Congratulations to Artavanis-Tsakonas, Struhl, and Greenwald on the Canada Gairdner Award for their work on Notch signalling. The Notch locus has been shown to have important roles in cancer, stem-cell development, brain disease, and many other areas important for human health. The three have played a key seeding role and allowed a field to grow. At the kernel of the mechanisms that determine the progressive allocation of cell-fate in animal development lie only a few key signalling pathways. These pathways involve the communication between cells—through contact, short-range signals and long-range signals—to alter the fate of the cell that receives the signal. These key players are Wnt, Hedgehog, Receptor Tyrosine Kinase, TGF-b, NF-kappa-b and, pertinent to our discussion, Notch. I don’t think I am very much off the mark if I were to say that the leading contributors to the discovery and understanding of all these signalling pathways, but for Notch, have been honoured by one or more major awards. By conferring the Canada Gairdner International Award on Spyros Aratavanis-Tsakonas, Gary Struhl and Iva Greenwald this gap has been properly bridged. Cells acquire their fate by two ways, Sydney Brenner famously said: By who their parents are (which he called the English model) or by who their neighbours are ( the American model). A cell can also stand out amongst equivalent cells in it its neighbourhood by suppressing others, and the principal mechanism it uses for this is by Notch-mediated lateral inhibition. Lateral inhibition was first ‘detected’ by Vincent Wigglesworth, using elegant transplantation experiments to study bristle spacing in the insect Rhodnius prolixus in 1940. The position of bristle- forming cells in a field of ‘bald’ cells is determined by lateral inhibition. The mechanistic underpinnings of this process was, of course not explorable at the time, but strangely, were laid a few years earlier. Derek Poulson, in 1936 pioneered what was later to be called developmental genetics, when he showed that deletions and null mutations at the Notch locus causes the expansion of neuronal tissue at the expense of epidermis. In the 1970s the revolution in molecular biology allowed the use of genetics to explore underlying molecular mechanisms of genes involved in development. Molecular cloning of genes, relatively straightforward now, was, as we all know a long-haul at that time even for ‘simple’ genes. For genetically complex loci, such as the bithorax- complex, the decapentaplegic ( TGF-b) gene and the Notch locus, only the most daring and intelligent would venture where others feared to tread. (About Struhl and Greenwald later, their contributions are no less impressive.) But here’s more about Artavanis-Tsakonas. His taking on this challenge is a tribute to his daring and his preparedness in going for the long-haul. Success was by no means guaranteed and there was little reason to second- guess evolution and presume that the molecular analysis would readily reveal cellular or organismal function. In the event, the long-haul was a very long one that still continues but the the fruits of this labour were found all along the way. The Notch pathway and its roles in cell communication, acquisition of cell fates, modulation of stem cells, and control of oncogenesis have truly illuminated all of biology. Thus, we must see Artavanis-Tsakonas’s contribution not just by the papers from his lab but by publications on Notch from other labs too. The pathway has become so famous that very few now cite the original pathbreaking papers any more. A true sign of a pioneer. Upon sequencing the Notch gene, the Artavanis-Tsakonas lab identified key EGF-like coding sequences that were its hallmark. This was also shown to be a feature of Notch ligands too, Delta and Serrate ( identified as a ligand by Artavanis-Tsakonas’s lab). Very soon, using cell- culture experiment Artavanis-Tsakonas’s lab show how ligand and receptor interact. They then worked out the intracellular components of the pathway. These are the Enhancer of split locus, which encodes seven independent helix-loop-helix proteins; the suppressor of Hairless and deltex. The Enhancer of split and suppressor of Hairless are two of the three major nuclear targets of Notch signal transduction and deltex is an intracellular protein that binds to and regulates Notch. Artavanis-Tsakonas and colleagues also cloned the mammalian homologues of the Enhancer of split genes and deltex demonstrating that the pathway was evolutionarily conserved. As Darwin famously said "from so simple a beginning endless forms most beautiful and most wonderful have been, and are being, evolved.” The work on Notch that started with flies and worms has taught us about cancers and dementia because all life on earth has a shared chemistry. By studying so-called simple and accessible organisms, we learn about nature, and we learn about our health too. Fundamental research is intertwined like a jalebi with application and the Notch pathway illustrates this beautifully.