Geoff Clarke

My research interests focus on theoretical and computational aspects of stem cell biology and engineering. Specifically, I am interested in how the behaviour of pluripotent stem cells (proliferation vs. differentiation, for example) is controlled at a molecular and cellular level both in vitro and in vivo. How do the myriad of signals impinging on a stem cell determine how it will behave, and can the rules of stem cell behaviour be described in simple yet mathematically robust ways? Can knowledge of these rules be used to quantitatively control cell behaviour in a way that is efficient and beneficial to regenerative medicine and tissue engineering? Although the majority of modeling work on this problem has so far focused on intracellular regulation (i.e. genetic and signaling cascades), the interactions between cells in a population are no doubt equally decisive factors in controlling fate choice in complex cell populations, both in vitro and in vivo. Currently, my research focuses on this second class of problem, in which I use methods and concepts from biology, physics, computer science, and mathematics to develop simulations and abstract models of interacting populations of stem cells to analyze and predict cell fate choices within these heterogeneous populations.

Proteins such as receptors and transporters appear on the surfaces of cells. Not only can they provide useful markers for distinguishing between cell types and stages of differentiation, they also enable the sorting of cells by flow cytometry and offer the potential for purification of a given class of cells from a mixed culture. Additionally, knowledge of the cell surface subproteome at given points in time can provide insight into the process of differentiation and transistion between cell types. Although many surface markers are already known, mass spectrometry based techniques are capable of detecting substantial subsets of cell surface proteomes, including many previously unobserved proteins. The process of assembling a cell surface protein index has only begun. My research goals are to illuminate and interpret specific cell surface proteomes, while implementing strategies to improve the existing methodology and developing means of visualizing the relationships between different cell states.

Human umbilical cord blood (UCB) is a source for haematopoietic stem cell transplantation. It is also considered an accessible and less immunogenic source for mesenchymal, unrestricted somatic and other stem cells with pluri/multipotent properties. One of the hopes for UCB enhancement strategies is to generate a sufficient number of haematopoetic progenitor cells (HPCs) to successfully perform "single umbilical cord transplant" (sUCBT). However, despite two decades of studies, no technology has been approved or adopted into clinical practice.

"Future development of successful UCB enhancement approaches should solve a number of existing controversies. First, does one need to select a subset of cells to expand, and if so, which cell subpopulation to expand must be defined. Second, the most optimal conditions for UCB ex vivo expansion need to be determined: whether or not liquid cultures, static or continuous perfusion cultures with or without stromal cells must be defined. Third, manipulation of the molecular pathways that regulate stem cell maintenance and self-renewal appears most promising, but this is still in its infancy of development. Fourth, better ways to increase cell yield at the time of collection, and reducing cell loss during processing and at time of thaw are important lines of inquiry. Fifth, methods to enhance homing are also promising but still need testing in clinical trials. Sixth, the long-term fate of expanded UCB progenitors also remains unclear and it is not known if certain manipulations may be associated with earlier senescence or apoptosis". (Norkin et al., 2012)

My project is associated with ex vivo manipulations to characterize and enhance UCB potency (hematopietic and non-hematopoietic) for preclinical and clinical approaches.