Written by Martin Bootman (The Open University), Antony Galione (University of Oxford) and Colin Taylor (University of Cambridge).

https://doi.org/10.36866/pn.118.50

Mike Berridge, pioneer, and mentor of the calcium (Ca2+) signalling field, died on 13 February 2020. His discovery that the signalling molecule inositol trisphosphate (IP3) links receptor activation to generation of intracellular Ca2+ signals and his talent for seeing the big picture transformed our understanding of cell regulation.

Mike was born in Southern Rhodesia (now Zimbabwe) in 1938, and his love of African wildlife, especially elephants, was channelled by an inspirational teacher into a life-long study of biology. He graduated from the University College of Rhodesia and Nyasaland in Salisbury (Harare), and in 1961 he was awarded a Commonwealth PhD Scholarship in the Department of Zoology, University of Cambridge under the father of insect physiology, Sir Vincent Wigglesworth (known as VBW). Here, Mike investigated the metabolic and excretory mechanisms of the Malpighian tubules of an insect pest, the cotton stainer. He became interested in how these processes were regulated by hormones; and he imbued the VBW ethos of working at the bench without a large group, with simple equipment and elegantly decisive experiments, and with an astonishing breadth of knowledge across biology.

At the University of Charlottesville, Virginia and then Case Western Reserve, Cleveland, Mike pursued his interests in hormone action and, with no cotton stainers available, he switched to blowflies. While dissecting their Malphigian tubules, he noticed two long transparent structures, the salivary glands, and showed that 5-HT stimulated them to secrete the prodigious amounts of saliva that allow the fly to feed before it can be swatted.

During those early years with fly salivary glands, Mike’s neighbour at Cleveland was Ted Rall, who had isolated cAMP and helped develop the “second messenger” concept with Earl Sutherland. With advice from Ted, Mike showed that cAMP also stimulated salivary secretion and that inhibitors of cAMP phosphodiesterases potentiated the effects of 5-HT. The work, published when a single decisive figure was enough for Science, led John Treherne to invite him to join the Agricultural Research Council Insect Physiology Unit back in the Department of Zoology, Cambridge.

Here, working with William Prince, Mike used electrophysiology to show that two different 5-HT receptors controlled secretion; one receptor coupled to formation of cAMP, and the other somehow required Ca2+. They also observed, in 1973, that agonists of salivary secretion evoked oscillations in the Ca2+-dependent transepithelial currents, the frequency of which increased with agonist concentration. The observation was both prescient – it was another 13 years before Peter Cobbold reported frequency-encoded Ca2+ oscillations in single hepatocytes, and it inspired Mike’s interests in the spatio-temporal organisation of Ca2+ signals. Some thought Mike’s early interest in fly spittle to be arcane, but from 1975 onwards his reviews and expanding research base demonstrated his ability to range widely and thoughtfully across cell biology, and they presaged his later career when well-crafted reviews and lectures brought cell signalling to diverse audiences.

Although salivary glands needed extracellular Ca2+ for sustained secretion, they could transiently secrete in response to stimulation of 5-HT receptors without it. These observations implied that there was an intracellular source of Ca2+ that could initiate salivary secretion; but how did the 5-HT receptor stimulate release of Ca2+ from this intracellular store? Here, the blowfly salivary gland and Mike’s inspired use of it, proved decisive. Bob Michell, drawing on earlier work from the Hokins and others, had published a landmark review in 1975 in which he argued that breakdown of phosphoinositides in the plasma membrane, the so-called ‘PI effect’, was causally linked to Ca2+ signalling. The gland is permeable to inositol and, during production of copious amounts of saliva, inositol is progressively lost, consequently leading to a reduced supply of inositol lipids on which the PI effect depends. Mike showed that during sustained stimulation, both the Ca2+-dependent secretion and the PI effect evoked by 5-HT were restored by addition of exogenous inositol. This work, along with other experiments, indicated that Ca2+ signalling was downstream of the PI response. He further showed, in what he described as his “eureka moment”, that inositol 1,4,5-trisphosphate (IP3) was the first water-soluble product of the PI effect. Hence, Ca2+ signals required the PI effect, and IP3 was the prime candidate for causing Ca2+ release from intracellular stores. By chance, Mike had recently heard Irene Schulz talk about her use of permeabilised pancreatic acinar cells to monitor Ca2+ fluxes, and Robin Irvine and Rex Dawson, phosphoinositide world experts, were only six miles away at Babraham. With Robin’s stock of IP3, Irene’s cells and her post-doc Hans-Peter Streb performing the experiments, it was straightforward to show that IP3 selectively evoked Ca2+ release from a non-mitochondrial Ca2+ store. The report in Nature, with just three simple panels and no supplementary materials, became a citation classic and its key findings were quickly confirmed in numerous cell types.

With IP3 firmly established as a ubiquitous intracellular messenger, Mike’s attention moved towards the physiological consequences of its activities. Mike collaborated with Roger Moreton in Zoology to build an imaging system, based on a design by Roger Tsien, to measure Ca2+ signals in living cells. Such systems are now commonplace, but in those days it was quite an undertaking, and it paved the way to exploring the intracellular complexity of Ca2+ signals. Mike was fascinated by how Ca2+ signals are organised in time and space, how the complexity of their organisation regulates specific cellular responses, and what happens when IP3-evoked Ca2+ signals go wrong.

In later years, Mike’s considerable impact came through his creative assimilation of observations from diverse areas of biology, and not least from the many posters to which he paid close attention at every meeting. In influential reviews and lucid talks, each invariably illustrated with instructive cartoons, Mike developed new ideas around the actions of Li+, mechanisms for oscillatory Ca2+ signals, and tied IP3-evoked Ca2+ signalling seamlessly into diverse areas of physiology and pathology. The trademark clarity of his diagrams formed the basis of his authoritative online textbook on cell signalling, Cell Signalling Biology, which can be viewed online.

Mike took particular interest in the careers of young scientists, and we were fortunate, as his PhD students, to have benefitted directly from that. Mike enjoyed seeing enthusiastic young scientists advancing in their careers. He established an annual prize to support young scientists, and the European Calcium Society established a lecture in his honour. He was elected a Fellow of The Royal Society in 1984, as a foreign member of the US National Academy of Sciences in 1999, and he was a founding member of the Academy of Medical Sciences. Among his many international prizes were the King Faisal International Prize, Louis- Jeantet Prize, Gairdner Award, Lasker Award, Wolf Prize, Shaw Prize and Royal and Croonian Medals from The Royal Society. He was knighted for his services to science in 1998.

Throughout his career, Mike was supported by his wife Sue, who, with their son and daughter, Paul and Rozanne, shared the excitement of his discoveries and provided the rock on which Mike built his exceptional career.

In addition to his own critical contributions to cell biology, Mike presided, in the most gentlemanly of ways, over the field of the Ca2+ signalling, and he inspired generations of future signallers. The three authors, all of whom continue to work on Ca2+ signalling, express their enormous gratitude for his mentorship, support and wonderful friendship throughout their careers.