This is a post by StemCultures CEO Jeffrey Stern PhD, MD.
When I think about the development of an organism, smooth edges, like the irresistible full folds and curves of a baby, come to mind. Throughout development, stem cells give rise first to the embryo, then later, through tissue-specific stem cells, to the final biological form, with naturally rounded shapes and few sharp edges. At the molecular level, I imagine similar changes—with gradual shifts in growth factors forming rolling gradients elastically linked to intrinsic gene regulation and protein expression. Over time and through evolution, the jagged peaks and shear faces of primitive organisms have been worn into smoother, more complex forms of life. As time softens sharp-edged mountain ranges into rounded, biologically complex environments, evolution shapes the sudden molecular and organismal changes that carve new pathways of development.
On the other hand, research seeks sharp, definitive, cut-and-dried explanations. Human nature seeks a clear path—with, when needed, stairs and a guide-rail—to follow. Indeed, the current revolution in stem cell science was enabled by the discovery of step-by-step protocols to expand cells without differentiation. Discoveries by pioneers such as Martin Evans, Irving Weissman, James Thomson, Benjamin Reubinoff, Rudolf Jaenisch, Shinya Yamanaka, Douglas Melton, and Austin Smith led to an understanding of the factors needed to maintain stem cells, providing the large quantities of cells needed for research and therapy. These pioneering results enable us to study stem cells and to discover just how complex the targeted biological processes are. As work progresses to refine protocols, they are beginning to evolve. Our recent work aims to mimic the more gradual changes, resembling environments encountered in normal development.
We’ve found that copying the normal developmental niche can have practical advantages, illustrated by our laboratory’s recent success using controlled levels of growth factor in stem cell cultures. Standard protocols add FGF2 daily in a step-wise fashion: suddenly via pipette, a bolus of this key growth factor is released onto the cells, causing a dramatic spike in levels. Surprisingly, half of the added FGF2 is lost in less than six hours, meaning there are extended periods of negligible FGF2 levels each day, followed by a sudden rise in concentration upon feeding. Using controlled-release to smooth these dramatic peaks and valleys results in more stem cells, increased stem markers, and decreased differentiation. The cells seem happier when these natural gradients replace sudden, dramatic changes in environment. For this discovery, like any other, it will take time to learn the full implications—but the philosophy of letting nature guide is one that we believe is worth following.
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