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Giving a talk at the Association of American Physicians meeting


Going to Johns Hopkins and work on haemoglobin
David Weatherall Scientist
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After the army, I wasn’t quite sure what I was going to do, but I had a letter from Cyril Clarke saying that they had developed an arrangement for swapping research Fellows with Victor McKusick at Johns Hopkins, and that David Price-Evans was there, leaving shortly and would I like to take his place at Hopkins. So yes, good idea, so I went home, I spent a week or two with my parents and then went straight over, well, straight over, I, because there was no way I was going to fly, so I went on one of the old Cunard steamers to New York, and then travelled down to Baltimore, and you know West Coast winters, and I’d just come after two years in Malaysia, it was awful actually, and I was not terribly happy at first in Baltimore. They put us in a place that was called the Peoples Palace, it was this medical residency where you had miniscule rooms and communal bathing, and I won’t go into details, but communal bathing in the United States is not pleasant. But Victor, I told him I wanted to work on thalassemia, because I was really hooked by then, and we discovered there was only one patient in Baltimore with thalassemia, so he put me into Ned Boyer’s lab. Boyer, I think was a terribly underrated scientist actually, he was a biochemical geneticist, he’d had some training at the Galton, and his genetics was very strong, but he was very good with his hands and an excellent teacher, and he had just started developing starch gel electrophoresis, which had been described by Oliver Smithies a year or two before, and he used to try to get me to work on stuff he was working on, but I said I’ve got to work on haemoglobin. So, we looked at the situation, and at that time haemoglobin genetics had just really started to be understood. Yes, there were two alpha chains and two beta chains, and there was a family from Baltimore which suggested that they might be on different chromosomes, that was about it. So, one of the key questions, you won’t believe this, it sounds so stupid now, was, it was not clear whether the alpha chains were controlled by the same genes when you’re a foetus, in foetal life, as in adult life, and, because clinically this was rather important because it would suggest that if you had bad alpha chain genes you’d be in trouble as a foetus. So we, oh dear, we decided to look for a foetal alpha chain variant, in other words, if, if there were alpha chain variants in the population, they would be expressed in foetal and adult life if they were controlled by the same genes, so I went trooping around the obstetric units in Baltimore, collecting cord blood, and running them on electro- on starch gel, and also collecting adult bloods, looking for somebody with a haemoglobin-like sickle, which didn’t sickle, haemoglobin D, because it could be alpha, it could be beta, and I was very lucky actually, because I found some families very quickly, and also found a couple of cord bloods with two major haemoglobins. The question was, how do you do the analysis, those days, because peptide mapping was not, there was nobody doing that at that time in the States, at least probably, no, certainly not in Baltimore. But what we used was something called symmetrical hybridised, or asymmetrical hybridisation, which was way before your time. If you take haemoglobin A and you put it in an acid PH it dissociates into sub units, and then if you raise the PH, they come back together again. So it had been shown by, by Schroeder and people, with moving boundary electrophoresis and all these fancy methods, that you could get this re-association, so if you mixed somebody with an alpha chain variant and somebody with a beta chain variant and dissociated and come together, you’d get four haemoglobins. You’d get normal, you’d get the two, and then you’d get a hybrid, so I thought well, let’s try and do this on starch gel, and it was very crude, just purified the haemoglobins and then, and then exposed them to some ascetic acid, and then dialysed them for a long time up to a normal PH, and it worked beautifully, we got beautiful bands on the gel, and then therefore you could then take the abnormal foetal haemoglobins and do the same thing. It turned out there was an alpha D gamma foetal haemoglobin, and we found that the adults had two A2s, so it was pretty clear that the genes must be working right through development. Not all that exciting really.

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: 5 minutes, 51 seconds

Date story recorded: July 2007

Date story went live: 02 June 2008