The future role of molecular and cell biology in medical practice in the tropical countries David Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK Downloaded from https://academic.oup.com/bmb/article/54/2/489/285007 by guest on 27 September 2021 Molecular and cell biology have a great deal to offer tropical medicine in the future. As well as helping to understand the population genetics and dynamics of both infectious and non-infectious diseases, they promise to provide a new generation of diagnostic and therapeutic agents, and to play a major role in the development of new vaccines and other approaches to the control of disease in tropical communities. Over the last 20 years there has been a gradual shift in the emphasis of basic biomedical research from the study of disease in patients and their organs to its definition at the level of molecules and cells. This new trend has been underpinned by a remarkable new technology which has made it possible to isolate and sequence genes, study their function and transfer them across the species barrier. In the short time during which this field has evolved, a great deal has been discovered about human pathology at the molecular level. Many monogenic diseases have been characterised, much has been learnt about the molecular and cell biology of cancer, and a start has been made in defining the different genes that comprise the complex interactions between nature and nurture that underlie many of the major killers of Western society. Enough is known already to suggest that this knowledge will have major implications for the development of more precise diagnostic and therapeutic agents in the future. There is little doubt that tropical medicine will benefit from this new technology, particularly as the demography of disease changes in emerging countries. The World Health Organization have predicted that by the year 2020 there will be a major shift in the pattern of disease1. As social conditions and standards of hygiene and nutrition improve, there Correspondence to: will be a gradual decline in infant and childhood mortality due to Professor Sir David infectious disease. On the other hand, it is predicted that there will be a Weatherall, Institute of steady increase in diseases of 'Westernisation', including heart disease, Molecular Medicine. diabetes, other forms of vascular disease, and the major psychoses. It is University of Oxford, John Radcliffe Hospital, already apparent from the epidemic of insulin-resistant diabetes that is Oxford OX2 9DS, UK affecting many of these countries, that populations respond in quite British Medical Bulletin 1998;54 (No. 2): 489-501 C The British Council 1998 Tropical medicine: achievements and prospects different ways to the introduction of high energy diets2. Though it is likely that both environmental and genetic factors are involved, there is increasing evidence that inheritance may play an important role in these different responses. It is important, therefore, that medical practice in the tropics prepares itself for the remarkable possibilities that the rapidly moving sciences of molecular and cell biology will have to offer it in the future. This has Downloaded from https://academic.oup.com/bmb/article/54/2/489/285007 by guest on 27 September 2021 particular implications for medical education; specialists in the field will have to be able to communicate with those working in the basic sciences so that their technology can be adapted most effectively for the benefit of the health of communities in the tropical world. Technical advances The application of molecular and cell biology to the study of human disease, or molecular medicine as it is rather optimistically called, has developed on the back of the technical advances of molecular biology3'4. One of the first was the discovery of how to isolate DNA and to cut it up into pieces of different sizes using restriction endonucleases, that is enzymes isolated from various bacteria that will slice DNA at predictable sequences of nucleotide bases. An early and quite seminal advance in the application of this approach to human pathology was called Southern blotting after the name of its inventor, Edwin Southern. In this technique restriction enzyme digests of DNA are separated into different sized fragments by electrophoresis in gels and then simply blotted onto nitrocellulose filters on which they can be immobilised. By constructing radioactive probes to hunt for particular genes on these filters it was possible to analyse potential disease loci for major deletions or re-arrangements of the particular genes involved. / It soon became possible to take mixtures of restricted DNA and to insert the different fragments into bacterial plasmids or other 'foreign' DNA vectors. This was the beginning of the era of recombinant DNA technology. The inserted DNA could be grown in bacteria and, hence, it became possible to construct libraries containing most of the human genome from which it was possible to isolate any gene of interest. Methods were soon developed for rapid sequencing of DNA and hence it became feasible to define the precise mutations in many single gene disorders. And by carrying out genetic linkage studies using highly variable regions of DNA as markers to pinpoint genes for diseases of unknown cause, and to deduce the function of their products from their sequence, a technique called 'reverse genetics', it became possible to characterise the molecular pathology of many common monogenic disorders of unknown cause. 490 British Medical Bulletin 1998,54 (No. 2) Future role of molecular and cell biology The next important step was to take isolated human genes and persuade them to function, either in cultured cells or in laboratory animals. This made it possible to learn about the major regulatory regions that are involved in ensuring that genes are expressed in the correct tissues at the right stages of development and at an appropriate level. Furthermore, as methods for sequencing genes became more efficient and were automated it became clear that it would be possible Downloaded from https://academic.oup.com/bmb/article/54/2/489/285007 by guest on 27 September 2021 to determine the complete sequence of the genome of any organism. Currently, this has already been achieved in the case of some bacteria and varieties of yeast, and the Human Genome Project, that is the determination of the complete sequence of the DNA of a human being, is well on course for completion early in the next millennium. Although the full benefits of this field for the improvement of health may not be evident for many years, and particularly until new developments in biomathematics and computer technology help us to understand how all our genes are orchestrated to subserve the complex metabolic functions of intact cells, organs, and whole organisms, there is no doubt that along the way there will be a steady accumulation of information that will make a major impact on tropical medicine. It is beyond the scope of this brief review to describe all these possibilities and hence I shall simply summarise a few that are already well advanced and try to predict some of the more important possibilities in the future. Molecular genetics in the tropics Single gene disorders Although many diseases are inherited in a simple Mendelian pattern, and are seen in every part of the world, most of them occur at a very low frequency which probably reflects the mutation rate. However, there are a few groups of genetic disorders which occur much more commonly and which will pose an important public health problem in the future. There is increasing evidence that they have reached their high frequency in many tropical countries by natural selection, reflecting heterozygote advantage against different forms of malaria. It is probably through this mechanism that the inherited disorders of haemoglobin have become the commonest human monogenic diseases5 Human adult haemoglobin consists of two pairs of a chains and two pairs of P chains (<x,P2). The a and P globin chains are controlled by a and P globin gene families which reside on chromosomes 16 and 11, respectively. There are two classes of mutations at these gene loci. First there are the structural haemoglobin variants, which result from single British Medical Bulletin 1998;54 (No. 2) 491 Tropical medicine: achievements and prospects amino acid substitutions or other structural alterations in the a or P globin chains. The second and more common disorders are those due to a reduced rate of synthesis of the a or P globin chains, the a and P thalassaemias. Studies at the molecular level have led to a broad understanding of the structure and regulation of the globin genes and of the molecular pathology of both the structural variants and the 5 thalassaemias . Downloaded from https://academic.oup.com/bmb/article/54/2/489/285007 by guest on 27 September 2021 Although several hundred structural haemoglobin variants have been described only three, haemoglobins S, C and E, reach very high frequencies in some tropical countries. The homozygous state for the sickle cell gene, sickle cell anaemia, is a major cause of childhood morbidity and mortality in sub-Saharan Africa, the Mediterranean region, the Middle East and in parts of India5. It also occurs frequently in countries with large African immigrant populations. Although much remains to be learnt about the mechanisms of sickling and the reasons for the remarkable clinical heterogeneity of sickle cell anaemia, considerable progress has been made towards its better management and prevention from research at the molecular and cellular level6. Haemoglobin E reaches very high frequencies throughout Bangladesh, Burma, and in many countries in southeast Asia. Although its homozygous state is characterised by a mild hypochromic anaemia, because it is synthesised at a reduced rate, when inherited together with P thalassaemia it often produces a crippling thalassaemic disorder.