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Transcript
Journal of Heredity 2011:102(5):640–641 Ó The American Genetic Association. 2011. All rights reserved. For permissions, please email: [email protected]. Book Review Thalassaemia: The Biography David Weatherall New York: Oxford University Press, 2010. 247 pp. Hardback, $24.95. ISBN: 9780199565603 As book review editor for the Journal of Heredity, a number of books cross my desk. My concern regarding any particular book is whether our readership would find it relevant to their interests and research programs. My first inclination on seeing the main title of this work, Thalassaemia, was not to review it since we publish very few articles on human genetics. But then I saw the subtitle. What an interesting idea—writing a biography of a disease. Sir David Weatherall, founder of the Institute of Molecular Medicine at Oxford, has been associated with research on the group of genetic blood disorders labeled thalassemia for over half a century. He begins this book describing his own first thalassemia patient, a Nepalese girl named Jaspir Thapa, whom he encountered when a young doctor in Singapore in the 1950s. He follows his personal story with a history of the discovery of the disease, first called Cooley’s anemia, and includes a charming description of how the disease got its name. He explains the various mutant phenotypes associated with the disorder, which result in symptoms ranging in severity from mild anemia to bone deformities, enlarged spleens, and the need for lifelong blood transfusions. Chapters 2–4 proceed through the chronology of beginning to understand the disease’s genetic basis, narrowing its cause to problems in hemoglobin production, and elucidating the biochemical pathways of defective hemoglobin synthesis. Thalassemia was first described as common in people from the countries surrounding the Mediterranean Sea. It would later be recognized in sub-Saharan Africa and Southeast Asia—Jaspir was possibly the first patient identified from the latter region. The prevalence of Mediterranean thalassemia patients prompted J. B. S. Haldane in 1948 to propose that malaria was the selective agent responsible for high frequencies of thalassemic mutant alleles, through a heterozygote advantage in resistance to infection. A. C. Allison later showed that for the related blood disorder, sickle cell anemia, heterozygotes have lower levels of parasites in their blood and, when inoculated with the parasites, are less frequently infected than normal individuals. The malarial hypothesis became part of the ‘‘dogma’’ of evolutionary biologists in the 1950s. T. G. Dobzhansky’s vision of populations was that genetic variation was extensive in natural populations and part of ‘‘coadapted gene complexes’’ maintained by balancing selection. The overdominance associated with globin mutant alleles, however, may be the only example in animal 640 populations where heterozygotes are the fittest genotype. More recent studies indicate that populations are highly variable due to directional selection for the increase and eventual fixation of advantageous alleles. In addition, neutral alleles and variants can be fixed by genetic drift or by hitchhiking when linked to a selectively advantageous allele. Genetic studies of thalassemia in the 1950s–1960s, in conjunction with the development of gel electrophoresis, revealed that the condition is caused by defects in the structure or production of either a- or b-globin chains. The best-known hemoglobin disease, sickle cell anemia, is due to an amino acid substitution in the adult b chain. Several notable geneticists and biochemists contributed to the early understanding of the association between thalassemia and abnormal hemoglobins, notably Linus Pauling, Max Perutz, and Vernon Ingram. Ingram was the first to propose the alpha and beta classes of thalassemias. Chapter 5, The molecular era and the birth of molecular medicine, is to me the best part of this book. Here, Sir David documents a lockstep between sequential advances in molecular genetics and our understanding of the molecular basis of the mutations causing thalassemia. For example, incorporation of radiolabeled amino acids in reticulocytes allowed Weatherall and his colleague, J. B. Clegg, to measure a- and b-chain synthesis in normal and thalassemic patients. Later, cDNAs were used to measure levels of globin mRNAs in various patients. With the arrival of restriction enzymes, Southern blotting, and cloning, the various a- and b-chain genes could be mapped with increasing accuracy. Haplotype analyses could determine the frequency of specific mutant alleles. Finally, DNA sequencing allowed molecular lesions to be definitively characterized. Despite successes in defining the molecular basis for the thalassemias, Sir David leaves us with 2 important caveats. First, no disease, even one caused by single mutant alleles, is simple. Pleiotropy and genetic modifiers will confuse the situation to various extents in different pedigrees. Examples abound in this book of these culprits causing clinical diversity in allelically identical patients, often involving changes in the levels of other globin chains. The second caveat is more serious. Sir David describes quite eloquently the evolution of therapeutic methods concurrent with development of the molecular techniques that led to precise identification of the mutant alleles. In doing so, however, he finds a dichotomy between the ability to provide precise molecular information and the provision of truly effective methods of treatment. Blood transfusion, for decades, was the only treatment available, followed by the administration of iron-chelating agents and spleen removal. Early applications of prenatal diagnostic methods led to population-based attempts at eugenics to reduce the frequency of thalassemia. Interestingly, one such attempt on Book Review Sardinia produced promising results. In recent years, less intrusive methods of prenatal diagnosis have used more precise DNA-based technologies. Bone marrow transplantation can be a cure but can only be considered in the most severe cases; it requires donor cells from a perfect match and is a risky and costly procedure. Ultimately, gene therapy may prove the best hope for a permanent solution to the problem of thalassemia, but vectors and effective delivery methods have yet to be developed. The disconnect between precise molecular characterization of cause and imprecise methods of treatment is, according to Sir David, really due to unrealistic expectations about the promise of molecular medicine. He asks, ‘‘has molecular medicine improved the lot of patients?’’ With regard to thalassemia, I think the answer is yes, certainly with prenatal diagnosis and possibly in the future with gene therapy. But Sir David cites other disorders, including cystic fibrosis, heart disease, and diabetes, where knowledge of mutations has had no effect on clinical treatment. He concludes: ‘‘Historians of the future will also want to understand why the time scale for the medical applications for the human genome project was so wildly underestimated and, incidentally, the effect that this may have had on the direction of medical science in subsequent years. There is no doubt that the successful completion of the human genome project was one of the most remarkable achievements in the biological sciences. But the degree of hyperbole about its potential for altering the whole pattern of medical practice was out of all proportion.’’ Given his memories of Jaspir Thapa and his obvious concern for all patients suffering from thalassemia, one can hardly blame Sir David for his impatience with the progress of molecular medicine. ROSS MACINTYRE Molecular Ecology & Genetics, Cornell University Ithaca, NY 14853 doi:10.1093/jhered/esr032 641