Austin Smith#

A short laudatio by Margaret Buckingham#

Austin Smith is a major international figure in the field of embryonic stem (ES) cell research, where he has made important contributions to understanding the molecular basis of self- renewal and pluripotency. He also analyses the developmental origins of ES cells in the mammalian embryo.

During his PhD and postdoctoral studies he identified the leukaemia inhibitory factor (LIF) as the key ES cell self-renewal stimulis. His own research team then dissected downstream signalling pathways to reveal that Stat3 is the key mediator of self-renewal and is antagonised by Ras/Erk signalling. At the same time Smith’s group determined that the POU transcription factor, Oct3/4, is required for both establishment and maintenance of pluripotent cells, and that it functions in a dose•dependent manner. More recently, they identified the convergence of these two pathways in the regulation of Kruppel-like factors Klf`2 and Klf4. They discovered the transcription factor, Nanog, which can sustain ES cell self-renewal independently of extrinsic factors. They found that Nanog is expressed in a fluctuating pattern and proposed that heterogeneity may be critical for lineage commitment by creating windows of susceptibility to differentiation cues. They also showed, to the surprise of many, that Nanog is not essential to maintain ES cells. They went on to show that neural determination is not a default but is an autoinductive process driven by fibroblast growth factor-4. In order to compare and contrast pluripotent and tissue-restricted stem cells, Smith’s group developed methodology for converting ES cells into stable adherent neural stern (NS) cells and for deriving similar NS cell lines from primary rodent and human foetal tissue.

Austin Smith and colleagues discovered that Bone Morphogenetic Protein (BMP) could replace serum and cooperate with LIF to support efficient ES cell propagation in defined media. They showed that the effect of BMP is mediated via Smadl/5/8 induction of Inhibitor of Differentiation (ID) proteins. The team identified that BMP/ID is necessary to counter the inductive effect of Fgf4 activation of Erk. Furthermore, they found that ES cells can be sustained without LIF or BMP by dual inhibition (2i) of the Erk cascade and glycogen synthase kinase-3. Smith formulated the hypothesis that the ES cell represents a basal cellular state that will self-maintain autonomously if shielded from inductive differentiation stimuli. In 2002, his laboratory showed that spontaneous fusion could underlie certain "plasticity" phenomena. In further studies, they reported that, after fusion, Nanog dramatically increases the efficiency of reprogramming and proposed that only a limited number of factors could mediate transfer of pluripotency. Following Shinya Yarnanaka’s discovery of induced pluripotency, Smith’s group showed that Nanog is essential for iPS cells and early embryo cells to attain full pluripotency. They also revealed that direct reprogramming is promoted by 2i culture, which overcomes the block in partially reprogrammed intermediates and enables progression to full pluripotency.

Austin Smith has played an important role in structuring stem cell research in Europe through his co-ordination of European collaborative projects in the 6th and now 7th Framework programmes. He is also co-organiser of the Advances in Stem Cell Research Series of European conferences, sponsored by EMBO. He has contributed to reports on stem cell research by the Royal Society and EMBO and has advised ministers and officials in various European countries.

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