Peter Sorger’s Stetten Lecture

November 3, 2010 § 1 Comment

Peter Sorger recently gave a talk at NIH entitled “Measuring and Modeling Life-Death Decisions in Single Cells” as part of the prestigious Stetten Lecture series. NIGMS sponsors the Stetten Lectures to honor Dr. DeWitt Stetten, Jr., who directed the Institute from 1970 to 1974 and had a strong commitment to basic research. Since NIH kindly put the video on line, I thought you might be interested to see it.

Here’s the lecture summary:

When monitoring signal transduction at the level of single living cells, we observe remarkably complex dynamics and great variability from one cell to the next. However, it is also clear that finely tuned interactions among processes operating on quite different time scales are essential in cell fate determination and, conversely, that errors in coordination underlie many oncogenic changes. How can the observed variability among genetically identical cells be reconciled with an apparent requirement for precise control, what is the impact of variability on the evolution of tumors and what are the implications for emergence of drug resistant cancers in patients?

I will begin to address these issues with an emphasis on cellular responses to TRAIL, a prototypical inducer of receptor-mediated (extrinsic) apoptosis and an investigational therapeutic. Some TRAIL-treated human cells die within ~40 min, some only after 12 hr, and yet others live indefinitely. We have explored three explanations for these differences: (i) genetic or epigenetic variation (ii) the involvement of one or more biochemical processes subject to stochastic fluctuation (iii) transient but deterministic differences in cell state. I will illustrate how all three interact on different time scales to determine those aspects of cellular physiology that are highly invariant and those that are variable. I will also illustrate how studying these problems requires mathematical analysis of the underlying biochemistry. This analysis involves a close interplay between model generation, model calibration against data and model verification through empirical testing of molecular hypotheses. I will advance the thesis that we must replace the informal pictorial models currently dominating molecular biology with probabilistic mathematical constructs that assign rigorous “degrees of belief” to specific biochemical hypothesis given prior knowledge and a specific set of empirical data.

Lecture Objectives:

1. To describe an approach to understanding signal transduction pathways that involves combining biochemical and cell-based measurement with mathematical modeling of relevant molecular processes. In my lecture the focus will be on receptor-mediated cell death triggered by TRAIL and Fas ligands

2. To present an analysis of variability from one cell to the next in responses to TRAIL and our determination that this variability has a non-genetic basis, arising from natural fluctuations in protein levels among otherwise non-identical cells.

3. To consider the impact of non-genetic variability on responses to therapeutic drugs more generally and on the likely connection between variability and fractional killing observed clinically. To advance the idea that non-genetic variability, having its origins in the inherently stochastic nature of biochemical reactions, is a probable explanation for many phenomena currently ascribed to tumor stem cells.

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