Towards molecular medicine; reminiscences of the haemoglobin field, 1960–2000

When historians of medicine in the twentieth century start to piece together the complex web of events that led from a change of emphasis of medical research from studies of patients and their organs to disease at the levels of cells and molecules they will undoubtedly have their attention drawn to the haemoglobin field, particularly the years that followed Linus Pauling's seminal paper in 1949 which described sickle-cell anaemia as a ‘molecular disease’. These personal reminiscences of some of the highlights of those exciting times, and of those who made them happen, make no attempt to provide a comprehensive account of how the field evolved. Readers who are interested to learn more of the history of haemoglobin and its diseases are referred to the short bibliography which follows this essay. Why, any aspiring young research haematologist might ask, should an English medical graduate become obsessed with a family of diseases which are restricted mainly to tropical climes? Although I have been asked this question many times, by far the most memorable was in 1962 during the oral examination of my Liverpool MD thesis on thalassaemia, conducted by the external examiner, Newcastle neurologist Henry Miller. ‘Well’, he said, ‘it looks alright but you must stop working on a disease that none of us has heard of; go into psychiatry before it is too late’. But it was already too late. My completely unplanned entry into the haemoglobin field 4 years earlier was due almost entirely to the administrative eccentricities of the British Army. Two years after qualifying in medicine in Liverpool, and armed with a Membership of the Royal College of Physicians (MRCP), obtained only because it took the Army a full year after my house jobs to find the correct address to dispatch my call-up papers, I had to serve for 2 years in the Royal Army Medical Corps (RAMC) as part of compulsory National Service. Terrified of aeroplanes, bullets and snakes, I volunteered to serve in the United Kingdom; 2 weeks later I was on a troop ship bound for Singapore, where, as I had no paediatric training, I was put in charge of the children's ward at the British Military Hospital. One of my first patients was a Nepalese Ghurka child who had been kept alive from the first few months of life with regular blood transfusion and who had defied the diagnostic might of the RAMC. I soon took to spending my spare time at the General Hospital in Singapore, where I met a lively biochemist from Malta, Frank Vella, who, after travelling the world, subsequently had a distinguished career in biochemistry in Canada. Frank, who had initiated a filter-paper electrophoresis survey for abnormal haemoglobins in Malaya, told me about a publication from Thailand which described some children with thalassaemia, suggesting that this disease is not, as previously had been thought, restricted to the Mediterranean region. Luckily, another paper had also just appeared, from the American immunologist, Henry Kunkel, which described how, using electrophoresis in slabs of starch, he had found a minor component of human haemoglobin (Hb), Hb A2, the proportion of which was elevated in some carriers of thalassaemia. After several weeks spent knee deep in potato starch, we found that the Ghurka child's parents had increased Hb A2 levels and, hence, that she was likely to be homozygous for thalassaemia. Frank and I rushed this breakthrough to the British Medical Journal, but my excitement on seeing my first paper in print was short lived; I was hauled up before the Director General of Medical Services for the Far East Land Forces and told that I could be court marshalled for not getting permission from the War House (Office) to publish information about military personnel. ‘And, in any case’, he added, ‘it is bad form to tell the world that one of our pukka regiments has bad genes; don’t do it again'. After a year in Singapore, I was sent to look after the medical wards at the British Military Hospital in Taiping, North Malaya. By now, completely bitten by the haemoglobin bug, I devised a simple electrophoresis system using car batteries to look for haemoglobin variants. Vella had left Singapore and so whenever I thought I had found one I posted it to Hermann Lehmann in London. Just before the end of my National Service I arranged to go to Johns Hopkins Hospital in Baltimore to train in genetics and haematology. While passing through London en route for the USA I visited Hermann to thank him for all his help. Encouragingly, he told me that I was wasting my time working on haemoglobin because there was ‘nothing left to do’. ‘Start exploring red cell enzymes’, he suggested. In the event, on arriving in Baltimore in 1960 it turned out that human genetics, and the haemoglobin field in particular, were bubbling with excitement and potential. The only lessons for those contemplating careers in medical research from this chapter of academic and military gaffs are that, regardless of the working conditions, when there are sick people there are always interesting research questions to be asked, and only take career advice along the way if you are determined to ignore it. The excitement of the haemoglobin field in 1960 reflected the chance amalgamation of several disciplines in the 1950s, particularly X-ray crystallography, protein chemistry, human genetics and haematology. From the early 1930s the structure of proteins became one of the central problems of biochemistry. At that time, the only way of tackling this problem was by X-ray crystallography. In 1937 Felix Haurowitz suggested to Max Perutz (Fig 1) that an X-ray study of haemoglobin might be a good subject for his doctoral thesis. He was given some large crystals of horse methaemoglobin which gave excellent X-ray diffraction patterns. However, there was a major snag; an X-ray diffraction pattern provided only half the information required to solve the structure of a protein, that is the amplitudes of diffracted rays, while the other half, their phases, could not be determined. Max Perutz. Photograph by B. Meya, Pressebild, Berlin. After numerous setbacks extending over many years, Perutz and his colleagues finally cracked the phase problem in 1953, when they discovered that it could be solved in by of the diffraction of a of haemoglobin with that of haemoglobin with which with its In to solve the structure in required the of the diffraction of at one and with with on the haemoglobin In this the first of at with X-ray during the In solved the structure of a which that proteins have and had for and of by paper In (Fig who, Max was a from was the of the structure of haemoglobin from patients with sickle-cell a that we will to part of this the after had been with the which only at and Although for of only were that haemoglobin of half of the of haemoglobin by in the United and 2 of and 2 of of These which were in with the X-ray suggested that haemoglobin is a of of which were and was soon found that the of which had been for over years to be to have and were at the on of in in The in the and on left are of the and for The are to the and seminal and one which was to the of was the chance of an on a train and Linus the protein and (Fig one of the of were from a in and to that he and his colleagues had that when red cells from patients with sickle-cell anaemia are and they in that this might a and sickle-cell haemoglobin which could be by a change in He gave this problem to one of his a young medical graduate At that time they that a had a for proteins to their charge by there was no of this in Pauling's and his colleagues to and they found that the haemoglobin of patients with sickle-cell anaemia to that of people in an field, that it must have a the haemoglobin of sickle-cell carriers was a of of was in in the a disease’. of haematology. is to are and The on the left is of of Medical who the at the Hospital. He was by who who the for his on and who should have also it. The the to where Perutz had become interested in sickle-cell He has how, after a paper suggesting that the of cells is due to the of he his to a at the in had also X-ray of cells to if they could a pattern but found that it was the as that of cells and that Perutz and his colleagues must have their years later obtained X-ray from cells and that the had because they had which in Perutz and suggested to that he should of to if he could find any and cell After haemoglobin with the by electrophoresis and in to he later He that his first a that had been left out in the But and he was to that the of and were for the of one a that had been a few years earlier by which a to be one at a time in a found that this was due to the of for at in the of Hb as how a disease from only a in the haemoglobin this had for Although was about the of the at the time, the were with the that the of the is a a of the suggested earlier by and from their studies of and a to the later studies of on which were to this the of simple paper haemoglobin became the of research during the and abnormal haemoglobins almost by the Although many were it was Hermann Lehmann (Fig who became the Hermann was in and, also the made his in He to as a and at the of the War had a short of as a at to Liverpool, an with many Max Perutz. He during his later in the and a which him to haemoglobin during his In Hermann and I were by the of to to on in the haemoglobin field (Fig He was a travelling into to blood and make The was only for me by to a with he to have an and spent all and paper to his in the that they might into the of Hermann was during a with the to in Hermann is some haemoglobin by of at Medical These early studies on human haemoglobin provided some information about the of While the first to be described to be of Hb in and research working at Johns Hopkins Hospital in discovered a family in which haemoglobin Hopkins 2 and in a of and that Hb Hopkins 2 is an it was that there must be at in haemoglobin and The of the and of and A2, that there must be at family studies and of from the of led to the of the By the early it was that the are and are in a The that sickle-cell are of haemoglobin from a of had been for some years that children with of might have of and it was found later that some carriers might have elevated levels of Hb that from a in Hb The seminal in of this from the study of patients who had the sickle-cell from one and from the was first described by and his in at the time they could not have the full of their because of of during the and of many of the studies of this to for many After the of haemoglobin and his colleagues in the USA found that the pattern of haemoglobin in patients with sickle-cell is to that of for the sickle-cell the of the is to the of Hb to that of Hb the to the in sickle-cell it was that the sickle-cell in the it could be that the of the was to the of from the from the few family studies in 1960 there was a that this form of might be an of the major that was made in the was the of and with a the of In and many of the that had over the in a seminal paper which a for the of thalassaemia. In they suggested that there are major and just as there are major of haemoglobin variants. the of Linus and who had suggested that in might be due to of the and that the might the in the of in the which it. and paper not and who a to in which they that the and studies on haemoglobin had not their about the of thalassaemia. the they that were for the to which the of to the and of had been was completely In on the of and haemoglobin in the had the field to a of is in the earlier of and In any in their paper and the of other and that had them to their of the of thalassaemia. of and the of from many disciplines into is by the of several on haemoglobin in the By 1960 there were only a of the central questions about the of haemoglobin had been an to those of us who the field at about that Although some of the who had to it many on to to some by they as more exciting questions in the field of but also by the that there were major in it not be to make an of the genetics and of particularly the of and were not by and over the years were to the for the of a of which on the field in the early when haemoglobin became a major for the of into the and of haemoglobin along the of the during the and and there was the the Perutz and his colleagues made an of which they finally in years after the first X-ray diffraction of haemoglobin were The first were of horse horse and human soon the of haemoglobin had become more and some of the of with which they are became The were discovered by due to were by led by and and and I described the first of due to a haemoglobin with a many of together with of the structure of Perutz and Lehmann to publish their The of in which with of of the haemoglobin provided an of the with haemoglobin at the Although some of this has been and few have been which are not to be found in this The of the reflected the but of and led to a of the the structure and of a in his to the world for the human haemoglobin was not a but had a of the and of he was He also had the as a of to with a of the of the careers of who are to the into the world of the as Perutz has attention to was While this paper was Perutz on in and was up by Lehmann with about in its My has to it a of minor I have been by the of In the the became of because of their and with the that they might the of in the of protein we our attention on to their using more particularly soon became that the are some with no with a in the family of in which there is no the soon on the and the were were in none of the of the disease which were in and the form of anaemia with Hb were found in In a in I to up to the we had Although a of had been made at the the genetics of the particularly the and, there were no of we had only the about their the other it was already that they had the to us a about abnormal as the for of a for many described with large of Hb and disease had been as a form of anaemia with of in the red studies which to the of gave because the in carriers were so However, the studies of and his colleagues in Thailand to make some of the and, when in discovered a family with that the must be to become this family had turned up years many of about the genetics of have been those who in genetics, in which their to in a few should have some for human (Fig and in red cells in the early but it to take this because there was no way of the of in a problem became particularly in described in the of patients with thalassaemia, just how be by an with the of that had was this some form of haemoglobin which was the of to to this in I to study in haemoglobin by the of into after of was to for several but the problem was how to the in which they were by with by the more of always of and in but the were not At about this time (Fig to with in the at Johns Hopkins had to Hopkins as a from the of the distinguished protein the of not his more to and they had to part first was an attempt to study the of and, as I had to time in the some protein from we soon to for to with other over our of one of suggested that it might be to of using an he had for the of while a research in in by a and which has to this The with at a in to our we were soon to excellent of the with full of in in which we from those with of thalassaemia. was soon that the major in all was many subsequently this to of thalassaemia. The that the to and red cells in might be due to the of the which are in was by (Fig and his colleagues in and later by in and at which led to a of the of the But were the not in In the early I had a by in which he described how, by for a short it was to how at the end and to end at the In he was to the of a in the cell and on the Why, I in my be in to the time it to make a and to is as be if and was However, had out his on with of which were in protein to the of patients with thalassaemia. However, after 2 years of we were with the of in to of from and and to the and pattern of their In the event, there was no and that the of and were not in later it was to that the of were it that, at in the of that we had the must a of for the that is Although this was more the end of the for the to the of thalassaemia, studies of the structure of haemoglobin which had been discovered over this also provided a to was in in the described a Hb which he found was of with which of part and part He suggested that this was the of a which in a of its and, hence, the of thalassaemia. After out this and a more in the to to his there he the examination required before the of because he was to is by In we were referred a family from by in which several patients with Hb disease had of an abnormal that this was an which is in and, hence, in the of thalassaemia. The which we Hb the of the in in which the family turned out to be in more its in that it had an which was by suggested that this might from a in the to as in the was which is by followed that there must be which is not in this is through another stop is From of the for proteins as was it was to a at the structure of this might which was with put it by our colleagues at the time, was when human was a few years this form of to the of the of to a of of the In the early several to in by it from and its in These were out by and at the National of and and in and later found that there was a in in this However, because they were and not it was not to the was in it was However, the by and Baltimore that an obtained from from it became to and which could be to the levels of in by and and their and later were to that there was a of in some red studies in which there was no in which there was of but In and (Fig determined the of from one of the and found that an for had to the the early it likely that some of might be by and turned to using to for the of After we had found that with no at any we to to who had had some of to it might be to the were in of this gave the problem to in his and the of our colleagues we obtained from a with the Hb and sent it together with to after first that there was no in this was found that the cells but that there was a more of had up a in and our papers, a as the for human disease for the first time, to in in By the for the of the had become had been an time to be working in this field the of the central it is how was made by which were so far from the we that the were and could from was also to that the on haemoglobin had into the for the of the haemoglobin and that our of the of the was to more of transfusion and the of and in the it was not that an of on the haemoglobin The that had been about the and of the in the years that the system was to them on a the haemoglobin were and their determined. it was found that their was that by the earlier However, there were some put haemoglobin in the of the of human structure and In the the of and and that the of the are up by an which was later to be for most and in found for a in the and that of might be it was found that are the but not in a In and using the found that the of is on a while that of patients with cell disease it is on that the was on a that also a the for the studies that this is a in some was the of the of for and, at the time, increased the of by first genetics and later were other in the early we on the and in some an which up a field of into of and the of in and a on the when is with and the years of the and led by the of (Fig and of from patients with of were and and a of the of the disease we had that the of of the of thalassaemia. from diagnostic some that had in for over years, were and one from an who was the first of from our in Liverpool in the early to the for this family of and the to the finally us to that at some of diseases are particularly because of and took the of in of the of thalassaemia, and there was a in their particularly in the Mediterranean a which to and had been a time to be in research in haemoglobin and its had the of a of mainly in several all of which met and which there was a of and Although it is to one of the and of the of in a of and many While for their their were the of the National for to the medical of the of the United discovered that he was only the to the of the Royal the first been an in the and the for by the in the USA to for the and the of was one of the in the of many of the medical in the publication of have spent the years as a in the human haemoglobin field has been an and has provided a at the in and cell and the to some of into The one is that the in human genetics, and in the of medicine in with the of the of more of and to patients with The of the of by transfusion and were in the and, in with the of there have been no major in is one From the it became that it might be to the and sickle-cell anaemia by haemoglobin on the complex of the of the from to haemoglobin by the of and and their by those of and have at some in the of sickle-cell anaemia thalassaemia. the other the of life and for children with thalassaemia, at in the has been by some excellent in the field the of transfusion by and the most to by and and the of more and to the of by and had been made in the of sickle-cell The of a more to the of the haemoglobin so about their should not The of the of medical over the century us that there is always a before in the the has to be an to and for diseases in which is it likely that it will be a time before problems are and when they the required be far too to to the where diseases are so and genetics in particular, has from lessons from the haemoglobin to the where of an by the that has from their study for their and the will on the part of the research and this could be to over the few this is not and of of children with sickle-cell anaemia and to in years of start to have a about it. The personal studies were the of with many particularly and our colleagues in the Medical and numerous the I thank Max and for and for this and the first and by Hermann of of the Royal of sickle-cell a and of molecules in The I made you In The in of and a of by B. an of the of some the of and by of in The the of a of and and

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