Biochemical and Biophysical Research Communications 485 (2017) 1e4

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Biochemical and Biophysical Research Communications

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An interview with Michael Berridge, eminent scientist in calcium signaling, by Ernesto Carafoli

1. Question N 1 were also actively doing research so it was a very good academic at- mosphere. Consequently, it turned out to be very supportive for my You were born in a small town of Southern Rhodesia, and have interest in doing research. As outlined below, one of the lecturers spent there the first part of your life, including the formative years. had a profound influence on my career. In a sense, then, you are African. Somewhere, you have written that the rich natural life that surrounded you as a young boy had fasci- 3. Question N 3 nated you, and directed your interests toward science. So my first question stems from that statement: do you think that you would The University of Rhodesia and Nyasaland, where you had have become a scientist if you had not spent your childhood in gained a BSc. in Chemistry and Biology, did not have a Ph.D. pro- that little town in Central Africa, but in a large European city where gram, but you obtained a Commonwealth Scholarship to do a natural life was non-existent ? Ph.D. in the Department of Zoology of the University of Cambridge, which at that time was directed by the famous insect physiologist 1.1. MJB Sir Vincent Wigglesworth. I understand that, while at the Univer- sity of Rhodesia and Nyasaland, your interest in insect physiology It is difficult to say, but I feel that my early childhood surrounded had been promoted by the lectures of Eina Bursell, possibly one by the African wilderness excited my imagination, which may not of the fateful scientific encounters I had mentioned in the previous have happened in a large European city. Where I lived, I was fasci- question. As I understand it, these first years in Cambridge turned nated by the animals that I saw and this inspired me to do some out to be very important in shaping your future research life: research to find out more about them. I had a number of African your project was the secretion of Nitrogen by an African insect, wild life books so I began researching the animals and made notes but you have written that towards the end of your Ph.D. studies that I then translated into a notebook. In retrospect, it was just like you had become interested in the hormonal control of the secretion writing a scientific review. It excited me to carry out such research of fluid by the Malpighian tubules of the insect, and carried out and then to summarize the data as a review, which is something some work on it: it was, so to say, your official entrance into the that has remained with me for the rest of my life. field of cell signaling, which was destined to be the lifelong founda- tion of your research life. It would be interesting to know how you 2. Question N 2 the transition from a small African Alma Mater to one of the most important research Institutions of the world had affected you, Most of the colleagues I have interviewed have mentioned char- and how you had handled it. ismatic personalities who have had a decisive influence in directing them toward science and/or towards a particular type of science. 3.1. MJB Naturally, if a young person moves his first steps in one of the famous world scientific Centers, such fateful encounters are more or less to I was very fortunate at the University of Rhodesia and Nyasaland, be expected. Your case is of special interest because you were not in because most of the lecturers were from overseas. One of my lec- one of these famous cathedrals of knowledge, but had enrolled in a turers was Eina Bursell and I really enjoyed his lectures and I ended forgotten outpost of science in Central Africa, the University of Rho- up helping him with his research on insect physiology. Professor Eric desia and Nyasaland. It would be interested to know whether, a stu- Edney, who was the head of Zoology, was acquainted with Sir Vin- dent there, such a fateful encounter nevertheless occurred. cent Wigglesworth who worked in Cambridge and is recognized as the father of insect physiology. When Edney found out that I 2.1. MJB was fascinated with doing research on insects, he contacted Sir Vin- cent who offered me a place as a research student. I managed to win When I joined the University, it had only been going for one a Commonwealth Scholarship that enabled to go to England to do a year. Consequently, I was part of the second intake of students. Ph D in the Zoology Dept at the University of Cambridge. We were fortunate in that we had some very good lecturers who My journey out of Africa was very exciting but also somewhat daunting as my new life in Cambridge was both different and chal- DOI of original article: http://dx.doi.org/10.1016/j.bbrc.2017.01.098. lenging. Before leaving Africa, I decided I should see some snow so I http://dx.doi.org/10.1016/j.bbrc.2017.01.097 0006-291X 2 E. Carafoli / Biochemical and Biophysical Research Communications 485 (2017) 1e4 joined a group and climbed Mt Kilimanjaro, but when we got to the 5.1. MJB top there was no snow but just ice. So my first experience of snow was in Cambridge and I had to walk through a foot of snow to get When I found out about the second messenger cyclic AMP, from my college room to the toilets on the other side of the court. which had been discovered by Earl Sutherland and Ted Rall, I It was both very cold but also an interesting experience. The other decided to see whether it activated the salivary glands. To my aspect that excited me about Cambridge University was not only its delight, cyclic AMP was able to exactly duplicate the action of 5- size but also all its traditions. Life in Gonville and Caius College HT. I was then at a loss about what to do next so I decided to go where I stayed was very different to my experiences in Africa. over to see Ted Rall and he was incredibly helpful. I remember What really excited me was the fact that I was surrounded by so that at our first meeting he asked me whether I had tried methyl many eminent scientists. In the Zoology laboratory at Cambridge, xanthines. I had never heard of these so he told me about theophy- I was surrounded by many research students and postdoctoral fel- liine and caffeine and how they act to inhibit the phosphodiesterase lows who had a great influence over my research. that inactivates cyclic AMP. I went back and was excited to find that the salivary glands began to secrete in response to theophylline. 4. Question N 4 When I went back to tell him he asked whether I had tried syner- gism and I can remember saying “please Dr Rall what is syner- The work on the control of fluid secretion had paved the way for gism?”. He then described how if I used a low dose of hormone the move to the USA as a postdoctoral fellow in the Laboratory of together with a low dose of theophylline, I may get a full response. Dietrich Bodenstein at the University of Virginia in Charlottesville, When I tried it out, that is exactly what happened. In this way, I was where cell signaling, in the way it was understood and studied in extraordinarily lucky to have the pedrson who discovered cyclic the early 1960s, was the general theme of work. I understand AMP guide me through all these experiments. Shortly after all that you had wanted to continue working on the Malpighian tu- this, I returned to a job back in the Zoology Dept in Cambridge. bules, but had run into technological problems in trying to set them up as model systems in vitro both in Charlottesville and in 6. Question N 6 your second period of postdoctoral research at Case Western Research University. The difficulties had persisted, making you, to It was only after your return to Cambridge in 1969 that you first use your words, increasingly desperate. But then, suddenly, luck became interested in calcium, as you had found that it somehow turned. The story has fascinating aspects, and it would be inter- regulated the flux of chloride during fluid secretion. I wonder esting to have a first hand account of it from you. It was, even if whether, when you had made that first finding, you had imagined serendipitous, a small Eureka moment. that calcium would have become your lifelong research companion. How early after your return to Cambridge did you begin to see that 4.1. MJB timid calcium connection was going to explode into the all- encompassing body of knowledge that now dominates all impor- By the time I began my second postdoctoral research at Case tant aspects of cell life ? western Reserve my research was not going well and it mainly had to do with the difficulty of studying Malpighian tubules 6.1. MJB in vitro. One day when I was dissecting out some tubules I saw a long clear tubule so I decided to set it up. It was a salivary gland When I got back to Cambridge I began to try to find out how cy- and much to my surprise it began secreting at a very fast rate. I clic AMP acted to initiate fluid secretion. In order to do this, I built a then found out that the rapid secretion was being driven by 5- small persplex perfusion chamber that enabled me to monitor the hydroxytryptamine (5-HT). When I set up the glands without 5- transepithelial potential while stimulating the glands with 5-HT. I HT there was very little secretion, but this was strongly accelerated found that at rest the lumen was slightly positive, but it rapidly when I added 5-HT. I then tried to find out how it might be working became negative upon stimulation with 5-HT. When I added cyclic and someone in the lab said I should try cyclic AMP, which had been AMP, I expected the same response, but it was completely different. discovered in the Dept of Pharmacology across the road. This was a Instead of going negative, the potential became more positive. It very exciting moment because it introduced me to the field of intra- turned out that cyclic AMP was driving the potassium pump, þ cellular signal transduction. whereas Ca2 stimulated chloride channels. When I discovered þ this action of Ca2 I began exploring the literature and it soon þ 5. Question N 5 became clear to me that Ca2 was a very important second messenger that was essential for “all important aspects of cell The serendipitous discovery that had led you to work on sali- life”. The big unsolved question was how agonists were able to þ vary glands had brought you deeper and deeper into the cell release Ca2 from internal stores. signaling word, which in the early 1960s was moving its first steps into modernity. Here you had a stroke of luck, since you 7. Question N 7 were, as you have written, at the right place in the right time. You had found that the secretion by salivary glands was Calcium signaling has developed, and is still developing, into a controlled by 5-hydroxytriptamine (5-HT), and you of course number of lines, but the one that his of most direct interest to wanted to find out how the hormone activated the secretion. As you is related to the role of that special phospholipid of the plasma luck had it, Ted Rall, the co-discoverer of the progenitor of all sec- membrane, phosphatidyil-inositol (PI). A very interesting story, ond messengers of cell signaling, cAMP, was working next door in initiated by the discovery by the Hokins in 1953 that agonists stim- the Department of Pharmacology. You had found that the effect of ulated the turnover of PI. Nobody had paid any attention to the 5-HT on secretion was duplicated by cAMP, and thus initiated an observation until Bob Michell suggested in 1975 that the Pi turn- intense interplay with him on all matters concerning cAMP. How over was linked to the increase of cytosolic calcium, the latter important was the interply with Ted Rall in shaping your future following the breakdown of PI. Bob had evidently come up with research activity ? the idea of linking the “PI response” to calcium signaling because Download English Version: https://daneshyari.com/en/article/5505274

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