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A family with alpha thalassemia in Jamaica


Work on haemoglobin synthesis (Part 2)
David Weatherall Scientist
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The next problem of course, was, well, if they’re not made at the right rate, why? And at that time, there were lots of people throwing theories around, but the question was there was no way to test them, and just after I got back to Baltimore at that time, it was just when Dintzis, Howard Dintzis, was being appointed, and they had a kind of professorial lectures, inauguration lectures, and I went to his lecture and he had done the most beautiful experiment, I think one of the most elegant, his paper, that I had always told students to read, because at that time people knew that there was a gene, they knew there was message, and they knew there was some kind of adaptor molecules which brought the amino acids to the message, that far, but nobody knew how a protein was put together on the template, I mean, did the amino acids just get jammed in randomly all over the place, or did it start at one end, or did it start at the other end and move sequentially? So the Dintzis experiment was to take very anaemic rabbits, at reticulocytes, and expose them to a very short period of label with leucine, and he used tritiated leucine, and then he made some absolutely uniformly labelled rabbit globin, and so used to, he took these peptides, at one minute incubation, three minutes, five minutes, and mixed the tritiated with the uniformly C¹4 labelled globin, and then measured the ratios of tritium to carbon, the long-labelled globin. And what you found, was that at very short periods of incubation, the N-terminal ends of the chains were hot, and then this hotness gradually spread through the chain, indicating that they must be synthesised from the, the N to C terminals, and you get very nice curves at, and the curves gradually dropping till you got uniform labelling, and there was no curve. The question I thought, well, could we do this with human material, because if the thalassemia defect saying initiation or termination of the chain, or maybe as people were suggesting, it’s a silent amino acid substitution that makes a wonky- So, the big problem was material. You could get the odd normal, with a high retic count, but to do this you needed a lot, and I, it was just impossible actually to do before we left Baltimore. But it, but I, I, went back to Liverpool knowing that, really wanted, we must do this, and by chance the WHO sent me out to Asia in the, about '66, I guess, '67, and I met the group from Bangkok, and of course, all these extraordinary patients, and I talked this experiment over with them and the, because we didn’t have the equipment in Liverpool at the time, but we gradually built, I got a spare room from the Department of Pathology, and, because the Nuffield Institute was being built, and we were going to have space by the late 60s, and Clegg went back from the States to work with César Millstein, and on immuno-globulin instruction, he kept ringing me up saying he was bored and wanted to get back to globin, well, do this experiment, so we managed to get Clegg a senior lectureship, and he came down to Liverpool, and I went out to Thailand, taught them how to incubate cells, how to purify retics so we could get some real hot material. And eventually we got the equipment and were able to do the experiments. It took about three years actually, and at the end of the day, the real problem was that when we finally got the results that the assembly of beta globin chains was completely normal, and which meant that termination and synthesis was unaffected, and there are a few more fiddly experiments to show that initiation was normal.

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: 4 minutes, 48 seconds

Date story recorded: July 2007

Date story went live: 02 June 2008