by D M Potts
When sperm or eggs are formed, the chromosomes go through an important phase when the pairs line up with each other and packages of genetic material are exchanged between individual pairs. We then pass on one chromosome of each pair to join with that of our partner in the production of the next generation. It is for this reason that our children share the genetic characteristics of the two parents and ultimately of the four grandparents, and so on back through our family trees.
The gender of an animal is determined by only one pair of chromosomes. In mammals like ourselves, females possess a pair of similar chromosomes called XX chromosomes while males have a dissimilar pair consisting of an X chromosome derived from the mother and a smaller Y chromosome derived from the father. The egg before fertilization contains one X chromosome as well as the twenty-two other chromosomes. Sperm contains twenty-two chromosomes together with either an X or Y chromosome. When two X chromosomes come together after fertilization, then a female is conceived, whereas an X and Y chromosome together will produce a male (see page 57).
Inherited characteristics may either be traced to one particular gene or may, as in the case of height, depend on the interaction of many genes. Some inherited factors not associated with sexual differentiation itself are carried on the sex chromosomes. This is the case in haemophilia where one of the genes controlling blood-clotting is carried on the X chromosome.
The clinical understanding of haemophilia and scientific understanding of genetics came together slowly. Once it became clear that the defect causing haemophilia was situated on the X chromosome, it explained why a woman could be a carrier but not a haemophiliac. If one of her chromosomes carried the abnormal gene then the other would be normal and would compensate for the defect. If she had a boy then he might inherit either her normal X chromosome, in which case the child would be unaffected and in no danger of passing the disease to his offspring, or he might inherit the abnormal X chromosome and manifest the disease. Being male he would have no second X chromosome to compensate for the deficiency. If an affected mother had a daughter, that daughter might inherit her mother’s abnormal X chromosome together with a normal X chromosome from her father, in which case she would also be a carrier. On average, half her sons would have the disease and half her daughters would carry it to the next generation. A haemophiliac man, on the other hand, if he lives and has children, will transmit the disease to every daughter, who will be carriers, but will pass on only the Y chromosome to his sons so that they will be perfectly normal. One of the cruel aspects of the disease is that daughters of mothers who carry the gene do not know if they are carriers themselves, even if they have several normal sons. If they in turn have daughters the disease may reappear in their grandsons. Some forms of colour-blindness are also determined by genes on that part of the X chromosome that is missing from the Y chromosome. Colour-blindness is therefore more common in males but as the defects are relatively frequent and not fatal they also occur in some females.
The inheritance of haemophilia through the mother
The inheritance of haemophilia through the father.
(Note that Leopold and Helene had only 2 children, one girl and one boy)
XH represents the normal chromosome, Xh the X chromosome carrying the defect causing haemophilia and Y, the Y chromosome
The inheritance of haemophilia
Queen Victoria’s descendants are a classic example of the inheritance of haemophilia. Two of her daughters were carriers who passed the gene to some of their sons, who were affected, and to some of their daughters who became new carriers. Prince Leopold, who was the only son of Victoria to manifest the disease, produced a daughter who was inevitably a carrier and a son who had to be free of the disease.
But how does haemophilia first arise? In order to answer that question, it is necessary to know something of the structure of genes and the nature of mutations. The genetic material which determines the structure and function of our bodies is carried as a simple biochemical code on strands of DNA. DNA is a long molecule consisting of hundreds of thousands of atoms. The molecule has a spiral thread-like structure and an ability to reproduce itself accurately so that the genetic code can be transmitted from generation to generation. If it were possible to take apart one living human cell and extract all the DNA and join the individual strands end to end, it would be about one metre long. However, in the microscopic living cell, the DNA is tightly parcelled into individual packages of genetic material which, in turn, are put together as chromosomes. The information in the chromosomes is transmitted to the rest of the cell by a complex companion molecule to DNA called RNA (ribonucleic acid) and finally translated once more into the building blocks of protein and other molecules that make up the cell and its secretions. This whole process involves millions of interactions at the molecular level but takes place rapidly, each strand of DNA being read about sixty times a second.
Whenever a cell divides, every atom on each strand of DNA must be copied exactly. Inevitably, errors occur, but there are a number of molecular processes for identifying and eliminating most mistakes. Certain chemicals and radiation, such as X-rays or cosmic rays, can damage DNA. A mistake or mutation in the DNA in the cells that will form the eggs or sperm has great potential significance.
Occasionally a mutation leads to some extra fitness and then an animal carrying such a beneficial mutation has very slightly more chance of succeeding in the struggle for existence than its brothers and sisters. Such mutations are the basis of the tiny steps by which evolution has taken place, but most mutations are so harmful that development never begins, or if it does it soon ends in a spontaneous abortion. (Abortion, although an unhappy event if the pregnancy is wanted, is a natural, necessary process that overcomes these and other errors of development and many spontaneous abortions involve embryos with chromosomal and other errors.)
In biological terms, haemophilia is a relatively mild mutation, compatible with life, and therefore can be passed on to the next generation. The fact that women have two X chromosomes and the defect only occurs in one, helps protect her against the otherwise certain death that would accompany childbirth or menstruation. There have been only two or three girls in the whole of medical history, who were the offspring of cousin marriages, who were unlucky enough to inherit two X chromosomes from both sides of the same family, each with the gene for haemophilia. They manifested the same symptoms as male haemophiliacs suffer and invariably died at puberty, when they began to menstruate.
In the nineteenth century the treatment of haemophilia was often even worse than the disease. Sometimes haemophiliac patients were bled deliberately, like everyone else. One haemophiliac died from the application of leeches, another from cupping and others from the deliberate opening of their veins. All too often in the history of medicine physicians have shown a tragic loyalty to current practices, as did the nineteenth-century surgeon who opened the knee joint of a haemophilic to let out the internal bleeding: not only did he kill that patient but he went on to try the same operation on another luckless victim, who also died. Even as late as 1894, the famous doctor William Osler, whom Victoria had knighted for his services to medicine, was still recommending blood-letting as a treatment for haemophilia.
Nevertheless, some early scientists did deduce that haemophiliacs must lack some special substance and therefore suggested blood transfusion as a treatment, not to replace blood lost by haemorrhage, but to make good whatever abnormality was preventing normal blood-clotting. Within three years of Queen Victoria’s coronation, and long before Leopold was born, Samuel Armstrong Lance, a London physician, treated a twelve-year old bleeder with a blood transfusion. However, the need to give a patient blood of their own group was not recognized in the nineteenth century so transfusion reactions usually frustrated treatment, and it was only from the 1930s that blood transfusion became a real option in treating haemophilia.
In the 1940s the constituent of normal blood that makes good the deficiency in a haemophiliac was isolated
and called anti-haemophiliac globulin. Nowadays, it is called Factor VIII – a name that underlines the many critical steps in the cascade of events involved in blood-clotting. It is a large molecule composed of hundreds of thousands of atoms, manufactured in the liver and passed into the bloodstream. A similar molecule is present in a haemophiliac’s blood but it must have some tiny abnormality that stops it working. Abnormalities in the way in which the atoms are arranged in large biological molecules are the cause of several diseases. For example, sickle cell anaemia, which afflicts some blacks, is caused by a difference of a few atoms in the haemoglobulin molecule that makes the molecules fold in an abnormal way, deforming red cells. Blood-clotting involves many steps and factors, so there are other forms of haemophilia apart from Factor VIII deficiency. Some of these rare forms of haemophilia are named after the doctor who described them, as in Von Willebrand’s disease, or after the patients in which they were first described, as in Christmas and Stuart disease.
In the 1950s and ’60s, through the work of Brinkhouse in Chapel Hill, North Carolina, and others, it became possible to concentrate Factor VIII in various ways, including freezing blood plasma. Factor VIII is easy to store and a haemophiliac can inject himself at home. Factor VIII can bring about a near-miracle in the life of a person with haemophilia and Russian history and world history might have been very different if Factor VIII had been available earlier in this century.
To secure enough Factor VIII to be effective, it must be extracted from literally thousands of blood donations – fortunately the blood remains perfectly usable after Factor VIII has been removed. However, in addition to concentrating Factor VIII, the process also pools some of the infections donors may have been carrying. In the early 1980s, when Aids first appeared and before the nature of the disease was understood, many doses of Factor VIII became infected with the human immunodeficiency virus – the cause of Aids. It was a cruel twist of fate and in many places the majority of people with haemophilia now carry the virus and more and more are dying of Aids. By the middle 1980s ways were devised to test for the Aids virus and Factor VIII is again safe to use. However, a great deal of damage occurred in the brief years when the spread of the disease was not understood. Some school-age haemophiliacs with the Aids virus have been treated as lepers in their own communities, even though they pose no danger of infection to others. On very rare occasions infected haemophiliacs passed the disease unknowingly to their wives through sexual intercourse and then, when pregnancy supervenes, there is also a risk that the virus may be transmitted to the infant.
It is now possible to make Factor VIII without having to collect it from blood plasma. This is done by genetic engineering – the practice of isolating critical sections of the DNA message and programming cultured mammalian cells or bacteria to produce the associated unique proteins. At first sight it would seem an almost unachievably complex task but bacteria and even human cells can be grown by the billion in the laboratory, and techniques are being developed to select out desired characteristics. Now, although haemophilia has not been cured, the ways of helping those who suffer from this unhappy disease have improved to the point where they may lead an almost normal life.
It is also now possible to find out whether or not a woman is a carrier. If she only has one X chromosome making Factor VIII she has measurably less in her blood. Women from haemophiliac families who may be carriers can now be advised on their chances of passing the disease on to their children. It is also possible that quite soon screening of pregnant women at risk as carriers will become common. It is already possible in the laboratory to identify genes associated with haemophilia from foetal cells collected in the tenth week of pregnancy, and ante-natal testing is likely to become easier with the passage of time. Women who carry the gene will then be able, if they wish, to abort any offspring with haemophilia, or who are carriers of the disease.
However, modern scientific insights also prompt some questions about the past: where did Queen Victoria’s gene come from?
SIX
MUTATION OR BASTARD?
Haemophilia is a dramatic, easily identified, lifelong affliction. The history of the royal houses of Europe is recorded in meticulous detail, both in public records and in innumerable pages of gossip found in private letters, magazines and newspapers. The course of the gene in Victoria’s descendants is easily traced; its origin is much more obscure. The Duke of Kent’s history is well documented and, whatever his defects, he was certainly not a haemophiliac. The gene Victoria transmitted has several possible origins. Her mother, Victoire, might have been a carrier herself; it might have arisen as a new mutation in Victoire; it might have been inherited from a haemophiliac father who was not the Duke of Kent; or the mutation might have occurred in the X chromosome of the Duke of Kent. These explanations will be examined in turn. The gene could not have come from the Prince Consort Albert as haemophiliac fathers cannot have haemophiliac sons, yet Leopold, Victoria’s youngest son, was a haemophiliac.
Was Victoire a carrier? Victoire had a son and daughter by her first marriage. The son was normal but Victoire could still have been a carrier, in which case one might expect to find cases of haemophilia among her ancestors. Her family tree on her mother’s side has been put together in exceptional detail and a deliberate search has been made for haemophilia. The relevant data still exists, although in an unpublished form. The story of why the work was done and how it has survived is an odd byway in medical history.
The writings of Darwin and speculation about the reasons for the different achievements of various groups of people stimulated an intense interest in all aspects of human heredity. Francis Galton, Charles Darwin’s first cousin, was a prolific writer and thinker in the area he called eugenics – ‘The science which deals with all influences that improve the inborn qualities of a race’. Galton played a leading role in demonstrating that each person has a unique pattern of fingerprints, and he was the first person to study identical and non-identical twins as a way of unravelling hereditary from environmental influences. One of his more original researches was into the efficacy of prayer, arguing that as the monarch and archbishops were prayed for every day in church, then if prayer were efficacious they should live longer than the average citizen. Galton’s statistical analysis showed that they did not. One of the first products of the Eugenics Society was a series entitled ‘Treasury of Human Inheritance’ and in 1911 William Bullock and Paul Fildes brought out the first volume, Haemophilia.1 Bullock and Fildes surveyed every article they could find on haemophilia from Britain, continental Europe and the United States and produced numerous well-documented family trees setting out the inheritance of the disease.
Queen Victoria is not mentioned in the Treasury volume, but her case was too obvious to miss and Bullock spent a great deal of time in private producing a handwritten genealogy that traces Queen Victoria’s mother’s ancestry back over eight generations. It is written in Indian ink in Bullock’s careful, round hand, on two linen scrolls 7 ft 6 in long, attached to 5 ft 6 in wooden rollers. We found these tied with red tape, and housed in a carefully morticed wooden box kept on the top shelf of the librarian’s office of the Royal Society of Medicine Library in Wimpole Street, London. The scrolls are unsigned but we checked the handwriting against letters and manuscripts signed by Bullock now in the Eugenic Society papers in the Wellcome History of Medicine Library in London. The first scroll carries the names of about 500 individuals. Victoire, Victoria and Victoria’s descendants are listed and the haemophiliacs and haemophilia carriers clearly marked.
If Queen Victoria’s mother had carried the haemophilia gene then her son, Charles, by her first marriage to the Prince of Leiningen, would have had a 50 per cent chance of manifesting the disease. Charles (1804–56) was a normal, healthy male. Her daughter, Feodora (1807–72), who would have a 50 per cent chance of being a carrier, married Ernest IV, Prince of Hohenlohe Langenburg, and had five children. None of the three sons of this second generation – Charles (born
1829), Herman (born 1832) and Victor (born 1833) – showed any signs of haemophilia. There is still a chance that Feodora might have inherited the gene and passed it to Victoire’s granddaughters, Adelheid (born 1835) and Feodora (born 1839). Adelheid married Frederick, Duke of Holstein (1829–80) and bore him four daughters and three sons. The eldest daughter, Augusta (born 1858), married into the German royal family, becoming the wife of Kaiser Wilhelm, of whom more later. The second child, Caroline Matilda (born 1860) married a duke of Holstein and a third daughter, Louise Sophie (born 1866), a duke of Prussia. The last daughter, yet another Feodora, died in infancy in 1874. Caroline was to have nine children, yet again no trace of haemophilia is apparent in any of her children or grandchildren, now four and five generations removed from Victoire. Two of Adelheid’s sons, Ernest Bernhard and Frederick, grew to be healthy adults, while Ernst Gunther died in infancy, although there is no suggestion that haemophilia was the cause. Finally, Victoire’s youngest granddaughter, Adelheid’s sister Feodora, the last child of Feodora and Ernest (born 1839), had two healthy sons.
In short, Queen Victoria’s half-brother and -sister did not carry the haemophilia gene. Of course, with a 50 per cent chance of each carrying the disease, there is a one in four possibility that they might have escaped even if their mother did carry it. While the gene was not present in Victoria’s half-sister and half-brother, what of her mother’s antecedents?