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Work on haemoglobin synthesis (Part 2)


Work on haemoglobin synthesis (Part 1)
David Weatherall Scientist
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We went back to Baltimore, and Stella went back briefly to work with Roger Harriet, and I was in the haematology Department then, and there was some methodology developing for looking at haemoglobin synthesis in the test tube, but it was all very much reliant on getting rabbits or other beasts and injecting them with phenylhydrazine till their red cells were kind of collapsing, and we got this enormous reticulocyte response and then labelling the cells, but with human beings of course, to get somebody with 50% reticulocytes is not common. So one had to do a lot of fiddling around with making reticulocyte rich preparations, but after a while it worked, and you could label them with leucine, and you could get linear synthesis in the test tube for at least an hour, an hour and a half, and while you’re looking at linear synthesis, you can feel reasonably assured that you’re looking at something close to the real world. But the problem was that to study thalassemia you really needed to be able to study the synthesis of the individual alpha and beta chains, and there were no methods available for separating them. There was, so initially I went back to my old asymmetrical hybridisation just to see, and so you could separate the haemoglobins that way, and then look at the labelling, and, and then another awful method, it started to be used, mainly I had some interaction with MIT with Vernon Ingram who’d moved to the States by then, and of course, Vernon was not in haemoglobin, but he was, he had a very bright research fellow called Lorado Baglioni who still worked on haemoglobin, and they’d been trying to do some separations with what they called counter-current distribution. This was a kind of differential solubility and they had machines to do it, but when I tried to do it, of course, I had to do it, what you did, you put your globin in these different concentrations and then shook like hell and then looked at the optical density of the supernate. You got something, and I imagine there was unequal labelling undoubtedly, but without real quantitation you’re never going to be sure, so this is when chance hit me, really. This was about 1963, at the end of '63, and Mike Naughton rang me up one day and said, there’s a young guy called Clegg coming over here, he’s in deep trouble, do you know him? So I said, no, and apparently this John Clegg had been a PHD student in Fred Sanger’s lab, and had done his PHD on separating fibrinogen chains, and he went over to do a post Doc with Hans Neurath in Seattle, the famous protein chemist. Neurath ran a very Germanic lab- you will be here at 8.30 for a journal club every morning. And you know John, that was not Clegg, I mean, in Cambridge we didn’t do that; we went in when we felt like it, and we went home when we felt like it, and we worked hard, but in our time. So he didn’t turn up, and he’s only been there about three weeks and he got a note on his desk, your presence is disturbing the morale of my laboratory, I would like to, you to go. So here was a young post doc, penniless, on the west coast of the States, nowhere to go, the only person he knew in America was Naughton, so Naughton got some money and he came over to this department where, with, it was run by a chap called Howard Dintzis, and a very clever guy, appointed very young, it was a new department of biophysics. A lot of talented people, and they put John on an impossible project actually, which was to try and pulse label, look at insulin synthesis basically, to put it crudely, and he’d been only there a few weeks and we started meeting for coffee, and he said to me one morning- that this is ridiculous, I’m not going to get anywhere with this, and what are you doing? So I said, well, I’m not getting anywhere either really, because I’m trying to measure haemoglobin synthesis, and I can’t get the globin chain to part, so he said- well, I wonder if that stuff I used in Cambridge, the 8 molar urea, mercaptoethanol might do. So we, we tried, and it worked a dream, it didn’t take, it only took a couple of weeks actually, and I had lots of labelled globin from thalassemics, so who knows, that I used to have to go to New York to get the thalassemics, come back on the evening train, incubate their cells, but anyway, we had the material. So, I started to do the chain separation over in the haematology department, but we had no equipment, and John didn’t have much equipment at the time, so I used to do the chain separations, but I had no fraction collector or anything, so I used to have to sit catching the drops off any of the tubes, and if you look at that first "Nature" paper on this subject, you find, you know, you usually get nice smooth peaks in chromatography, but they’re very bumpy, and those bumps I think, just represent the fact I dozed off, and so the volume in these tubes are slightly uneven. Anyway, we looked at beta thalassemia in normal people and alpha thalassemia, and found that what was really happening was that it wasn’t so much the defect in haemoglobin synthesis, as imbalanced globin synthesis. You made alpha chains that apparently at a normal rate in beta thalassemia, and then of course they precipitated and that fitted in very nicely because Phaedon Fessas in '63, I think, just a year or so before, had described these big chunks of junk in red cell pre-cursors as they called them, Fessas bodies, for a while, and of course, the question was what were they. Were they some unstable haemoglobin, when it turned out that they were alpha chains then the whole thing started to look sensible, and lots of people started doing that kind of thing.

British Scientist Sir David Weatherall (1933-2018) was a world renowned expert on blood diseases, in particular thalassaemias, and used his expertise to help control and prevent these diseases in developing countries. He founded the Institute of Molecular Medicine at Oxford in 1989 and was knighted in 1987.

Listeners: Marcus Pembrey

Marcus Pembrey, now Emeritus, was Professor of Paediatric Genetics at the Institute of Child Health, University College London and consultant clinical geneticist at Great Ormond Street Hospital for Children London. He is a visiting Professor at the University of Bristol UK, where he was the Director of Genetics within the Avon Longitudinal Study of Parents and Children until 2006. A past president of the European Society of Human Genetics, he is also the founding Chairman of the Progress Educational Trust.

Duration: 7 minutes, 15 seconds

Date story recorded: July 2007

Date story went live: 02 June 2008