Diabetes remission by insulin-secreting alpha-cells Speaker: Professor Pedro Herrera, Group Leader, University of Geneva Pedro Herrera is Full Professor at the Faculty of Medicine of Geneva University (Switzerland); he is the founding director of the University’s Transgenic Core Facility and has been the president of the Animal Ethics Committee for many years. He completed a master's degree in biology in Madrid (Universidad Complutense), and obtained the PhD degree in Geneva under the guidance of Jean-Dominique Vassalli. In 1996 he became an independent scientist at the Faculty of Medicine in Geneva, where he has a research laboratory ever since. Pedro Herrera is recognized as a leader in diabetes and pancreatic research. He originally studied the emergence of the different pancreatic endocrine cell types in developing mouse embryos, and their interactions, by performing a series of experiments of selective cell-type ablation in utero (Herrera et al, PNAS 1994). This work was truly innovative from an experimental perspective. Soon thereafter, already as an independent young investigator, he pioneered the field of mouse developmental biology by performing the first series of in vivo cell lineage tracing analyses in mammalian embryos using, in a disruptive way, the genetic Cre/loxP system (Herrera, Development 2000; a single-authored paper). In short, this was the first report describing how to irreversibly “tag” with Cre recombinase any specific cell type in a mouse embryo, in order to follow its progeny in the adult. This procedure became the standard approach to study the lineages of cells, from embryo to adult, in health and disease. In the mouse genetics field, the Cre/loxP was initially devised to “inactivate” genes in a cell-type-specific fashion; what Pedro Herrera did instead is to selectively “activate” a gene that he called “reporter”, in order to label cells in mouse tissues. The seminal paper was regarded as bringing ground-breaking discoveries obtained with elegant experiments (see “The Molecular Biography of the Cell”, Cell 120, 729-31, 2005). During the following years, he made significant contributions to the knowledge of the biology of the pancreas. He demonstrated the existence of developmental “competence windows” for selected cell signalling pathways (beta-catenin) in exocrine cells during pancreatic growth (Strom et al, Development 2007). In 2009, using a sophisticated transgenic cell-labeling refinement, he showed that there is a population of embryonic pancreatic islet precursor cells that is multipotent as a population but, interestingly, at the single-cell level, each precursor cell is strictly unipotent, giving rise to only one endocrine cell (Desgraz & Herrera, Development 2009). Also, and again thanks to the Cre/loxP-based technique of genetic (irreversible) cell lineage tracing in vivo, he found that adult pancreatic exocrine cells (termed “acinar cells”) change their identity and become adipose cells during normal ageing and in certain pathological conditions (Bonal et al, Gastroenterology 2009). This work shed light on the controversial origin of adipose tissue during degeneration associated with age, and more broadly, on adult cell plasticity. The most recent contribution of Pedro Herrera is in the field of regenerative biology. Observations made in his lab and reported in studies published in the journal Nature (2010, 2014 and 2019), and Nature Cell Biology (2018), have led to an innovative breakthrough in the approach to developing new cell replacement therapies for diabetes. Still an early discovery, he has shown that the adult pancreas retains the ability to generate new insulin-producing cells after the near-total loss of the -cells, which are the native insulin producers. This unexpected finding revealed a high degree of cellular plasticity in adult organs, for the reconstituted beta-like cells were indeed mature glucagon-producing alpha-cells, and somatostatin-producing sigma-cells, which had spontaneously reprogrammed to produce insulin (Thorel et al, 2010; Chera et al, 2014; Cigliola et al, 2018). These mechanisms, involving a high degree of cellular plasticity (namely, the functional interconversion of different cell types) had never been described in mammals before. Beyond diabetes, any degenerative disease will likely benefit from the paradigm shift. This is particularly striking now, for his laboratory has shown that this functional plasticity is also a feature of human pancreatic cells (Furuyama et al, 2019).

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Sponsor: King's College London