The population genetics and dynamics of the thalassemias.

The inherited disorders of hemoglobin, including the thalassemias, are by far the commonest monogenic diseases. Although several factors are responsible for their very high frequency, the major mechanism seems to be natural selection mediated by heterozygote protection against severe forms of malaria. Recent work has highlighted the complexity of the interplay among the different hemoglobin variants themselves and among different levels of malaria resistance, and is helping to explain the extraordinary heterogeneity in the distribution of the hemoglobin disorders even within short geographical distances. Some progress has also been made toward understanding the cellular and immune mechanisms that may underlie heterozygote protection against malaria in these conditions. In addition to providing valuable information about human evolutionary biology, work in this field has an increasingly important influence on the development of programs for the better management of the hemoglobin disorders, particularly in the poorer countries of the tropical world.

Molecular medicine; the road to the better integration of the medical sciences in the twenty-first century.

The history of the evolution of medical research is characterized by a long period of division between the basic biological sciences and the health sciences, reflecting the seventeenth-century trends towards the experimental and the empirical. It was not until the middle of the twentieth century that, by their ability to straddle both worlds, the work of small groups of basic scientists in the U.S.A. and Europe led to closer integration between the medical sciences. This change in direction is well exemplified by the work of the Cambridge scientists Max Perutz, Vernon Ingram and Herman Lehmann, from 1950 onwards. Their research, and its later development by others, was to lay the basis for what became known as 'molecular medicine', and at the same time set the scene for a more integrated approach to medical research that continued into the new millennium.

Thalassemia as a global health problem: recent progress toward its control in the developing countries.

The thalassemias, together with sickle cell anemia and its variants, are by far the most common monogenic diseases. They occur at their highest frequency in countries of the developing world where their control and management is hampered by a lack of knowledge of their true prevalence, adequate services for their management and control, and support by their governments and international health agencies. However, there has been some progress recently in addressing these problems and there are several ways in which the lot of children with thalassemia in poor countries could be improved in the future. Over the last 20 years there has been considerable improvement in the control and management of the thalassemias in the richer countries of the world. Unfortunately, however, this is not the case for many of the developing countries, where there have been few improvements in the control of the numbers of births of babies with thalassemia or in the care of thalassemic children since the frequency of the problem started to become evident in the 1960s. Here, I will try to assess the current situation in these countries and examine some of the potential approaches for improving the current situation.

Interaction of malaria with a common form of severe thalassemia in an Asian population.

In many Asian populations, the commonest form of severe thalassemia results from the coinheritance of HbE and beta thalassemia. The management of this disease is particularly difficult because of its extreme clinical diversity; although some genetic and adaptive factors have been identified as phenotypic modifiers, the reasons remain unclear. Because the role of the environment in the course of severe thalassemia has been neglected completely and because malaria due to both Plasmodium falciparum and Plasmodium vivax has been prevalent in Sri Lanka, we carried out a pilot study of patients with HbE beta thalassemia that showed high frequencies of antibodies to both parasite species and that 28.6% of the children had DNA-based evidence of current infection with P. vivax. Malarial antibodies then were assessed in patients with HbE beta thalassemia compared with those in age-matched controls. There was a significant increase in the frequency of antibodies in the thalassemic patients, particularly against P. vivax and in young children. There was also a higher frequency in those who had been splenectomized compared with those with intact spleens, although in the latter it was still higher than that in the controls. The thalassemic patients showed significant correlations between malaria antibody status and phenotype. Patients with HbE beta thalassemia may be more prone to malaria, particularly P. vivax, which is reflected in their clinical severity. Because P. vivax malaria is widespread in Asia, further studies of its interaction with HbE beta thalassemia and related diseases are required urgently as a part of ongoing thalassemia control programs.

The alpha thalassaemias.

Recent work in the alpha thalassaemia field has started to provide some indication of the mechanisms involved in the very high frequency of the different forms of alpha thalassaemia among the populations of tropical countries, and, at the same time, is starting to define at least some of the mechanisms for its remarkable phenotypic heterogeneity. These diseases continue to provide extremely valuable models for the better understanding of the regulation of the alpha globin genes, and for human molecular pathology in general. The much less common disorders, ATR-16 and ATR-X are also providing valuable information about the spectrum of molecular lesions associated with different forms of mental retardation and about the molecular mechanisms involved in their varying phenotypes.

Recent insights into the population genetics and dynamics of the inherited disorders of hemoglobin.

The inherited disorders of hemoglobin are by far the commonest monogenic diseases and there is considerable evidence that they have reached their very high frequencies due to heterozygote advantage against malaria. Recent studies have begun to clarify the effect of interactions between malaria and some of the more severe inherited hemoglobin disorders and demonstrated how complex epistatic interactions between different hemoglobin variants with respect to malaria resistance and modification of their phenotypic severity may explain the remarkable heterogeneity of distribution and the frequency of these conditions both between and within individual populations.

Genetic variation and susceptibility to infection: the red cell and malaria.

There is now convincing evidence that the extremely high frequencies of certain genetic disorders of the red cell involving haemoglobin, the red-cell membrane, or its metabolic pathways reflect relative resistance to malaria over thousands of years. At least some progress has been made towards an understanding of the cellular mechanisms involved, although much remains to be learnt. As well as the extremely valuable information that this field is providing about how exposure to infection has moulded the current structure of the human genome, recent research in this field is starting to provide some valuable new approaches to the better control of parasitic and other infections that remain a major global health problem.

Is the beta thalassaemia trait of clinical importance?

Although the beta thalassaemia trait affects millions of people worldwide, there have been no controlled studies to determine whether it is associated with any clinical disability or abnormal physical signs. To address this question, 402 individuals were studied: 217 with beta thalassaemia trait, of whom 154 were aware of the diagnosis and 63 were unaware until after the completion of the study; 89 normal controls; and 96 controls with mild hypochromic anaemia. There was a significant increase in symptoms ascribable to anaemia and episodes of pyrexia in those with the beta thalassaemia trait that were not influenced by prior knowledge that they had this condition. There was no difference in physical findings, notably splenomegaly, between those with beta thalassaemia trait and either control group.

Age-related changes in adaptation to severe anemia in childhood in developing countries.

Severe forms of anemia in children in the developing countries may be characterized by different clinical manifestations at particular stages of development. Whether this reflects developmental changes in adaptation to anemia or other mechanisms is not clear. The pattern of adaptation to anemia has been assessed in 110 individuals with hemoglobin (Hb) E beta-thalassemia, one of the commonest forms of inherited anemia in Asia. It has been found that age and Hb levels are independent variables with respect to erythropoietin response and that there is a decline in the latter at a similar degree of anemia during development. To determine whether this finding is applicable to anemia due to other causes, a similar study has been carried out on 279 children with severe anemia due to Plasmodium falciparum malaria; the results were similar to those in the patients with thalassemia. These observations may have important implications both for the better understanding of the pathophysiology of profound anemia in early life and for its more logical and cost-effective management.

Alpha+ -thalassaemia and pregnancy in a malaria endemic region of Papua New Guinea.

The effect of maternal alpha+ -thalassaemia on pregnancy was assessed in the north coastal region of Papua New Guinea (PNG), where malaria is hyperendemic and alpha+ -thalassaemia is extremely common. In a prospective study of 987 singleton hospital deliveries, we correlated maternal alpha-globin genotype with markers of reproductive fitness (age in primigravidae, gravidity, pregnancy interval and the number of miscarriages and stillbirths), Plasmodium falciparum(P. falciparum) infection of the mother and placenta, maternal haemoglobin, preterm delivery and birthweight. The frequency of the -alpha genotype in mothers was 0.61. Markers of reproductive fitness were similar in women with and without alpha+ -thalassaemia. Median haemoglobin concentration during pregnancy and after delivery was about 1.0 g/dl lower in homozygous alpha+ -thalassaemia than in women with a normal alpha- globin genotype (P < or = 0.001). The frequency of placental P. falciparum infection and systemic malaria infection after delivery showed no consistent relationship to alpha-globin genotype. The frequency of preterm delivery and low birthweight did not vary significantly according to maternal alpha-globin genotype. Maternal alpha+ -thalassaemia does not affect reproductive fitness or susceptibility to malaria during pregnancy. Although median haemoglobin concentration was significantly lower in mothers homozygous for alpha+ -thalassaemia than those with a normal alpha-globin genotype, this did not result in an adverse outcome of pregnancy.

Muscle cell injury, haemolysis and dark urine in children with falciparum malaria in Papua New Guinea.

During a prospective study of red cell variants and severe malaria in children, a surprising observation was the occurrence of dark urine. Children were grouped according to urine findings: 22 had dark urine that contained a haem protein (Group I), 93 had urine of normal colour that contained a haem protein (Group II) and 236 had normal urine (Group III). To investigate the cause of dark urine, haemolysis and muscle cell injury were assessed. Intravascular haemolysis was greater in Group I than in Groups II and III. However, anaemia was more severe in Group III and is likely to have resulted mainly from extravascular haemolysis. Median plasma myoglobin concentrations were greater in Groups I and II than Group III (P = 0.00060). Plasma myoglobin was greater in children with cerebral malaria, hyperlactataemia and those who died but was not associated with acidosis. Urine myoglobin was greater in Group I than Groups II and III (P = 0.00054). It is likely that both haemoglobin and myoglobin contributed to dark urine. The association between muscle cell injury and coma suggests sequestration of parasitized red cells as a common underlying pathology. In malaria, hyperlactataemia may result directly from breakdown of muscle protein as well as tissue hypoxia.

Phenotype/genotype relationships in sickle cell disease: a pilot twin study.

The roles of genetic and non-genetic factors in the haematology, growth and clinical features of sickle cell disease have been studied in nine identical twin pairs (six homozygous sickle cell disease, three sickle cell-haemoglobin C disease). A comparison group of 350 age-gender matched sibling pairs, selected to have an age difference of <5 years, was used for assessing the concordance of numerical data. Attained height, weight at attained height, fetal haemoglobin, total haemoglobin, mean cell volume, mean cell haemoglobin and total bilirubin levels showed significantly greater correlation in identical twins than in siblings. Twins showed similarities in the prevalence and degree of splenomegaly, susceptibility to priapism, and in onset of menarche, but other clinical complications were discordant in prevalence and severity. These findings suggest that physical growth and many haematological characteristics are subject to genetic influences, but that non-genetic factors contribute to the variance in disease manifestations.