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Spotlight

This month's Spotlight falls on the new Therapeutic Screening Center at HSCI. The group's leader, Lee Rubin, discusses the highly anticipated lab's direction and expected capabilities.

New Therapeutic Screening Group at HSCI

by Lee Rubin

The new Therapeutic Screening Center at HSCI is being established to take comprehensive advantage of some of the unique aspects of stem cell biology to identify reagents and compounds that either affect cell differentiation or could be therapeutic agents themselves. The lab will be equipped with robotic liquid handling systems, a conventional plate reader for standard measurements such as needed for cell-based luciferase assays, and a high throughput confocal microscope-based detector that will allow non-homogeneous differentiation assays (using, for example, GFP or other fluorescent reporters) to be set up. The group has a special interest in orphan nervous system disorders, but anticipates working with other members of the HSCI community and third parties, including those who have a direct interest in translational research.

We plan to carry out several types of studies: (a) identification of reagents that stimulate cell differentiation along desired lineages; (b) pathway modulation using ES cells as sensitive detectors of many of the major developmentally regulated pathways; (c) directed cell differentiation followed by disease-specific screens and mechanistic studies; (d) discovery of therapeutic agents that act by targeting particular types of stem cells.

We will be conducting several types of screens. For example, cell differentiation can be readily assessed in a "high content" (microscope-based) format by having the desired cell type express GFP under the control of a transcription factor specific to that cell. Screening algorithms are available for quantifying the numbers of GFP+ cells in each well in a rapid way. Molecules that increase the number of GFP+ cells are scored as hits in this type of assay. Another type of assay is constructed around ES cells differentiating, for instance, into a specific type of neuron, such as a motor neuron. Since ES cells can be grown in virtually unlimited numbers it becomes possible to obtain motor neurons in similarly large numbers (billions per week), which allows types of studies not generally possible with non-proliferating cells. One simple screen would be directed at trying to identity molecules or pathways that prevent motor neuron degeneration. The algorithm used for this high content screen is a straightforward count of live cells. Since the ES cells used to generate neurons can be derived from a mouse model of a human disease, this experiment can be further elaborated to become more disease-specific: which pathways or molecules can modulate the survival of motor neurons with an ALS (Lou Gehrig's Disease) or Spinal Muscular Atrophy genotype? Finally, stem cell-directed therapeutics - whether they are molecules that mobilize adult stem cells to promote tissue repair after damage or those that inhibit proliferation of tumor stem cells - can in principle be detected with relatively straightforward high content screens.

All screens need diverse compound libraries to test. We are assembling a large small molecule collection that will, we hope, be comprehensive enough to provide hits in numerous assays and be sufficiently drug-like to facilitate more translational research when that becomes an important goal. We will also be in a position to screen other types of libraries, whether protein or siRNA-based.

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The Harvard Stem Cell Institute is a scientific collaborative established to fulfill the promise of stem cell biology as the basis for cures and treatments for a wide range of chronic medical conditions.

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