstrom, UW, with technology development oversight performed by Associate Director, Babak Amir Parviz. Individual research teams are led by team leaders:

• Team I - Systems Integration - Mark Holl, Deirdre Meldrum
• Team II - Biology - Lloyd Burgess, Mary Lidstrom
• Team III - Vanguard Technologies - Babak Amir Parviz, Alex Jen

The three major causes of mortality in the US, heart disease, stroke, and cancer, will not be cured until the pathways involving these disease states are understood. Understanding pathways identifies targets for both early diagnosis and early intervention, the keys to driving down the cost of healthcare. In addition, the complex interplay of genomic predisposition and environmental factors comes together when core pathways to disease are elucidated. Genome sequence data enable global, high throughput approaches that link genomic differences to the physiological outcomes that ultimately lead to disease (Fig. A1.1). However, the Achilles heel of global approaches is reliance on averaged cell populations. It is becoming increasingly clear that cells are highly heterogeneous in both gene expression and phenotype [1]. A nascent but growing body of data suggests that in many disorders, such as cancer and inflammatory response-linked diseases, cellular heterogeneity underlies transitions to disease states [2-4]. In addition, cellular heterogeneity confounds the interpretation of the link between genomics, phenotype, and disease and also the interpretation of response to therapeutic intervention. In fact, heterogeneity underlies most failures of current therapies for cancer. In order to realize the promise of genomics in curing major diseases, it will be necessary to elucidate pathways involved in disease at the single-cell level, to both 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 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 in Fig. A1.2. In the past four years, the MLSC has developed a microsystem-based platform (the Living Cell Array, LCA) with core capabilities for measuring gene expression and physiological parameters in individual cells. In the second term (years 06-10), we propose to apply these core capabilities to questions that focus on the balance between cell proliferation and cell death. Cancer, heart disease and stroke all involve an imbalance in this cellular decision-making process. Because of intrinsic cellular heterogeneity in the live/die decision, this fundamental cellular 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.