Prof Sir David Weatherall KBE FRS FMedSci

Research Area: Global Health
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The world distribution of the Thalassaemias

The world distribution of the Thalassaemias

The original transfusion ward catering for over 700 children with Thalassaemia in Kurunegala, Sri Lanka.  With the help of the Wellcome Trust this has now been replaced by a modern, three-storey Treatment Centre

The original transfusion ward catering for over 700 children with Thalassaemia in Kurunegala, Sri ...

The major research areas include the genetic, adaptive and environmental factors that modify the phenotype of common forms of thalasaemia in Asia, notably HbE beta thalassaemia, the population genetics of the thalassaemis with particular respect to varying susceptibility to malaria, and the development of partnerships between countries with and without expertise for the improved avoidance and management of the thalassaemias in Asian countries.

Receiving the Wallace H. Coulter Award in 2013

There are no collaborations listed for this principal investigator.

Hay D, Hatton CSR, Weatherall DJ. 2017. The future of academic haematology. Br J Haematol, 176 (5), pp. 721-727. | Show Abstract | Read more

Recent advances in the basic medical sciences, particularly cell biology and genomics, have great promise for the future development of all aspects of haematological practice. They will also impinge on the hitherto neglected fields of haematology, including haematology involving the care of the rapidly increasing number of elderly patients and the complex problems of haematological practice in the developing countries. To obtain the maximum benefit from these new developments it will be necessary to review the patterns of training of haematologists of the future at every level. In short, it will be important to try to design and develop various career pathways for training haematologists including those who wish to work full time in basic research, combine research with clinical practice, or commit all their time to clinical work and teaching.

Wray K, Allen A, Evans E, Fisher C, Premawardhena A, Perera L, Rodrigo R, Goonathilaka G, Ramees L, Webster C et al. 2017. Hepcidin detects iron deficiency in Sri Lankan adolescents with a high burden of hemoglobinopathy: A diagnostic test accuracy study. Am J Hematol, 92 (2), pp. 196-203. | Show Abstract | Read more

Anemia affects over 800 million women and children globally. Measurement of hepcidin as an index of iron status shows promise, but its diagnostic performance where hemoglobinopathies are prevalent is unclear. We evaluated the performance of hepcidin as a diagnostic test of iron deficiency in adolescents across Sri Lanka. We selected 2273 samples from a nationally representative cross-sectional study of 7526 secondary schoolchildren across Sri Lanka and analyzed associations between hepcidin and participant characteristics, iron indices, inflammatory markers, and hemoglobinopathy states. We evaluated the diagnostic accuracy of hepcidin as a test for iron deficiency with estimation of the AUCROC, sensitivity/specificity at each hepcidin cutoff, and calculation of the Youden Index to find the optimal threshold. Hepcidin was associated with ferritin, sTfR, and hemoglobin. The AUCROCfor hepcidin as a test of iron deficiency was 0.78; hepcidin outperformed Hb and sTfR. The Youden index-predicted cutoff to detect iron deficiency (3.2 ng/mL) was similar to thresholds previously identified to predict iron utilization and identify deficiency in African populations. Neither age, sex, nor α- or β-thalassemia trait affected diagnostic properties of hepcidin. Hepcidin pre-screening would prevent most iron-replete thalassemia carriers from receiving iron whilst still ensuring most iron deficient children were supplemented. Our data indicate that the physiological relationship between hepcidin and iron status transcends specific populations. Measurement of hepcidin in individuals or populations could establish the need for iron interventions. Am. J. Hematol. 92:196-203, 2017. © 2016 Wiley Periodicals, Inc.

Roberts DJ, Weatherall DJ. 2016. Global Hematology. Hematol Oncol Clin North Am, 30 (2), pp. xiii-xiv. | Read more

Roberts DJ, Weatherall DJ. 2016. Introduction: The Complexity and Challenge of Preventing, Treating, and Managing Blood Diseases in the Developing Countries. Hematol Oncol Clin North Am, 30 (2), pp. 233-246. | Show Abstract | Read more

Managing hematologic disorders in developing countries poses problems not encountered in Western societies. The clinical features of hematologic conditions may be modified by malnutrition, chronic bacterial infection, or parasitic illness. Iron deficiency is the major factor in anemia worldwide. Anemia is more common in the wet season when malaria transmission peaks. After anemia, eosinophilia is the next most common hematologic abnormality in children in the tropics. Infection with the human immunodeficiency virus can cause hematologic abnormalities. The pattern of distribution of primary disorders of the blood varies among populations and some disorders are unique to certain parts of the world.

Fucharoen S, Weatherall DJ. 2016. Progress Toward the Control and Management of the Thalassemias. Hematol Oncol Clin North Am, 30 (2), pp. 359-371. | Show Abstract | Read more

Because of the particularly high frequency of different severe forms of both α and β thalassemia in Asia, the development of approaches for their prevention and management is particularly challenging. However, because of earlier partnerships with richer countries, so-called North/South partnerships, and help from their governments, considerable progress toward the better control of the thalassemias has been achieved in some countries. It is vital that the global health importance of the thalassemias and related disorders, by far the commonest genetic diseases, is emphasized to the appropriate international health agencies.

Piel FB, Weatherall DJ. 2015. Sickle-cell disease: a call to action. Trans R Soc Trop Med Hyg, 109 (6), pp. 355-356. | Read more

Perera PS, Silva I, Hapugoda M, Wickramarathne MN, Wijesiriwardena I, Efremov DG, Fisher CA, Weatherall DJ, Premawardhena A. 2015. Rare hemoglobin variants: Hb G-Szuhu (HBB: c.243C>G), Hb G-Coushatta (HBB: c.68A>C) and Hb Mizuho (HBB: c.206T>C) in Sri Lankan families. Hemoglobin, 39 (1), pp. 62-65. | Show Abstract | Read more

In this short communication, we describe the clinical presentation of unusual hemoglobin (Hb), variants in three Sri Lankan cases under study for β-thalassemia intermedia (β-TI). We believe this is the first report on their occurrence in Sri Lanka as well as from the Indian subcontinent. During a molecular study performed on β-TI patients, we identified three unusual Hb variants as Hb G-Szuhu (HBB: c.243C>G), Hb G-Coushatta (HBB: c.68A>C) and Hb Mizuho (HBB: c.206T>C) in three unrelated families. Hb G-Szuhu and Hb G-Coushatta were found in combination with the common β-thalassemia (β-thal) mutation, IVS-I-5 (G>C). Both probands had mild anemia with greatly reduced red cell indices and had non palpable livers and spleens, however, by ultrasound, both were observed to be enlarged. The final Hb variant, Hb Mizuho, was identified as a heterozygous mutation found in both proband and his mother. Both family members had severe anemia and were regularly transfused and had increased red cell parameters.

Weatherall DJ. 2015. Is medical research in danger of suffering the same fate as the NHS? QJM, 108 (7), pp. 519-522. | Read more

Jones E, Pasricha S-R, Allen A, Evans P, Fisher CA, Wray K, Premawardhena A, Bandara D, Perera A, Webster C et al. 2015. Hepcidin is suppressed by erythropoiesis in hemoglobin E β-thalassemia and β-thalassemia trait. Blood, 125 (5), pp. 873-880. | Show Abstract | Read more

Hemoglobin E (HbE) β-thalassemia is the most common severe thalassemia syndrome across Asia, and millions of people are carriers. Clinical heterogeneity in HbE β-thalassemia is incompletely explained by genotype, and the interaction of phenotypic variation with hepcidin is unknown. The effect of thalassemia carriage on hepcidin is also unknown, but it could be relevant for iron supplementation programs aimed at combating anemia. In 62 of 69 Sri Lankan patients with HbE β-thalassemia with moderate or severe phenotype, hepcidin was suppressed, and overall hepcidin inversely correlated with iron accumulation. On segregating by phenotype, there were no differences in hepcidin, erythropoiesis, or hemoglobin between severe or moderate disease, but multiple linear regression showed that erythropoiesis inversely correlated with hepcidin only in severe phenotypes. In moderate disease, no independent predictors of hepcidin were identifiable; nevertheless, the low hepcidin levels indicate a significant risk for iron overload. In a population survey of Sri Lankan schoolchildren, β-thalassemia (but not HbE) trait was associated with increased erythropoiesis and mildly suppressed hepcidin, suggesting an enhanced propensity to accumulate iron. In summary, the influence of erythropoiesis on hepcidin suppression associates with phenotypic disease variation and pathogenesis in HbE β-thalassemia and indicates that the epidemiology of β-thalassemia trait requires consideration when planning public health iron interventions.

Penman BS, Gupta S, Weatherall DJ. 2015. Epistasis and the sensitivity of phenotypic screens for beta thalassaemia. Br J Haematol, 169 (1), pp. 117-128. | Show Abstract | Read more

Genetic disorders of haemoglobin, particularly the sickle cell diseases and the alpha and beta thalassaemias, are the commonest inherited disorders worldwide. The majority of affected births occur in low-income and lower-middle income countries. Screening programmes are a vital tool to counter these haemoglobinopathies by: (i) identifying individual carriers and allowing them to make informed reproductive choices, and (ii) generating population level gene-frequency estimates, to help ensure the optimal allocation of public health resources. For both of these functions it is vital that the screen performed is suitably sensitive. One popular first-stage screening option to detect carriers of beta thalassaemia in low-income countries is the One Tube Osmotic Fragility Test (OTOFT). Here we introduce a population genetic framework within which to quantify the likely sensitivity and specificity of the OTOFT in different epidemiological contexts. We demonstrate that interactions between the carrier states for beta thalassaemia and alpha thalassaemia, glucose-6-phosphate dehydrogenase deficiency and Southeast Asian Ovalocytosis have the potential to reduce the sensitivity of OTOFTs for beta thalassaemia heterozygosity to below 70%. Our results therefore caution against the widespread application of OTOFTs in regions where these erythrocyte variants co-occur.

Piel FB, Weatherall DJ. 2014. The α-thalassemias. N Engl J Med, 371 (20), pp. 1908-1916. | Show Abstract | Read more

More than 100 varieties of α-thalassemia have been identified. Their geographic distribution and the challenges associated with screening, diagnosis, and management suggest that α-thalassemias should have a higher priority on global public health agendas.

Villar J, Cheikh Ismail L, Victora CG, Ohuma EO, Bertino E, Altman DG, Lambert A, Papageorghiou AT, Carvalho M, Jaffer YA et al. 2014. International standards for newborn weight, length, and head circumference by gestational age and sex: the Newborn Cross-Sectional Study of the INTERGROWTH-21st Project. Lancet, 384 (9946), pp. 857-868. | Show Abstract | Read more

BACKGROUND: In 2006, WHO published international growth standards for children younger than 5 years, which are now accepted worldwide. In the INTERGROWTH-21(st) Project, our aim was to complement them by developing international standards for fetuses, newborn infants, and the postnatal growth period of preterm infants. METHODS: INTERGROWTH-21(st) is a population-based project that assessed fetal growth and newborn size in eight geographically defined urban populations. These groups were selected because most of the health and nutrition needs of mothers were met, adequate antenatal care was provided, and there were no major environmental constraints on growth. As part of the Newborn Cross-Sectional Study (NCSS), a component of INTERGROWTH-21(st) Project, we measured weight, length, and head circumference in all newborn infants, in addition to collecting data prospectively for pregnancy and the perinatal period. To construct the newborn standards, we selected all pregnancies in women meeting (in addition to the underlying population characteristics) strict individual eligibility criteria for a population at low risk of impaired fetal growth (labelled the NCSS prescriptive subpopulation). Women had a reliable ultrasound estimate of gestational age using crown-rump length before 14 weeks of gestation or biparietal diameter if antenatal care started between 14 weeks and 24 weeks or less of gestation. Newborn anthropometric measures were obtained within 12 h of birth by identically trained anthropometric teams using the same equipment at all sites. Fractional polynomials assuming a skewed t distribution were used to estimate the fitted centiles. FINDINGS: We identified 20,486 (35%) eligible women from the 59,137 pregnant women enrolled in NCSS between May 14, 2009, and Aug 2, 2013. We calculated sex-specific observed and smoothed centiles for weight, length, and head circumference for gestational age at birth. The observed and smoothed centiles were almost identical. We present the 3rd, 10th, 50th, 90th, and 97th centile curves according to gestational age and sex. INTERPRETATION: We have developed, for routine clinical practice, international anthropometric standards to assess newborn size that are intended to complement the WHO Child Growth Standards and allow comparisons across multiethnic populations. FUNDING: Bill & Melinda Gates Foundation.

Kassebaum NJ, Jasrasaria R, Naghavi M, Wulf SK, Johns N, Lozano R, Regan M, Weatherall D, Chou DP, Eisele TP et al. 2014. A systematic analysis of global anemia burden from 1990 to 2010. Blood, 123 (5), pp. 615-624. | Show Abstract | Read more

Previous studies of anemia epidemiology have been geographically limited with little detail about severity or etiology. Using publicly available data, we estimated mild, moderate, and severe anemia from 1990 to 2010 for 187 countries, both sexes, and 20 age groups. We then performed cause-specific attribution to 17 conditions using data from the Global Burden of Diseases, Injuries and Risk Factors (GBD) 2010 Study. Global anemia prevalence in 2010 was 32.9%, causing 68.36 (95% uncertainty interval [UI], 40.98 to 107.54) million years lived with disability (8.8% of total for all conditions [95% UI, 6.3% to 11.7%]). Prevalence dropped for both sexes from 1990 to 2010, although more for males. Prevalence in females was higher in most regions and age groups. South Asia and Central, West, and East sub-Saharan Africa had the highest burden, while East, Southeast, and South Asia saw the greatest reductions. Iron-deficiency anemia was the top cause globally, although 10 different conditions were among the top 3 in regional rankings. Malaria, schistosomiasis, and chronic kidney disease-related anemia were the only conditions to increase in prevalence. Hemoglobinopathies made significant contributions in most populations. Burden was highest in children under age 5, the only age groups with negative trends from 1990 to 2010.

Piel FB, Tatem AJ, Huang Z, Gupta S, Williams TN, Weatherall DJ. 2014. Global migration and the changing distribution of sickle haemoglobin: a quantitative study of temporal trends between 1960 and 2000. Lancet Glob Health, 2 (2), pp. e80-e89. | Show Abstract | Read more

BACKGROUND: Changes in the geographical distribution of genetic disorders are often thought to happen slowly, especially when compared with infectious diseases. Whereas mutations, genetic drift, and natural selection take place over many generations, epidemics can spread through large populations within a few days or weeks. Nevertheless, population movements can interfere with these processes, and few studies have been done of their eff ect on genetic disorders. We aimed to investigate the eff ect of global migration on the distribution of the sickle-cell gene-the most common and clinically significant haemoglobin structural variant. METHODS: For each country, we extracted data from the World Bank’s Global Bilateral Migration Database about international human migrations between 1960 and 2000. We combined this information with evidence-based estimates of national HbS allele frequencies, generated within a Bayesian geostatistical framework, to analyse temporal changes in the net numbers of migrants, and classified countries with an index summarising these temporal trends. FINDINGS: The number of international migrants increased from 92.6 million in 1960, to 165.2 million in 2000. The estimated global number of migrants with HbS increased from about 1.6 million in 1960, to 3.6 million in 2000. This increase was largely due to an increase in the number of migrants from countries with HbS allele frequencies higher than 10%, from 3.1 million in 1960, to 14.2 million in 2000. Additionally, the mean number of countries of origin for each destination country increased from 70 (SE 46) in 1960, to 98 (48) in 2000, showing an increasing diversity in the network of international migrations between countries. Our index of change map shows a patchy distribution of the magnitude of temporal changes, with the highest positive and negative values scattered across all continents. INTERPRETATION: Global human population movements have had a substantial eff ect on the distribution of the HbS gene. Population movements can create a long-term burden on health-care systems. Our findings, which emphasise countries in which migration fluxes are changing the most, should increase awareness about the global burden of haemoglobinopathies and encourage policy makers to implement specific public health interventions, such as screening programmes and genetic counselling. FUNDING: Wellcome Trust, European Research Council, Bill & Melinda Gates Foundation, National Institute of Allergy and Infectious Diseases-National Institutes of Health, the Research and Policy for Infectious Disease Dynamics program, Fogarty International Center.

Weatherall DJ. 2014. A journey in science: early lessons from the hemoglobin field. Mol Med, 20 (JULY-DECEMBER 2014), pp. 478-485. | Show Abstract | Read more

Real innovations in medicine and science are historic and singular; the stories behind each occurrence are precious. At Molecular Medicine we have established the Anthony Cerami Award in Translational Medicine to document and preserve these histories. The monographs recount the seminal events as told in the voice of the original investigators who provided the crucial early insight. These essays capture the essence of discovery, chronicling the birth of ideas that created new fields of research; and launched trajectories that persisted and ultimately influenced how disease is prevented, diagnosed, and treated. In this volume, the Cerami Award Monograph is by David J Weatherall, Founder, Weatherall Institute of Molecular Medicine, Oxford University, John Radcliffe Hospital. A visionary in the field of hemoglobin, this is the story of Professor Weatherall's scientific journey.

Weatherall DJ. 2013. The role of the inherited disorders of hemoglobin, the first "molecular diseases," in the future of human genetics. Annu Rev Genomics Hum Genet, 14 (1), pp. 1-24. | Show Abstract | Read more

Although the inherited hemoglobin disorders were the first genetic diseases to be explored at the molecular level, they still have important messages for the future of medical genetics. In particular, they can offer a better understanding of the evolutionary and population biology of genetic disease, the mechanisms that underlie the phenotypic diversity of monogenic disease, and how, by developing appropriate partnerships, richer countries can help low-income countries to evolve programs for the control and management of these diseases where, in many cases, they are particularly common.

Piel FB, Hay SI, Gupta S, Weatherall DJ, Williams TN. 2013. Global burden of sickle cell anaemia in children under five, 2010-2050: modelling based on demographics, excess mortality, and interventions. PLoS Med, 10 (7), pp. e1001484. | Show Abstract | Read more

BACKGROUND: The global burden of sickle cell anaemia (SCA) is set to rise as a consequence of improved survival in high-prevalence low- and middle-income countries and population migration to higher-income countries. The host of quantitative evidence documenting these changes has not been assembled at the global level. The purpose of this study is to estimate trends in the future number of newborns with SCA and the number of lives that could be saved in under-five children with SCA by the implementation of different levels of health interventions. METHODS AND FINDINGS: First, we calculated projected numbers of newborns with SCA for each 5-y interval between 2010 and 2050 by combining estimates of national SCA frequencies with projected demographic data. We then accounted for under-five mortality (U5m) projections and tested different levels of excess mortality for children with SCA, reflecting the benefits of implementing specific health interventions for under-five patients in 2015, to assess the number of lives that could be saved with appropriate health care services. The estimated number of newborns with SCA globally will increase from 305,800 (confidence interval [CI]: 238,400-398,800) in 2010 to 404,200 (CI: 242,500-657,600) in 2050. It is likely that Nigeria (2010: 91,000 newborns with SCA [CI: 77,900-106,100]; 2050: 140,800 [CI: 95,500-200,600]) and the Democratic Republic of the Congo (2010: 39,700 [CI: 32,600-48,800]; 2050: 44,700 [CI: 27,100-70,500]) will remain the countries most in need of policies for the prevention and management of SCA. We predict a decrease in the annual number of newborns with SCA in India (2010: 44,400 [CI: 33,700-59,100]; 2050: 33,900 [CI: 15,900-64,700]). The implementation of basic health interventions (e.g., prenatal diagnosis, penicillin prophylaxis, and vaccination) for SCA in 2015, leading to significant reductions in excess mortality among under-five children with SCA, could, by 2050, prolong the lives of 5,302,900 [CI: 3,174,800-6,699,100] newborns with SCA. Similarly, large-scale universal screening could save the lives of up to 9,806,000 (CI: 6,745,800-14,232,700) newborns with SCA globally, 85% (CI: 81%-88%) of whom will be born in sub-Saharan Africa. The study findings are limited by the uncertainty in the estimates and the assumptions around mortality reductions associated with interventions. CONCLUSIONS: Our quantitative approach confirms that the global burden of SCA is increasing, and highlights the need to develop specific national policies for appropriate public health planning, particularly in low- and middle-income countries. Further empirical collaborative epidemiological studies are vital to assess current and future health care needs, especially in Nigeria, the Democratic Republic of the Congo, and India.

Piel FB, Howes RE, Nyangiri OA, Moyes CL, Williams TN, Weatherall DJ, Hay SI. 2013. Online biomedical resources for malaria-related red cell disorders. Hum Mutat, 34 (7), pp. 937-944. | Show Abstract | Read more

Warnings about the expected increase of the global public health burden of malaria-related red cell disorders are accruing. Past and present epidemiological data are necessary to track spatial and temporal changes in the frequencies of these genetic disorders. A number of open access biomedical databases including data on malaria-related red cell disorders have been launched over the last two decades. Here, we review the content of these databases, most of which focus on genetic diversity, and we describe a new epidemiological resource developed by the Malaria Atlas Project. To tackle upcoming public health challenges, the integration of epidemiological and genetic data is important. As many countries are considering implementing national screening programs, strategies to make such data more accessible are also needed.

Jones E, Allen A, Evans P, Fisher C, Pasricha S-R, Premawardhena A, Olivieri N, Porter J, St Pierre T, Drakesmith H, Weatherall D. 2013. DIFFERENCES IN HEPCIDIN REGULATION DISTINGUISH MILD AND SEVERE PHENOTYPES OF E-BETA THALASSAEMIA AMERICAN JOURNAL OF HEMATOLOGY, 88 (5), pp. E22-E22.

Piel FB, Howes RE, Patil AP, Nyangiri OA, Gething PW, Bhatt S, Williams TN, Weatherall DJ, Hay SI. 2013. The distribution of haemoglobin C and its prevalence in newborns in Africa. Sci Rep, 3 (1), pp. 1671. | Show Abstract | Read more

Haemoglobin C (HbC) is one of the commonest structural haemoglobin variants in human populations. Although HbC causes mild clinical complications, its diagnosis and genetic counselling are important to prevent inheritance with other haemoglobinopathies. Little is known about its contemporary distribution and the number of newborns affected. We assembled a global database of population surveys. We then used a Bayesian geostatistical model to create maps of HbC frequency across Africa and paired our predictions with high-resolution demographics to calculate heterozygous (AC) and homozygous (CC) newborn estimates and their associated uncertainty. Data were too sparse outside Africa for this methodology to be applied. The highest frequencies were found in West Africa but HbC was commonly found in other parts of the continent. The expected annual numbers of AC and CC newborns in Africa were 672,117 (interquartile range (IQR): 642,116-705,163) and 28,703 (IQR: 26,027-31,958), respectively. These numbers are about two times previous estimates.

Piel FB, Patil AP, Howes RE, Nyangiri OA, Gething PW, Dewi M, Temperley WH, Williams TN, Weatherall DJ, Hay SI. 2013. Global epidemiology of sickle haemoglobin in neonates: a contemporary geostatistical model-based map and population estimates. Lancet, 381 (9861), pp. 142-151. | Show Abstract | Read more

BACKGROUND: Reliable estimates of populations affected by diseases are necessary to guide efficient allocation of public health resources. Sickle haemoglobin (HbS) is the most common and clinically significant haemoglobin structural variant, but no contemporary estimates exist of the global populations affected. Moreover, the precision of available national estimates of heterozygous (AS) and homozygous (SS) neonates is unknown. We aimed to provide evidence-based estimates at various scales, with uncertainty measures. METHODS: Using a database of sickle haemoglobin surveys, we created a contemporary global map of HbS allele frequency distribution within a Bayesian geostatistical model. The pairing of this map with demographic data enabled calculation of global, regional, and national estimates of the annual number of AS and SS neonates. Subnational estimates were also calculated in data-rich areas. FINDINGS: Our map shows subnational spatial heterogeneities and high allele frequencies across most of sub-Saharan Africa, the Middle East, and India, as well as gene flow following migrations to western Europe and the eastern coast of the Americas. Accounting for local heterogeneities and demographic factors, we estimated that the global number of neonates affected by HbS in 2010 included 5,476,000 (IQR 5,291,000-5,679,000) AS neonates and 312,000 (294,000-330,000) SS neonates. These global estimates are higher than previous conservative estimates. Important differences predicted at the national level are discussed. INTERPRETATION: HbS will have an increasing effect on public health systems. Our estimates can help countries and the international community gauge the need for appropriate diagnoses and genetic counselling to reduce the number of neonates affected. Similar mapping and modelling methods could be used for other inherited disorders. FUNDING: The Wellcome Trust.

Suresh S, Fisher C, Ayyub H, Premawardhena A, Allen A, Perera A, Bandara D, Olivieri N, Weatherall D. 2013. Alpha thalassaemia and extended alpha globin genes in Sri Lanka. Blood Cells Mol Dis, 50 (2), pp. 93-98. | Show Abstract | Read more

The α-globin genes were studied in nine families with unexplained hypochromic anaemia and in 167 patients with HbE β thalassaemia in Sri Lanka. As well as the common deletion forms of α(+) thalassaemia three families from an ethnic minority were found to carry a novel form of α(0) thalassaemia, one family carried a previously reported form of α(0) thalassaemia, --(THAI), and five families had different forms of non-deletional thalassaemia. The patients with HbE β thalassaemia who had co-inherited α thalassaemia all showed an extremely mild phenotype and reduced levels of HbF and there was a highly significant paucity of α(+) thalassaemia in these patients compared with the normal population. Extended α gene arrangements, including ααα, αααα and ααααα, occurred at a low frequency and were commoner in the more severe phenotypes of HbE β thalassaemia. As well as emphasising the ameliorating effect of α thalassaemia on HbE β thalassaemia the finding of a novel form of α(0) thalassaemia in an ethnic minority, together with an unexpected diversity of forms of non-deletion α thalassaemia in Sri Lanka, further emphasises the critical importance of micro-mapping populations for determining the frequency of clinically important forms of the disease.

Allen A, Fisher C, Premawardhena A, Bandara D, Perera A, Allen S, St Pierre T, Olivieri N, Weatherall D. 2012. Methemoglobinemia and ascorbate deficiency in hemoglobin E β thalassemia: metabolic and clinical implications. Blood, 120 (15), pp. 2939-2944. | Show Abstract | Read more

During investigations of the phenotypic diversity of hemoglobin (Hb) E β thalassemia, a patient was encountered with persistently high levels of methemoglobin associated with a left-shift in the oxygen dissociation curve, profound ascorbate deficiency, and clinical features of scurvy; these abnormalities were corrected by treatment with vitamin C. Studies of erythropoietin production before and after treatment suggested that, as in an ascorbate-deficient murine model, the human hypoxia induction factor pathway is not totally dependent on ascorbate levels. A follow-up study of 45 patients with HbE β thalassemia showed that methemoglobin levels were significantly increased and that there was also a significant reduction in plasma ascorbate levels. Haptoglobin levels were significantly reduced, and the high frequency of the 2.2 haptoglobin genotype may place an additional pressure on ascorbate as a free-radical scavenger in this population. There was, in addition, a highly significant correlation between methemoglobin levels, splenectomy, and factors that modify the degree of globin-chain imbalance. Because methemoglobin levels are modified by several mechanisms and may play a role in both adaptation to anemia and vascular damage, there is a strong case for its further study in other forms of thalassemia and sickle-cell anemia, particularly when splenic function is defective.




Fucharoen S, Weatherall DJ. 2012. The Hemoglobin E Thalassemias Cold Spring Harbor Perspectives in Medicine, 2 (8), pp. a011734-a011734. | Show Abstract | Read more

Hemoglobin E (HbE) is an extremely common structural hemoglobin variant that occurs at high frequencies throughout many Asian countries. It is a β-hemoglobin variant, which is produced at a slightly reduced rate and hence has the phenotype of a mild form of β thalassemia. Its interactions with different forms of α thalassemia result in a wide variety of clinical disorders, whereas its coinheritance with β thalassemia, a condition called hemoglobin E β thalassemia, is by far the most common severe form of β thalassemia in Asia and, globally, comprises approximately 50% of the clinically severe β-thalassemia disorders. © 2012 Cold Spring Harbor Laboratory Press all rights reserved.

Pang T, Weatherall D. 2012. Genomics and world health: a decade on. Lancet, 379 (9829), pp. 1853-1854. | Read more

Weatherall DJ. 2012. Commentary on "The modifying effect of Xmn1-HBG2 on thalassemic phenotype is associated with its linked elements in the beta globin locus control region, including the palindromic site at 5' HS4" by M. Neishabury et al. Blood Cells Mol Dis, 48 (1), pp. 6. | Read more

Vos T, Flaxman AD, Naghavi M, Lozano R, Michaud C, Ezzati M, Shibuya K, Salomon JA, Abdalla S, Aboyans V et al. 2012. Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet, 380 (9859), pp. 2163-2196. | Show Abstract | Read more

BACKGROUND: Non-fatal health outcomes from diseases and injuries are a crucial consideration in the promotion and monitoring of individual and population health. The Global Burden of Disease (GBD) studies done in 1990 and 2000 have been the only studies to quantify non-fatal health outcomes across an exhaustive set of disorders at the global and regional level. Neither effort quantified uncertainty in prevalence or years lived with disability (YLDs). METHODS: Of the 291 diseases and injuries in the GBD cause list, 289 cause disability. For 1160 sequelae of the 289 diseases and injuries, we undertook a systematic analysis of prevalence, incidence, remission, duration, and excess mortality. Sources included published studies, case notification, population-based cancer registries, other disease registries, antenatal clinic serosurveillance, hospital discharge data, ambulatory care data, household surveys, other surveys, and cohort studies. For most sequelae, we used a Bayesian meta-regression method, DisMod-MR, designed to address key limitations in descriptive epidemiological data, including missing data, inconsistency, and large methodological variation between data sources. For some disorders, we used natural history models, geospatial models, back-calculation models (models calculating incidence from population mortality rates and case fatality), or registration completeness models (models adjusting for incomplete registration with health-system access and other covariates). Disability weights for 220 unique health states were used to capture the severity of health loss. YLDs by cause at age, sex, country, and year levels were adjusted for comorbidity with simulation methods. We included uncertainty estimates at all stages of the analysis. FINDINGS: Global prevalence for all ages combined in 2010 across the 1160 sequelae ranged from fewer than one case per 1 million people to 350,000 cases per 1 million people. Prevalence and severity of health loss were weakly correlated (correlation coefficient -0·37). In 2010, there were 777 million YLDs from all causes, up from 583 million in 1990. The main contributors to global YLDs were mental and behavioural disorders, musculoskeletal disorders, and diabetes or endocrine diseases. The leading specific causes of YLDs were much the same in 2010 as they were in 1990: low back pain, major depressive disorder, iron-deficiency anaemia, neck pain, chronic obstructive pulmonary disease, anxiety disorders, migraine, diabetes, and falls. Age-specific prevalence of YLDs increased with age in all regions and has decreased slightly from 1990 to 2010. Regional patterns of the leading causes of YLDs were more similar compared with years of life lost due to premature mortality. Neglected tropical diseases, HIV/AIDS, tuberculosis, malaria, and anaemia were important causes of YLDs in sub-Saharan Africa. INTERPRETATION: Rates of YLDs per 100,000 people have remained largely constant over time but rise steadily with age. Population growth and ageing have increased YLD numbers and crude rates over the past two decades. Prevalences of the most common causes of YLDs, such as mental and behavioural disorders and musculoskeletal disorders, have not decreased. Health systems will need to address the needs of the rising numbers of individuals with a range of disorders that largely cause disability but not mortality. Quantification of the burden of non-fatal health outcomes will be crucial to understand how well health systems are responding to these challenges. Effective and affordable strategies to deal with this rising burden are an urgent priority for health systems in most parts of the world. FUNDING: Bill & Melinda Gates Foundation.

Williams TN, Weatherall DJ. 2012. World distribution, population genetics, and health burden of the hemoglobinopathies. Cold Spring Harb Perspect Med, 2 (9), pp. a011692. | Show Abstract | Read more

Although information about the precise world distribution and frequency of the inherited hemoglobin disorders is still limited, there is no doubt that they are going to pose an increasing burden on global health resources in the future. Their high frequency is a reflection of natural selection combined with a high frequency of consanguineous marriages in many countries, together with an epidemiological transition; whereby, as public health measures improve in the poorer countries of the world, more babies with these disorders are surviving to present for treatment.

Williams TN, Weatherall DJ. 2012. World distribution, population genetics, and health burden of the hemoglobinopathies Cold Spring Harbor Perspectives in Biology, 4 (9), | Show Abstract | Read more

Although information about the precise world distribution and frequency of the inherited hemoglobin disorders is still limited, there is no doubt that they are going to pose an increasing burden on global health resources in the future. Their high frequency is a reflection of natural selection combined with a high frequency of consanguineous marriages in many countries, together with an epidemiological transition; whereby, as public health measures improve in the poorer countries of the world, more babies with these disorders are surviving to present for treatment. © 2012 Cold Spring Harbor Laboratory Press; all rights reserved.

Weatherall DJ. 2012. The definition and epidemiology of non-transfusion-dependent thalassemia. Blood Rev, 26 Suppl 1 (SUPPL.1), pp. S3-S6. | Show Abstract | Read more

Inherited hemoglobin-related disorders, which include the structural variants (hemoglobin S, C, and E) and the alpha (α)- and beta (β)-thalassemias, affect more than 300,000 children annually, particularly in malaria-endemic regions stretching from sub-Saharan Africa and the Mediterranean to Southeast Asia. Screening for carriers of these traits is important to provide prenatal genetic counseling and to accurately estimate the true prevalence and public health burden of these disorders. The clinical course of thalassemias, which affect nearly 70,000 children annually, is highly variable depending on the mixture of inherited alleles. The primary forms of non-transfusion-dependent thalassemia include β-thalassemia intermedia, hemoglobin E β-thalassemia, and hemoglobin H disease. Early clinical recognition of these disorders is essential to prevent affected children from being mistakenly placed on life-long transfusion therapy.

Murray CJL, Vos T, Lozano R, Naghavi M, Flaxman AD, Michaud C, Ezzati M, Shibuya K, Salomon JA, Abdalla S et al. 2012. Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet, 380 (9859), pp. 2197-2223. | Show Abstract | Read more

BACKGROUND: Measuring disease and injury burden in populations requires a composite metric that captures both premature mortality and the prevalence and severity of ill-health. The 1990 Global Burden of Disease study proposed disability-adjusted life years (DALYs) to measure disease burden. No comprehensive update of disease burden worldwide incorporating a systematic reassessment of disease and injury-specific epidemiology has been done since the 1990 study. We aimed to calculate disease burden worldwide and for 21 regions for 1990, 2005, and 2010 with methods to enable meaningful comparisons over time. METHODS: We calculated DALYs as the sum of years of life lost (YLLs) and years lived with disability (YLDs). DALYs were calculated for 291 causes, 20 age groups, both sexes, and for 187 countries, and aggregated to regional and global estimates of disease burden for three points in time with strictly comparable definitions and methods. YLLs were calculated from age-sex-country-time-specific estimates of mortality by cause, with death by standardised lost life expectancy at each age. YLDs were calculated as prevalence of 1160 disabling sequelae, by age, sex, and cause, and weighted by new disability weights for each health state. Neither YLLs nor YLDs were age-weighted or discounted. Uncertainty around cause-specific DALYs was calculated incorporating uncertainty in levels of all-cause mortality, cause-specific mortality, prevalence, and disability weights. FINDINGS: Global DALYs remained stable from 1990 (2·503 billion) to 2010 (2·490 billion). Crude DALYs per 1000 decreased by 23% (472 per 1000 to 361 per 1000). An important shift has occurred in DALY composition with the contribution of deaths and disability among children (younger than 5 years of age) declining from 41% of global DALYs in 1990 to 25% in 2010. YLLs typically account for about half of disease burden in more developed regions (high-income Asia Pacific, western Europe, high-income North America, and Australasia), rising to over 80% of DALYs in sub-Saharan Africa. In 1990, 47% of DALYs worldwide were from communicable, maternal, neonatal, and nutritional disorders, 43% from non-communicable diseases, and 10% from injuries. By 2010, this had shifted to 35%, 54%, and 11%, respectively. Ischaemic heart disease was the leading cause of DALYs worldwide in 2010 (up from fourth rank in 1990, increasing by 29%), followed by lower respiratory infections (top rank in 1990; 44% decline in DALYs), stroke (fifth in 1990; 19% increase), diarrhoeal diseases (second in 1990; 51% decrease), and HIV/AIDS (33rd in 1990; 351% increase). Major depressive disorder increased from 15th to 11th rank (37% increase) and road injury from 12th to 10th rank (34% increase). Substantial heterogeneity exists in rankings of leading causes of disease burden among regions. INTERPRETATION: Global disease burden has continued to shift away from communicable to non-communicable diseases and from premature death to years lived with disability. In sub-Saharan Africa, however, many communicable, maternal, neonatal, and nutritional disorders remain the dominant causes of disease burden. The rising burden from mental and behavioural disorders, musculoskeletal disorders, and diabetes will impose new challenges on health systems. Regional heterogeneity highlights the importance of understanding local burden of disease and setting goals and targets for the post-2015 agenda taking such patterns into account. Because of improved definitions, methods, and data, these results for 1990 and 2010 supersede all previously published Global Burden of Disease results. FUNDING: Bill & Melinda Gates Foundation.

Weatherall DJ. 2012. Cyril Clarke and the prevention of rhesus haemolytic disease of the newborn. Br J Haematol, 157 (1), pp. 41-46. | Show Abstract | Read more

Cyril Clarke was an outstanding general physician and lepidopterist. Late in his career, and stimulated by his work on the genetics of mimicry in butterflies, he became interested in the evolving field of medical genetics. His work on the relationship of blood groups to particular diseases led him and his team in Liverpool to evolve a remarkably successful approach to the prevention of Rhesus haemolytic disease of the newborn.

Salomon JA, Vos T, Hogan DR, Gagnon M, Naghavi M, Mokdad A, Begum N, Shah R, Karyana M, Kosen S et al. 2012. Common values in assessing health outcomes from disease and injury: disability weights measurement study for the Global Burden of Disease Study 2010. Lancet, 380 (9859), pp. 2129-2143. | Show Abstract | Read more

BACKGROUND: Measurement of the global burden of disease with disability-adjusted life-years (DALYs) requires disability weights that quantify health losses for all non-fatal consequences of disease and injury. There has been extensive debate about a range of conceptual and methodological issues concerning the definition and measurement of these weights. Our primary objective was a comprehensive re-estimation of disability weights for the Global Burden of Disease Study 2010 through a large-scale empirical investigation in which judgments about health losses associated with many causes of disease and injury were elicited from the general public in diverse communities through a new, standardised approach. METHODS: We surveyed respondents in two ways: household surveys of adults aged 18 years or older (face-to-face interviews in Bangladesh, Indonesia, Peru, and Tanzania; telephone interviews in the USA) between Oct 28, 2009, and June 23, 2010; and an open-access web-based survey between July 26, 2010, and May 16, 2011. The surveys used paired comparison questions, in which respondents considered two hypothetical individuals with different, randomly selected health states and indicated which person they regarded as healthier. The web survey added questions about population health equivalence, which compared the overall health benefits of different life-saving or disease-prevention programmes. We analysed paired comparison responses with probit regression analysis on all 220 unique states in the study. We used results from the population health equivalence responses to anchor the results from the paired comparisons on the disability weight scale from 0 (implying no loss of health) to 1 (implying a health loss equivalent to death). Additionally, we compared new disability weights with those used in WHO's most recent update of the Global Burden of Disease Study for 2004. FINDINGS: 13,902 individuals participated in household surveys and 16,328 in the web survey. Analysis of paired comparison responses indicated a high degree of consistency across surveys: correlations between individual survey results and results from analysis of the pooled dataset were 0·9 or higher in all surveys except in Bangladesh (r=0·75). Most of the 220 disability weights were located on the mild end of the severity scale, with 58 (26%) having weights below 0·05. Five (11%) states had weights below 0·01, such as mild anaemia, mild hearing or vision loss, and secondary infertility. The health states with the highest disability weights were acute schizophrenia (0·76) and severe multiple sclerosis (0·71). We identified a broad pattern of agreement between the old and new weights (r=0·70), particularly in the moderate-to-severe range. However, in the mild range below 0·2, many states had significantly lower weights in our study than previously. INTERPRETATION: This study represents the most extensive empirical effort as yet to measure disability weights. By contrast with the popular hypothesis that disability assessments vary widely across samples with different cultural environments, we have reported strong evidence of highly consistent results. FUNDING: Bill & Melinda Gates Foundation.

Allen A, Fisher C, Premawardhena A, Peto T, Allen S, Arambepola M, Thayalsutha V, Olivieri N, Weatherall D. 2011. Adaptation to anemia in hemoglobin E-beta thalassemia (vol 116, pg 5368, 2011) BLOOD, 118 (26), pp. 6994-+.

Weatherall D. 2011. The inherited disorders of haemoglobin: an increasingly neglected global health burden. Indian J Med Res, 134 pp. 493-497. | Show Abstract

An estimated 300,000 babies are born each year with a severe inherited disease of haemoglobin and that over 80 per cent of these births occur in low- or middle-income countries. As these countries go through the epidemiological transition, characterized by a reduction in childhood and infant mortality due to improved public health measures, infants who had previously died of these conditions before they were recognised are now surviving to present for diagnosis and treatment. For a variety of reasons, even in the rich countries there are limited data about the true frequency, natural history, and survival of patients with these disorders, information that is absolutely critical towards providing governments and international health agencies with accurate information about the true global health burden of these conditions. The situation can only be improved by major action on the part of the rich countries together with the formation of partnerships between rich and poor countries and input from the major international health agencies and funding organisations.

Sankaran VG, Xu J, Byron R, Greisman HA, Fisher C, Weatherall DJ, Sabath DE, Groudine M, Orkin SH, Premawardhena A, Bender MA. 2011. A Functional Element Necessary for Fetal Hemoglobin Silencing New England Journal of Medicine, 365 (9), pp. 807-814. | Read more

Weatherall DJ. 2011. Thalassaemia: the long road from the bedside through the laboratory to the community. Transfus Med, 21 (4), pp. 218-223. | Read more

Weatherall DJ. 2011. The quiet art revisited. Lancet, 377 (9781), pp. 1912-1913. | Read more

Weatherall DJ. 2011. Hydroxycarbamide for sickle-cell anaemia in infancy. Lancet, 377 (9778), pp. 1628-1630. | Read more

Howes RE, Patil AP, Piel FB, Nyangiri OA, Kabaria CW, Gething PW, Zimmerman PA, Barnadas C, Beall CM, Gebremedhin A et al. 2011. The global distribution of the Duffy blood group. Nat Commun, 2 (1), pp. 266. | Show Abstract | Read more

Blood group variants are characteristic of population groups, and can show conspicuous geographic patterns. Interest in the global prevalence of the Duffy blood group variants is multidisciplinary, but of particular importance to malariologists due to the resistance generally conferred by the Duffy-negative phenotype against Plasmodium vivax infection. Here we collate an extensive geo-database of surveys, forming the evidence-base for a multi-locus Bayesian geostatistical model to generate global frequency maps of the common Duffy alleles to refine the global cartography of the common Duffy variants. We show that the most prevalent allele globally was FY*A, while across sub-Saharan Africa the predominant allele was the silent FY*B(ES) variant, commonly reaching fixation across stretches of the continent. The maps presented not only represent the first spatially and genetically comprehensive description of variation at this locus, but also constitute an advance towards understanding the transmission patterns of the neglected P. vivax malaria parasite.

Weatherall DJ. 2011. The quiet art revisited The Lancet, 377 (9781), pp. 1912-1913. | Read more

Weatherall DJ. 2011. The challenge of haemoglobinopathies in resource-poor countries. Br J Haematol, 154 (6), pp. 736-744. | Show Abstract | Read more

The haemoglobinopathies, inherited disorders of the structure or synthesis of haemoglobin, are the commonest monogenic diseases. Approximately 80% of the annual births of babies with these conditions occur in low-or middle-income countries, many of which have extremely limited facilities for their control and management. Given that the population size of many of them is growing and, as social and public health facilities improve, increasing numbers of these babies will survive to present for diagnosis and treatment. Hence, the haemoglobinopathies will constitute an increasing global health burden. Hitherto, they have been largely ignored by governments of high-frequency countries and by the international health agencies. However, a start has been made in developing control programmes in some low-income countries and there is already considerable evidence that much can be done to improve the situation by the development of partnerships between groups in richer countries and centres in low-income countries. The natural extension of this approach is the further development of partnerships between countries where expertise in this field has been developed and adjacent countries where no such expertise exists. It is vital that the haematology community of the richer countries becomes involved in programmes of this type while, at the same time, putting pressure on their governments and on international health agencies for support for this work.

Weatherall DJ. 2011. Systems biology and red cells. N Engl J Med, 364 (4), pp. 376-377. | Read more

Weatherall D. 2011. Science and medical education: is it time to revisit Flexner? Med Educ, 45 (1), pp. 44-50. | Show Abstract | Read more

CONTEXT: An important issue facing medical education concerns whether integrating the bioscientific basis of medical practice and research with other subject matter in so-called 'self-directed learning approaches' will ensure that medical graduates meet the needs of the 21st century. DISCUSSION: Although it may be possible to continue to integrate the more traditional medical sciences such as anatomy and physiology throughout the student curriculum, given the rapid development, continuous change and increasing breadth of the other biological sciences that underpin medical research and practice, and in view of the increasingly narrow specialisation of many clinical departments, it may become increasingly difficult to maintain courses in which the medical sciences and clinical practice are partially or totally integrated. CONCLUSIONS: The 100th anniversary of the Flexner Report is an appropriate time to revisit some of the principles that it contains and, in particular, to discuss whether well-intentioned efforts to humanise students' medical school experiences and to make students more responsive to the needs of patients threaten a core value that is as relevant as it was in Flexner's day: namely, competence in contemporary biomedical science.

Taher AT, Musallam KM, Cappellini MD, Weatherall DJ. 2011. Optimal management of β thalassaemia intermedia. Br J Haematol, 152 (5), pp. 512-523. | Show Abstract | Read more

Our understanding of the molecular and pathophysiological mechanisms underlying the disease process in patients with β thalassaemia intermedia (TI) has substantially increased over the past decade. The hallmark of disease process in patients with TI includes ineffective erythropoiesis, chronic haemolytic anaemia, and iron overload. There are a number of options currently available for managing patients with TI including splenectomy, transfusion therapy, iron chelation therapy, modulation of fetal haemoglobin production, and several other agents targeting specific clinical complications. Limited studies assessed the efficacy and safety of these modalities; hence, there are currently no clear guidelines for managing patients with TI. Until solid evidence-based guidelines are available, individualised treatment should be entertained.

Allen A, Fisher C, Premawardhena A, Peto T, Allen S, Arambepola M, Thayalsutha V, Olivieri N, Weatherall D. 2011. Adaptation to anemia in hemoglobin E-β thalassemia (Blood (2010) 116, 24 (5368-5370)) Blood, 118 (26), pp. 6994-6995. | Read more

Allen A, Fisher C, Premawardhena A, Peto T, Allen S, Arambepola M, Thayalsutha V, Olivieri N, Weatherall D. 2010. Adaptation to anemia in hemoglobin E-ß thalassemia. Blood, 116 (24), pp. 5368-5370. | Show Abstract | Read more

Hemoglobin E β thalassemia is the commonest form of severe thalassemia in many Asian countries. Its remarkably variable clinical phenotype presents a major challenge to determining its most appropriate management. In particular, it is not clear why some patients with this condition can develop and function well at very low hemoglobin levels. Here, we demonstrate that patients with hemoglobin Eβ thalassemia have a significant decrease in the oxygen affinity of their hemoglobin, that is an increased P(50) value, in response to anemia. This may in part reflect the lower level of hemoglobin F in this condition compared with other forms of β thalassemia intermedia. The ability to right-shift the oxygen dissociation curve was retained across the spectrum of mild and severe phenotypes, despite the significantly higher levels of hemoglobin F in the former, suggesting that efforts directed at producing a modest increase in the level of hemoglobin F in symptomatic patients with this disease should be of therapeutic value.

Weatherall DJ, Williams TN, Allen SJ, O'Donnell A. 2010. The population genetics and dynamics of the thalassemias. Hematol Oncol Clin North Am, 24 (6), pp. 1021-1031. | Show Abstract | Read more

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.

Piel FB, Patil AP, Howes RE, Nyangiri OA, Gething PW, Williams TN, Weatherall DJ, Hay SI. 2010. Global distribution of the sickle cell gene and geographical confirmation of the malaria hypothesis. Nat Commun, 1 (8), pp. 104. | Show Abstract | Read more

It has been 100 years since the first report of sickle haemoglobin (HbS). More than 50 years ago, it was suggested that the gene responsible for this disorder could reach high frequencies because of resistance conferred against malaria by the heterozygous carrier state. This traditional example of balancing selection is known as the 'malaria hypothesis'. However, the geographical relationship between the transmission intensity of malaria and associated HbS burden has never been formally investigated on a global scale. Here, we use a comprehensive data assembly of HbS allele frequencies to generate the first evidence-based map of the worldwide distribution of the gene in a Bayesian geostatistical framework. We compare this map with the pre-intervention distribution of malaria endemicity, using a novel geostatistical area-mean comparison. We find geographical support for the malaria hypothesis globally; the relationship is relatively strong in Africa but cannot be resolved in the Americas or in Asia.

Weatherall D. 2010. Thalassemia: the long road from the bedside through the laboratory to the community. Nat Med, 16 (10), pp. 1112-1115. | Read more

O'Riordan S, Hien TT, Miles K, Allen A, Quyen NN, Hung NQ, Anh DQ, Tuyen LN, Khoa DB, Thai CQ et al. 2010. Large scale screening for haemoglobin disorders in southern Vietnam: implications for avoidance and management. Br J Haematol, 150 (3), pp. 359-364. | Show Abstract | Read more

In order to obtain an approximate assessment of the public health burden that will be posed by the inherited disorders of haemoglobin in southern Vietnam, several thousand individuals were screened for these conditions. A smaller sample was screened for glucose-6-phosphate dehydrogenase (G6PD) deficiency. The important haemoglobin disorders identified were beta thalassaemia, haemoglobin E and a variety of different forms of alpha thalassaemia. There were sufficient G6PD-deficient individuals to materially affect malaria control programme design. The most remarkable finding was wide variation in the gene frequencies of these conditions among the ethnic groups sampled. The approximate number of babies expected to be born with clinically significant haemoglobin disorders in Vietnam was estimated from the gene-frequency data. This study emphasizes the importance of wide-scale population screening, including ethnic subgroups, to establish the requirements for inherited haemoglobin disorder programmes in resource-limited settings.

Weatherall DJ. 2010. Is modern genetics a blind alley? No. BMJ, 340 (mar30 2), pp. c1088. | Read more

Weatherall DJ. 2010. The importance of micromapping the gene frequencies for the common inherited disorders of haemoglobin. Br J Haematol, 149 (5), pp. 635-637. | Read more

Weatherall DJ. 2010. Molecular medicine; the road to the better integration of the medical sciences in the twenty-first century. Notes Rec R Soc Lond, 64 Suppl 1 (Suppl_1), pp. S5-15. | Show Abstract | Read more

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.

Weatherall DJ. 2010. Is modern genetics a blind alley? No. BMJ (Clinical research ed.), 340

Olivieri NF, Thayalsuthan V, O'Donnell A, Premawardhena A, Rigobon C, Muraca G, Fisher C, Weatherall DJ. 2010. Emerging insights in the management of hemoglobin E beta thalassemia. Ann N Y Acad Sci, 1202 (1), pp. 155-157. | Show Abstract | Read more

Globally, hemoglobin (Hb) E beta thalassemia accounts for approximately half the severe forms of beta thalassemia. Because of its wide clinical diversity and the ability of patients with this condition to adapt unusually well to low hemoglobin levels, the management of Hb E beta thalassemia, particularly the decision to instigate regular blood transfusion, is particularly difficult. Here, we present a summary of our work in patients with this condition, which attempts to define clinical, adaptive, and genetic factors of possible value in determining the early management of this condition.

Penman BS, Pybus OG, Weatherall DJ, Gupta S. 2009. Epistatic interactions between genetic disorders of hemoglobin can explain why the sickle-cell gene is uncommon in the Mediterranean. Proc Natl Acad Sci U S A, 106 (50), pp. 21242-21246. | Show Abstract | Read more

Several human genetic disorders of hemoglobin have risen in frequency because of the protection they offer against death from malaria, sickle-cell anemia being a canonical example. Here we address the issue of why this highly protective mutant, present at high frequencies in subSaharan Africa, is uncommon in Mediterranean populations that instead harbor a diverse range of thalassemic hemoglobin disorders. We demonstrate that these contrasting profiles of malaria-protective alleles can arise and be stably maintained by two well-documented phenomena: an alleviation of the clinical severity of alpha- and beta-thalassemia in compound thalassemic genotypes and a cancellation of malaria protection when alpha-thalassemia and the sickle-cell trait are coinherited. The complex distribution of globin mutants across Africa and the Mediterranean can therefore be explained by their specific intracellular interactions.

Lok CY, Merryweather-Clarke AT, Viprakasit V, Chinthammitr Y, Srichairatanakool S, Limwongse C, Oleesky D, Robins AJ, Hudson J, Wai P et al. 2009. Iron overload in the Asian community. Blood, 114 (1), pp. 20-25. | Show Abstract | Read more

Hereditary hemochromatosis is an iron overload disorder that can lead to the impairment of multiple organs and is caused by mutations in one or more different genes. Type 1 hemochromatosis is the most common form of the disease and results from mutations in the HFE gene. Juvenile hemochromatosis (JH) is the most severe form, usually caused by mutations in hemojuvelin (HJV) or hepcidin (HAMP). The autosomal dominant form of the disease, type 4, is due to mutations in the SLC40A1 gene, which encodes for ferroportin (FPN). Hereditary hemochromatosis is commonly found in populations of European origin. By contrast, hemochromatosis in Asia is rare and less well understood and can be masked by the presence of iron deficiency and secondary iron overload from thalassemia. Here, we provide a comprehensive report of hemochromatosis in a group of patients of Asian origin. We have identified novel mutations in HJV, HAMP, and SLC40A1 in countries not normally associated with hereditary hemochromatosis (Pakistan, Bangladesh, Sri Lanka, and Thailand). Our family studies show a high degree of consanguinity, highlighting the increased risk of iron overload in many countries of the developing world and in countries in which there are large immigrant populations from these regions.

Higgs DR, Weatherall DJ. 2009. The alpha thalassaemias. Cell Mol Life Sci, 66 (7), pp. 1154-1162. | Show Abstract | Read more

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.

Weatherall D. 2009. Ruminations of a geriatric Emeritus Regius Professor of Medicine. Clin Med (Lond), 9 (2), pp. 104-107. | Show Abstract | Read more

The potential for the holder of a senior academic post to influence the medical world is usually enshrined in their job description. Even though Oxford University failed to provide one, this account of 25 years of undirected activity suggests that such posts can influence events, albeit to a limited extent and not always in the expected direction.

Weatherall DJ. 2009. RECENT INSIGHTS INTO THE POPULATION GENETICS AND DYNAMICS OF THE INHERITED DISORDERS OF HEMOGLOBIN Mediterranean Journal of Hematology and Infectious Diseases, | Read more

O'Donnell A, Fowkes FJI, Allen SJ, Imrie H, Alpers MP, Weatherall DJ, Day KP. 2009. The acute phase response in children with mild and severe malaria in Papua New Guinea. Trans R Soc Trop Med Hyg, 103 (7), pp. 679-686. | Show Abstract | Read more

The production of acute phase proteins during infection is an important part of innate immunity and limits inflammation. However, little is known of the acute phase response in malaria. We measured acute phase proteins in plasma in children attending clinics and admitted to hospital with acute malaria in Papua New Guinea. Plasma ferritin concentration increased progressively with disease severity with markedly elevated levels in the most severely ill children. Plasma ferritin was >500 ng/ml in 7/99 (7.1%) outpatients with uncomplicated malaria, 22/100 (22.0%) hospital non-severe cases, 64/175 (36.6%) severe malaria cases who survived and 7/9 (77.8%) severe malaria deaths (P<0.001). The greatest concentration of ferritin (3561 ng/ml) was observed in a child who died. By contrast, C-reactive protein concentration was markedly increased in 153 children with uncomplicated malaria [median 203 (interquartile range 51-365) microg/ml] but, surprisingly, was only moderately increased in 135 children with one or more severe manifestations of malaria [47 (17-97) microg/ml; P<0.001] and in 6 children who died [41 (22-280) microg/ml]. Excessive free-radical damage resulting from a combination of iron-induced oxidant stress and reduced levels of C-reactive protein may be an important pathological mechanism in severe malaria and amenable to therapeutic intervention.

Robson KJH, Weatherall DJ. 2009. Malarial anemia and STAT6. Haematologica, 94 (2), pp. 157-159. | Read more

O'Donnell A, Premawardhena A, Arambepola M, Samaranayake R, Allen SJ, Peto TEA, Fisher CA, Cook J, Corran PH, Olivieri NF, Weatherall DJ. 2009. Interaction of malaria with a common form of severe thalassemia in an Asian population. Proc Natl Acad Sci U S A, 106 (44), pp. 18716-18721. | Show Abstract | Read more

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.

Olivieri NF, Muraca GM, O’Donnell A, Premawardhena A, Fisher C, Weatherall DJ. 2008. Studies in haemoglobin E beta-thalassaemia British Journal of Haematology, 141 (3), pp. 388-397. | Read more

Weatherall D. 2008. Editorial. Symposium on Erythropoiesis and Red Cell Disorders. Br J Haematol, 141 (3), pp. 275. | Read more

Weatherall DJ. 2008. Who killed Cockrobin? The limitations of pathobiography. Lancet, 372 (9633), pp. 108-109. | Read more

Weatherall D. 2008. The importance of the rare phenotype: Haemoglobin and its disorders Biochemist, 30 (1), pp. 10-13. | Show Abstract

The inherited disorders of haemoglobin are the commonest monogenic diseases. Extensive studies of their molecular pathology, as well as leading to a better understanding of their remarkable clinical diversity, has provided invaluable information about the functions of haemoglobin and the regulation of its synthesis. Recent work in this field has continued to highlight the value of the study of rare phenotypes at the molecular level as a basis for a better understanding of the mechanisms of gene action. © 2008 The Biochemical Society.

Weatherall DJ. 2008. The centenary of Garrod's Croonian lectures. Clin Med (Lond), 8 (3), pp. 309-311. | Show Abstract | Read more

Archibald Garrod's Croonian lectures, Inborn errors of metabolism, were delivered at the Royal College of Physicians in June 1908. Although their significance remained dormant for many years, and is still not fully appreciated, they are now recognised as the foundation of medical genetics.

Fowkes FJI, Allen SJ, Allen A, Alpers MP, Weatherall DJ, Day KP. 2008. Increased microerythrocyte count in homozygous alpha(+)-thalassaemia contributes to protection against severe malarial anaemia. PLoS Med, 5 (3), pp. e56. | Show Abstract | Read more

BACKGROUND: The heritable haemoglobinopathy alpha(+)-thalassaemia is caused by the reduced synthesis of alpha-globin chains that form part of normal adult haemoglobin (Hb). Individuals homozygous for alpha(+)-thalassaemia have microcytosis and an increased erythrocyte count. Alpha(+)-thalassaemia homozygosity confers considerable protection against severe malaria, including severe malarial anaemia (SMA) (Hb concentration < 50 g/l), but does not influence parasite count. We tested the hypothesis that the erythrocyte indices associated with alpha(+)-thalassaemia homozygosity provide a haematological benefit during acute malaria. METHODS AND FINDINGS: Data from children living on the north coast of Papua New Guinea who had participated in a case-control study of the protection afforded by alpha(+)-thalassaemia against severe malaria were reanalysed to assess the genotype-specific reduction in erythrocyte count and Hb levels associated with acute malarial disease. We observed a reduction in median erythrocyte count of approximately 1.5 x 10(12)/l in all children with acute falciparum malaria relative to values in community children (p < 0.001). We developed a simple mathematical model of the linear relationship between Hb concentration and erythrocyte count. This model predicted that children homozygous for alpha(+)-thalassaemia lose less Hb than children of normal genotype for a reduction in erythrocyte count of >1.1 x 10(12)/l as a result of the reduced mean cell Hb in homozygous alpha(+)-thalassaemia. In addition, children homozygous for alpha(+)-thalassaemia require a 10% greater reduction in erythrocyte count than children of normal genotype (p = 0.02) for Hb concentration to fall to 50 g/l, the cutoff for SMA. We estimated that the haematological profile in children homozygous for alpha(+)-thalassaemia reduces the risk of SMA during acute malaria compared to children of normal genotype (relative risk 0.52; 95% confidence interval [CI] 0.24-1.12, p = 0.09). CONCLUSIONS: The increased erythrocyte count and microcytosis in children homozygous for alpha(+)-thalassaemia may contribute substantially to their protection against SMA. A lower concentration of Hb per erythrocyte and a larger population of erythrocytes may be a biologically advantageous strategy against the significant reduction in erythrocyte count that occurs during acute infection with the malaria parasite Plasmodium falciparum. This haematological profile may reduce the risk of anaemia by other Plasmodium species, as well as other causes of anaemia. Other host polymorphisms that induce an increased erythrocyte count and microcytosis may confer a similar advantage.

Weatherall DJ. 2008. Hemoglobinopathies worldwide: present and future. Curr Mol Med, 8 (7), pp. 592-599. | Show Abstract | Read more

The genetic disorders of hemoglobin, the commonest monogenic diseases, occur at some of their highest frequencies in the developing countries, particularly those of Sub-Saharan Africa and Asia. Although progress towards their control and management continues to be made, the prospects for curing them, apart from marrow transplantation, remain uncertain. In many countries expertise and facilities for their control are extremely limited. Although a great deal can be done to help the situation by developing further North/South and South/South partnerships for disseminating better practice, the major problem for the future lies in the unwillingness of governments and international health agencies to accept that the hemoglobinopathies represent a health burden comparative to that of communicable and other major diseases. However, preliminary analyses suggest that, at least in the case of Asia, this may not be true. Further work of this type, together with more detailed frequency and economic data, is required to provide solid evidence for the health burden posed by the hemoglobin disorders, particularly in the developing world. Unless this is done, the increasingly large populations of patients with these diseases will continue to be neglected.

Weatherall D, Munn H. 2007. Animal research: the debate continues. J Intern Med, 262 (6), pp. 591-592. | Read more

Weatherall D, Munn H. 2007. Moving the primate debate forward. Science, 316 (5822), pp. 173. | Read more

Weatherall D. 2007. Animal research: the debate continues. Lancet, 369 (9568), pp. 1147-1148. | Read more

Weatherall DJ. 2007. Current trends in the diagnosis and management of haemoglobinopathies. Scand J Clin Lab Invest, 67 (1), pp. 1-2. | Read more

O'Donnell A, Premawardhena A, Arambepola M, Allen SJ, Peto TEA, Fisher CA, Rees DC, Olivieri NF, Weatherall DJ. 2007. Age-related changes in adaptation to severe anemia in childhood in developing countries. Proc Natl Acad Sci U S A, 104 (22), pp. 9440-9444. | Show Abstract | Read more

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.

O'Donnell A, Raiko A, Clegg JB, Weatherall DJ, Allen SJ. 2006. Alpha+ -thalassaemia and pregnancy in a malaria endemic region of Papua New Guinea. Br J Haematol, 135 (2), pp. 235-241. | Show Abstract | Read more

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.

Wambua S, Mwangi TW, Kortok M, Uyoga SM, Macharia AW, Mwacharo JK, Weatherall DJ, Snow RW, Marsh K, Williams TN. 2006. The effect of alpha+-thalassaemia on the incidence of malaria and other diseases in children living on the coast of Kenya. PLoS Med, 3 (5), pp. e158. | Show Abstract | Read more

BACKGROUND: The alpha-thalassaemias are the commonest genetic disorders of humans. It is generally believed that this high frequency reflects selection through a survival advantage against death from malaria; nevertheless, the epidemiological description of the relationships between alpha-thalassaemia, malaria, and other common causes of child mortality remains incomplete. METHODS AND FINDINGS: We studied the alpha+-thalassaemia-specific incidence of malaria and other common childhood diseases in two cohorts of children living on the coast of Kenya. We found no associations between alpha+-thalassaemia and the prevalence of symptomless Plasmodium falciparum parasitaemia, the incidence of uncomplicated P. falciparum disease, or parasite densities during mild or severe malaria episodes. However, we found significant negative associations between alpha+-thalassaemia and the incidence rates of severe malaria and severe anaemia (haemoglobin concentration < 50 g/l). The strongest associations were for severe malaria anaemia (> 10,000 P. falciparum parasites/mul) and severe nonmalaria anaemia; the incidence rate ratios and 95% confidence intervals (CIs) for alpha+-thalassaemia heterozygotes and homozygotes combined compared to normal children were, for severe malaria anaemia, 0.33 (95% CI, 0.15,0.73; p = 0.006), and for severe nonmalaria anaemia, 0.26 (95% CI, 0.09,0.77; p = 0.015). CONCLUSIONS: Our observations suggest, first that selection for alpha+-thalassaemia might be mediated by a specific effect against severe anaemia, an observation that may lead to fresh insights into the aetiology of this important condition. Second, although alpha+-thalassaemia is strongly protective against severe and fatal malaria, its effects are not detectable at the level of any other malaria outcome; this result provides a cautionary example for studies aimed at testing malaria interventions or identifying new malaria-protective genes.

Weatherall D. 2006. Genomics and world health: hopes and realities. J Zhejiang Univ Sci B, 7 (2), pp. 161. | Show Abstract | Read more

Due to lack of appreciation of the complexities of the interactions between nature and nurture, claims for the rapid improvements in medical care following the human genome project have been exaggerated. Although some progress has been made in certain fields, the full scope of genomic medicine may not be realised for many years.

Weatherall DJ. 2006. Science in the undergraduate curriculum during the 20th century. Med Educ, 40 (3), pp. 195-201. | Show Abstract | Read more

BACKGROUND: The conflict between the art and science of medical practice has always posed problems for the presentation of the scientific basis of medicine to medical students. This issue is examined by a brief description of the changing methods of medical education over the last century. OBSERVATIONS: The various approaches to attempting to teach the scientific basis of medical practice are discussed, together with the increasing complexities that followed the explosion of knowledge in the basic biological fields towards the end of the 20th century. Although progress was made by a more integrated approach to medical education, there are still considerable problems in presenting the basic sciences to students in a way that convinces them that such material is relevant to their future practice. CONCLUSIONS: A more broadly based background in modern biology, including evolutionary biology and biological complexity, would undoubtedly better prepare students for dealing with the infinite complexities they will encounter in sick people.

Weatherall SDJ. 2006. Personalized medicine – pharmacogenetics Personalized Medicine, 3 (1), pp. 9-9. | Read more

O'Donnell A, Weatherall DJ, Taylor AM, Reeder JC, Allen SJ. 2006. Muscle cell injury, haemolysis and dark urine in children with falciparum malaria in Papua New Guinea. Trans R Soc Trop Med Hyg, 100 (9), pp. 817-825. | Show Abstract | Read more

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.

Sloane-Stanley J, Roberts NA, Olivieri N, Weatherall DJ, Wood WG. 2006. Globin gene expression in Hb Lepore-BAC transgenic mice. Br J Haematol, 135 (5), pp. 735-737. | Show Abstract | Read more

We generated five lines of transgenic mice carrying 1-3 copies of the Hb Lepore deltabeta fusion gene, in the context of a Bacterial Artificial Chromosome containing the whole human beta globin gene cluster. Normal developmental regulation of human genes occurred at levels approximating to those of endogenous genes. Deltabeta transgene expression became detectable during fetal life and rose to a mean level of 13.0% in adults, similar to that of humans. Low levels of human gamma chains were detectable as F cells in adult mice, but numbers did not increase after treatment with drugs that raise F cells in human subjects, even on a thalassaemic background.

Weatherall DJ. 2006. Genetics and molecular biology: From a monastery garden to rebuilding the heart Dialogues in Cardiovascular Medicine, 11 (2), pp. 148-155. | Show Abstract

The advent of molecular cardiology stems from advances in knowledge of genetics spanning over 400 years. The seeds of what was to grow into a forest of knowledge were planted by Harvey, Leeuvenhoek, and Virchow. Mighty trunks arose from the works of Darwin, Galton, and Gregor Mendel (pea breeding experiments). Branches started shooting out with experiments on the fruit fly (Drosophila) and the works of Morgan, Garrod, Fisher, Haldane, and Penrose. After that, discoveries simply bloomed, culminating in human molecular genetics, the human genome projects, and the beginnings of the postgenomic era in which we are just starting to find out how the whole thing works. In this forest, molecular cardiology is but one tree, yet one that holds enormous promise for the future. Copyright © 2006 LLS SAS. All rights reserved.

Weatherall MW, Higgs DR, Weiss H, Weatherall DJ, Serjeant GR. 2005. Phenotype/genotype relationships in sickle cell disease: a pilot twin study. Clin Lab Haematol, 27 (6), pp. 384-390. | Show Abstract | Read more

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.

Williams TN, Mwangi TW, Wambua S, Peto TEA, Weatherall DJ, Gupta S, Recker M, Penman BS, Uyoga S, Macharia A et al. 2005. Negative epistasis between the malaria-protective effects of alpha+-thalassemia and the sickle cell trait. Nat Genet, 37 (11), pp. 1253-1257. | Show Abstract | Read more

The hemoglobinopathies, disorders of hemoglobin structure and production, protect against death from malaria. In sub-Saharan Africa, two such conditions occur at particularly high frequencies: presence of the structural variant hemoglobin S and alpha(+)-thalassemia, a condition characterized by reduced production of the normal alpha-globin component of hemoglobin. Individually, each is protective against severe Plasmodium falciparum malaria, but little is known about their malaria-protective effects when inherited in combination. We investigated this question by studying a population on the coast of Kenya and found that the protection afforded by each condition inherited alone was lost when the two conditions were inherited together, to such a degree that the incidence of both uncomplicated and severe P. falciparum malaria was close to baseline in children heterozygous with respect to the mutation underlying the hemoglobin S variant and homozygous with respect to the mutation underlying alpha(+)-thalassemia. Negative epistasis could explain the failure of alpha(+)-thalassemia to reach fixation in any population in sub-Saharan Africa.

Weatherall D. 2005. What is the Royal Society for? Lancet, 365 (9478), pp. 2173-2174. | Read more

Haverfield EV, McKenzie CA, Forrester T, Bouzekri N, Harding R, Serjeant G, Walker T, Peto TEA, Ward R, Weatherall DJ. 2005. UGT1A1 variation and gallstone formation in sickle cell disease. Blood, 105 (3), pp. 968-972. | Show Abstract | Read more

Pigment gallstones are a common clinical complication of sickle cell (SS) disease. Genetic variation in the promoter of uridine diphosphate (UDP)-glucuronosyltransferase 1A1 (UGT1A1) underlies Gilbert syndrome, a chronic form of unconjugated hyperbilirubinemia, and appears to be a risk factor for gallstone formation. We investigated the association between UGT1A1 (TA)(n) genotype, hyperbilirubinemia, and gallstones in a sample of Jamaicans with SS disease. Subjects were from the Jamaican Sickle Cell Cohort Study (cohort sample, n = 209) and the Sickle Cell Clinic at the University of the West Indies, Kingston, Jamaica (clinic sample, n = 357). The UGT1A1 (TA)(n) promoter region was sequenced in 541 SS disease subjects and 111 healthy controls (control sample). Indirect bilirubin levels for (TA)(7)/(TA)(7) and (TA)(7)/(TA)(8) genotypes were elevated compared with (TA)(6)/(TA)(6) (clinic sample, P < 10(-5); cohort sample, P < 10(-3)). The (TA)(7)/(TA)(7) genotype was also associated with symptomatic presentation and gallstones in the clinic sample (odds ratio [OR] = 11.3; P = 7.0 x 10(-4)) but not in the younger cohort sample. These unexpected findings indicate that the temporal evolution of symptomatic gallstones may involve factors other than the bilirubin level. Although further studies of the pathogenesis of gallstones in SS disease are required, the (TA)(7)/(TA)(7) genotype may be a risk factor for symptomatic gallstones in older people with SS disease.

Weatherall D, Hofman K, Rodgers G, Ruffin J, Hrynkow S. 2005. A case for developing North-South partnerships for research in sickle cell disease. Blood, 105 (3), pp. 921-923. | Show Abstract | Read more

For a better understanding of the pathophysiology and mechanisms of phenotypic diversity of sickle cell disease, and for the improvement of its management globally, there is a strong case for developing sustainable research partnerships between rich and poor countries.

May R, Read D, Weatherall D, Horton R. 2005. What is the Royal Society for? [1] (multiple letters) Lancet, 365 (9478), pp. 2173-2174. | Read more

Roberts DJ, Casals-Pascual C, Weatherall DJ. 2005. The clinical and pathophysiological features of malarial anaemia. Curr Top Microbiol Immunol, 295 pp. 137-167. | Show Abstract

This review will focus on the principal clinical and pathophysiological features of the anaemia of falciparum malaria, including the problems of treating malarial anaemia, and also will suggest how recent advances in genomics may help our understanding of cellular and molecular mechanisms underlying this syndrome.

Singer ST, Kuypers FA, Olivieri NF, Weatherall DJ, Mignacca R, Coates TD, Davies S, Sweeters N, Vichinsky EP. 2005. Single and combination drug therapy for fetal hemoglobin augmentation in hemoglobin E-beta 0-thalassemia: Considerations for treatment. Ann N Y Acad Sci, 1054 (1), pp. 250-256. | Show Abstract | Read more

Patients with hemoglobin E (Hb E)-beta 0-thalassemia, one of the most common hemoglobinopathies worldwide, could benefit from drugs that increase fetal and total hemoglobin levels and thereby decrease the need for transfusions. The long-term clinical outcome of such therapy, its hematologic effects, and which patients are likely to benefit from treatment are unknown. Consequently, the use of such drugs for Hb E-beta 0-thalassemia is limited, and countries where resources for safe and regular transfusion are scarce cannot benefit from them. In a multicenter trial of 42 patients treated with hydroxyurea for two years, almost half the patients demonstrated a significant increase in steady-state hemoglobin level. Drug toxicity was minimal. Combined treatment of hydroxyurea with erythropoietin benefited selected patients, but the addition of sodium phenyl butyrate was ineffective. After 5 years of follow-up, a subset of patients remained off transfusions. Hydroxyurea should be considered for a subset of Hb E-beta 0-thalassemia patients.

Williams T, Mwangi T, Wambua S, Uyoga S, Weatherall D, Gupta S, Recker M, Macharia A, Snow R, Marsh K. 2005. Negative epistasis between the malaria-protective effects of alpha (+) thalassaemia and the sickle cell trait [MIM-TW-395505] ACTA TROPICA, 95 pp. S91-S91.

Premawardhena A, Fisher CA, Olivieri NF, de Silva S, Arambepola M, Perera W, O'Donnell A, Peto TEA, Viprakasit V, Merson L et al. 2005. Haemoglobin E beta thalassaemia in Sri Lanka. Lancet, 366 (9495), pp. 1467-1470. | Show Abstract | Read more

Haemoglobin E beta thalassaemia is the commonest form of severe thalassaemia in many Asian countries, but little is known about its natural history, the reasons for clinical diversity, or its management. We studied 109 Sri Lankan patients with the disorder over 5 years. 25 patients were not receiving transfusion; transfusion was stopped with no deleterious effect in a further 37. We identified several genetic and environmental factors that might contribute to the phenotypic diversity of the disorder, including modifiers of haemoglobin F production, malaria, and age-related changes in adaptive function. Our findings suggest that haemoglobin E beta thalassaemia can be managed without transfusion in many patients, even with low haemoglobin levels. Age-related changes in the pattern of adaptation to anaemia suggest that different and more cost-effective approaches to management should be explored.

Singer ST, Kuypers FA, Olivieri NF, Weatherall DJ, Mignacca R, Coates TD, Davies S, Sweeters N, Vichinsky EP, E/beta Thalassaemia Study Group. 2005. Fetal haemoglobin augmentation in E/beta(0) thalassaemia: clinical and haematological outcome. Br J Haematol, 131 (3), pp. 378-388. | Show Abstract | Read more

Patients with E/beta(0) thalassaemia, the most common haemoglobinopathy in many Asian countries, might benefit from drugs that increase fetal and total haemoglobin and thereby decrease the need for transfusions. The long-term clinical efficacy and safety of such therapy is unknown, limiting its use in countries where resources for safe and regular transfusion are scarce. In this study, 45 patients were treated with hydroxyurea (18-20 mg/kg) for 24+/-9 months, hydroxyurea with sodium phenyl butyrate (n=8) and hydroxyurea with erythropoietin (n=9), each for approximately 6 months, and followed for 3 years from study exit. Hydroxyurea had minimal toxicity, resulted in a mean 1.3 g/dl steady-state increase in haemoglobin in 40% of patients, and a milder response (<OR=1 g/dl) in the others. Baseline haemoglobin F was significantly associated with an increase in haemoglobin (P<0.001). Combined treatment with erythropoietin benefited selected patients, but the addition of sodium phenyl butyrate had no effect. Of the 27/45 patients who discontinued regular transfusions before the study, 13 remained transfusion independent during long-term follow-up, 6/13 continued hydroxyurea. Hydroxyurea moderately increased steady-state haemoglobin in a sub-group of E/beta(0) thalassaemia patients and can be considered for patients with intermediate severity disease, thus delaying or avoiding the need for life-long transfusions. Continuous monitoring of toxicity and growth is required.




Williams TN, Mwangi TW, Roberts DJ, Alexander ND, Weatherall DJ, Wambua S, Kortok M, Snow RW, Marsh K. 2005. An immune basis for malaria protection by the sickle cell trait PLoS Medicine, 2 (5), pp. 0441-0445. | Show Abstract | Read more

Background: Malaria resistance by the sickle cell trait (genotype HbAS) has served as the prime example of genetic selection for over half a century. Nevertheless, the mechanism of this resistance remains the subject of considerable debate. While it probably involves innate factors such as the reduced ability of Plasmodium falciparum parasites to grow and multiply in HbAS erythrocytes, recent observations suggest that it might also involve the accelerated acquisition of malaria-specific immunity. Methods and Findings: We studied the age-specific protection afforded by HbAS against clinical malaria in children living on the coast of Kenya. We found that protection increased with age from only 20% in the first 2 y of life to a maximum of 56% by the age of 10 y, returning thereafter to 30% in participants greater than 10 y old. Conclusions: Our observations suggest that malaria protection by HbAS involves the enhancement of not only innate but also of acquired immunity to the parasite. A better understanding of the underlying mechanisms might yield important insights into both these processes. © 2005 Williams et al.

Premawardhena A, Fisher CA, Olivieri NF, de Silva S, Sloane-Stanley J, Wood WG, Weatherall DJ. 2005. A novel molecular basis for beta thalassemia intermedia poses new questions about its pathophysiology. Blood, 106 (9), pp. 3251-3255. | Show Abstract | Read more

During a study of the molecular basis for severe forms of beta thalassemia in Sri Lanka, 2 patients were found to be heterozygous for beta thalassemia mutations. Further analysis revealed that one of them has a previously unreported molecular basis for severe thalassemia intermedia, homozygosity for quadruplicated alpha globin genes in combination with heterozygous beta thalassemia. The other is homozygous for a triplicated alpha globin gene arrangement and heterozygous for beta thalassemia. Their differences in clinical phenotype are explainable by the interaction of other genetic factors and, in particular, their early management. The clinical course of the 2 propositi underlines the importance of full genotyping and a long period of observation before treatment is instituted, particularly in patients with beta thalassemia intermedia associated with extended alpha globin gene arrangements. The hemoglobin (Hb) F levels in these patients with severe beta thalassemia intermedia, compared with other forms of this condition in the Sri Lankan population and elsewhere, are unusually low, a consistent finding in extended alpha globin gene interactions and in dominant beta thalassemia, raising the possibility that increased levels of HbF production in beta thalassemia may require mutations at both beta globin gene loci.

Weatherall DJ. 2005. 1 Disorders of haemoglobin: from phenotype to genotype Studies in Multidisciplinarity, 3 (C), pp. 1-13. | Show Abstract | Read more

Using a brief outline of the development of the human haemoglobin field, the characteristics and importance of interdisciplinary research groups for developing both theory and experimental basis for its validation have been described. The subject evolved from the chance coming together of disparate disciplines to the concept of a more organised and integrated approach, at least within the university system. So far, the multidiscipliary group approach has covered only a limited number of disciplines. For the full exploitation of the potential of the remarkable developments in the biological sciences of the last 10 years it may, in the longer term, be necessary to expand the scope of these groups, incorporating the fields of epidemiology, public health, and social sciences. It should be emphasised that these collaborations and integrations cannot be forced on science; they tend to happen naturally when a field is at a particular state of development. Hence it is the role of universities, and other bodies in which medical research is carried out, to ensure that the appropriate facilities are available to house and support integrated groups of this type, or to plant the geography of research facilities such that close interaction, including social contact, is widely encouraged. © 2006 Elsevier B.V. All rights reserved.

Premawardhena A, De Silva S, Arambepola M, Olivieri N, Merson L, Muraco J, Allen A, Fisher C, Peto T, Vichinsky E, Weatherall D. 2004. Thalassemia in Sri Lanka: a progress report. Hum Mol Genet, 13 Spec No 2 (suppl_2), pp. R203-R206. | Show Abstract | Read more

The thalassemias pose an increasing burden for health-care services in many Asian countries. In order to conserve rare resources, it is essential to determine the reasons for the remarkable phenotypic heterogeneity and natural history of these disorders so that the most cost-effective methods for their control and management can be established. A long-term observational study of patients with different forms of thalassemia in Sri Lanka suggests that in addition to the well-defined primary, secondary and tertiary genetic modifiers, environmental factors, particularly malaria, and variation in the ability to adapt to the profound anaemia which characterizes these conditions, may play a significant role in determining their clinical severity. These findings may have important implications for the control and management of thalassemia in Asian populations.

Robson KJH, Merryweather-Clarke AT, Cadet E, Viprakasit V, Zaahl MG, Pointon JJ, Weatherall DJ, Rochette J. 2004. Recent advances in understanding haemochromatosis: a transition state. J Med Genet, 41 (10), pp. 721-730. | Show Abstract | Read more

Mutations in the hepcidin gene HAMP and the hemojuvelin gene HJV have recently been shown to result in juvenile haemochromatosis (JH). Hepcidin is an antimicrobial peptide that plays a key role in regulating intestinal iron absorption. Hepcidin levels are reduced in patients with haemochromatosis due to mutations in the HFE and HJV genes. Digenic inheritance of mutations in HFE and HAMP can result in either JH or hereditary haemochromatosis (HH) depending upon the severity of the mutation in HAMP. Here we review these findings and discuss how understanding the different types of haemochromatosis and our increasing knowledge of iron metabolism may help to elucidate the host's response to infection.

Weatherall D. 2004. 2003 William Allan Award address. The Thalassemias: the role of molecular genetics in an evolving global health problem. Am J Hum Genet, 74 (3), pp. 385-392. | Read more




Weatherall D. 2004. The Thalassemias: The Role of Molecular Genetics in an Evolving Global Health Problem**Previously presented at the annual meeting of The American Society of Human Genetics, in Los Angeles, on November 7, 2003. The American Journal of Human Genetics, 74 (3), pp. 385-392. | Read more

Weatherall DJ. 2004. Thalassaemia: the long road from bedside to genome. Nat Rev Genet, 5 (8), pp. 625-631. | Show Abstract | Read more

The evolution of research into inherited haemoglobin disorders posed some fascinating questions for historians of the medical sciences in the twentieth century. Of particular interest is how the study of what initially seemed to be a group of rare genetic anaemias turned out to be the forerunner of a new era of medical science. For, in effect, it was the description of their molecular basis that led to the idea of 'molecular disease', and, later, to 'molecular medicine' - a change of emphasis from the characterization of illness in patients and their organs to a description of its pathology at the level of cells and molecules.

Weatherall D. 2003. Evolving with the enemy NEW SCIENTIST, 180 (2422), pp. 44-47. | Show Abstract

The alteration or mutation in the human genome due to bacteria, viruses, and other freeloaders is discussed. Increase in thalassaemia mutations in areas where malaria is endemic, provided carriers protection against the parasite. Various genes have been identified as major players in conferring different degrees of susceptibility to a wide range of bacterial and viral infections, including tuberculosis, leprosy, HIV/AIDS, and hepatitis. The studies of infectious disease from its evolutionary aspect suggest gradual moulding in the genetic make-up due to the continuous struggle against infective agents.

Fisher CA, Premawardhena A, de Silva S, Perera G, Rajapaksa S, Olivieri NA, Old JM, Weatherall DJ, Sri Lanka Thalassaemia Study Group. 2003. The molecular basis for the thalassaemias in Sri Lanka. Br J Haematol, 121 (4), pp. 662-671. | Show Abstract | Read more

The beta-globin gene mutations and the alpha-globin genes of 620 patients with the phenotype of severe to moderate thalassaemia from seven centres in Sri Lanka were analysed. Twenty-four beta-globin gene mutations were identified, three accounting for 84.5% of the 1240 alleles studied: IVSI-5 (G-->C) 56.2%; IVSI-1 (G-->A) 15.2%; and haemoglobin E (codon (CD)26 GAG-->GAA) 13.1%. Three new mutations were found; a 13-bp deletion removing the last nucleotide in CD6 to CD10 inclusively, IVSI-129 (A-->C) in the consensus splice site, and a frame shift, CD55 (-A). The allele frequency of alpha+ thalassaemia was 6.5% and 1.1% for -alpha3.7 and -alpha4.2 deletions respectively. Non-deletion alpha-thalassaemia was not observed. Triplicate or quadruplicate alpha-globin genes were unusually common. In 1.5% of cases it was impossible to identify beta-thalassaemia alleles, but in Kurunegala detailed family studies led to an explanation for the severe thalassaemia phenotype in every case, including a previously unreported instance of homozygosity for a quadruplicated alpha-globin gene together with beta-thalassaemia trait. These findings have implications for the control of thalassaemia in high-frequency populations with complex ethnic histories.

Brittenham GM. 2003. Deferiprone and hepatic fibrosis Blood, 101 (>12), pp. 5089-5091. | Read more

Brittenham GM, Nathan DG, Olivieri NF, Pippard MJ, Weatherall DJ. 2003. Deferiprone versus desferrioxamine in thalassaemia, and T2* validation and utility The Lancet, 361 (9352), pp. 183-183. | Read more

Constantinou G, Melides S, Modell B, Spino M, Tricta F, Nathan DG, Weatherall DJ. 2003. The Olivieri case [4] (multiple letters) New England Journal of Medicine, 348 (9), pp. 860-863. | Read more

Premawardhena A, Fisher CA, Liu YT, Verma IC, de Silva S, Arambepola M, Clegg JB, Weatherall DJ. 2003. The global distribution of length polymorphisms of the promoters of the glucuronosyltransferase 1 gene (UGT1A1): hematologic and evolutionary implications. Blood Cells Mol Dis, 31 (1), pp. 98-101. | Show Abstract | Read more

The promoter region of the UDP glucuronosyltransferase 1 gene (UGT1A1) contains a run of thymine-adenine (TA) repeats, usually six (TA)(6). As well as its relationship to Gilbert's syndrome, homozygosity for the extended sequence, (TA)(7) (TA)(7), has been found to be an important risk factor for hyperbilirubinemia and gallstones in patients with hemoglobin E-beta-thalassemia and other intermediate forms of beta thalassemia. To assess the importance of this polymorphism in these common disorders a wide-scale population study of the relative frequency of the size alleles of the UGT1A1 promoter has been carried out. Homozygosity for the (TA)(7) allele occurs in 10-25% of the populations of Africa and the Indian subcontinent, with a variable frequency in Europe. It occurs at a much lower frequency in Southeast Asia, Melanesia, and the Pacific Islands, ranging from 0 to 5%. African populations show a much greater diversity of length alleles than other populations. These findings define those populations with a high frequency of hemoglobin E-beta-thalassemia and related disorders that are at increased risk for hyperbilirubinemia and gall bladder disease and provide evolutionary insights into how these polymorphisms have arisen and are so unequally distributed among human populations.

Weatherall D. 2003. Problems for biomedical research at the academia-industrial interface. Sci Eng Ethics, 9 (1), pp. 43-48. | Show Abstract | Read more

Throughout much of the world, universities have driven towards industrial partnerships. This collaboration, which, in the biochemical field at least, has to continue if potential benefits for patients are to be realised, has brought with it a number of problems. These include the neglect of long-term research in favour of short-term projects, the curtailing of free dissemination of research information within university departments and the biasing of results of clinical trials by the financial interests of the investigators. It is very important that governments, universities, and industry itself address these problems. Universities should monitor the amount of basic, curiosity-driven research that is being carried on, compared with that which is more short-term goal orientated. PhD students and post-doctoral fellows should be exposed to the principles of bioethics early on in their careers. Further work is necessary on the terms of research contracts to protect, on the one hand, the rights of individual scientists and, on the other, industry from rogue scientists. Where problems arise, procedures should be in place for independent reviews to be conducted by bodies such as the Medical Research Council in the UK or the National Institutes of Health in the USA. The conflict-of-interest rules recently introduced for publication in medical journals should be extended to all branches of science.

Weatherall DJ. 2003. Genomics and global health: time for a reappraisal. Science, 302 (5645), pp. 597-599. | Show Abstract | Read more

Although currently there are only a limited number of genomic technologies that are applicable to health care in the developing countries, this is unlikely to be the case in the near future. If, however, the full potential of genomics for health care is to be fulfilled, there will have to be a complete change of emphasis in education and research in the richer countries toward a more global view of disease and its consequences.

St Pierre TG. 2003. Deferiprone versus desferrioxamine in thalassaemia, and T2* validation and utility. Lancet, 361 (9352), pp. 182. | Read more

Weatherall DJ. 2003. A New Year's resolution after a lost decade. BMJ, 327 (7429), pp. 1415-1416. | Read more

Weatherall DJ. 2003. Pharmacological treatment of monogenic disease. Pharmacogenomics J, 3 (5), pp. 264-266. | Read more

Weatherall DJ, Clegg JB. 2002. Genetic variability in response to infection: malaria and after. Genes Immun, 3 (6), pp. 331-337. | Show Abstract | Read more

Recent studies have shown that the relatively short period of exposure of human populations to malaria has left in its wake a wide range of genetic diversity. And there is growing evidence that other infectious agents have, or are, having the same effect. By integrating further studies of human populations with genetic analyses of susceptibility to murine malaria it should now be possible to determine some of the mechanisms involved in the variation of susceptibility to infectious disease, information which may have important practical implications for both the diagnosis and better management of these conditions.

Williams TN, Weatherall DJ, Newbold CI. 2002. The membrane characteristics of Plasmodium falciparum-infected and -uninfected heterozygous alpha(0)thalassaemic erythrocytes. Br J Haematol, 118 (2), pp. 663-670. | Show Abstract | Read more

The alpha thalassaemias are the commonest known human genetic disorders. Although they have almost certainly risen to their current frequencies through natural selection by malaria, the precise mechanism of malaria protection remains unknown. We have investigated the characteristics of red blood cells (RBCs) from individuals heterozygous for alpha(0)thalassaemia (-/alphaalpha) from a range of perspectives. On the basis of the hypothesis that defects in membrane transport could be relevant to the mechanism of malaria protection, we investigated sodium and potassium transport and the activity of the Plamodium falciparum-induced choline channel but found no significant differences in -/alphaalpha RBCs. Using flow cytometry, we found that thalassaemic P. falciparum-infected RBCs (IRBCs) bound 44% more antibody from immune plasma than control IRBCs. This excess binding was abrogated by predigestion of IRBCs with trypsin but was not directed at the variant surface molecule PfEMP1. Furthermore, we found no evidence for altered cytoadhesion of alpha-thalassaemic IRBCs to the endothelial receptors intercellular adhesion molecule-1 (ICAM-1), CD36 or thrombospondin. We hypothesize that altered red-cell membrane band 3 protein may be a target for enhanced antibody binding to alpha-thalassaemic IRBCs and could be involved in the mechanism of malaria protection.

Pang T, Weatherall D. 2002. Genomics and global health. BMJ, 324 (7345), pp. 1051-1052. | Read more

Weatherall D. 2002. Spreading germs: Disease theories and medical practice in Britain, 1865-1900 ENGLISH HISTORICAL REVIEW, 117 (470), pp. 214-214. | Read more

Weatherall D. 2002. Sir Cyril Astley Clark, C.B.E., 22 August 1907 - 21 November 2000. Biogr Mem Fellows R Soc, 48 pp. 71-85. | Show Abstract

Cyril Clarke was an outstanding physician, medical scientist and lepidopterist. His career was unusual in that he developed a serious interest in medical research only after many years in clinical practice, a change of direction from the life of a busy consultant physician that was undoubtedly stimulated by his lifelong interest in butterflies. This remarkable transition was to result in his leading the team in Liverpool that developed a method for preventing rhesus haemolytic disease of the newborn, one of the major advances in preventative medicine of the second half of the twentieth century.

Weatherall DJ, Miller LH, Baruch DI, Marsh K, Doumbo OK, Casals-Pascual C, Roberts DJ. 2002. Malaria and the red cell. Hematology Am Soc Hematol Educ Program, 2002 (1), pp. 35-57. | Show Abstract | Read more

Because of the breakdown of malaria control programs, the constant emergence of drug resistant parasites, and, possibly, climatic changes malaria poses a major problem for the developing countries. In addition, because of the speed of international travel it is being seen with increasing frequency as an imported disease in non-tropical countries. This update explores recent information about the pathophysiology of the disease, its protean hematological manifestations, and how carrier frequencies for the common hemoglobin disorders have been maintained by relative resistance to the malarial parasite. In Section I, Dr. Louis Miller and colleagues consider recent information about the pathophysiology of malarial infection, including new information about interactions between the malarial parasite and vascular endothelium. In Section II, Dr. David Roberts discusses what is known about the complex interactions between red cell production and destruction that characterize the anemia of malaria, one of the commonest causes of anemia in tropical countries. In Section III, Dr. David Weatherall reviews recent studies on how the high gene frequencies of the thalassemias and hemoglobin variants have been maintained by heterozygote advantage against malaria and how malaria has shaped the genetic structure of human populations.

Weatherall DJ, Kwiatkowski D. 2002. Hematologic disorders of children in developing countries. Pediatr Clin North Am, 49 (6), pp. 1149-1164. | Show Abstract | Read more

This article outlines a few of the hematologic problems that are particular to developing countries, particularly those of the tropics. Because of globalization and the increasing movement of populations, hematologists in wealthier countries must be aware of the general patterns of hematologic change in the important infectious diseases that are common in developing countries. Their manifestations are protean, and any of these diseases, malaria in particular, may present in ways that are atypical from the standard textbook descriptions. In short, the handling of hematologic disorders in developing or tropical countries is no longer confined to the physicians who work in these countries; these diseases are now part of the work of every hematologist.

Premawardhena A, Fisher CA, Fathiu F, de Silva S, Perera W, Peto TE, Olivieri NF, Weatherall DJ. 2001. Genetic determinants of jaundice and gallstones in haemoglobin E beta thalassaemia. Lancet, 357 (9272), pp. 1945-1946. | Show Abstract | Read more

Chronic hyperbilirubinaemia, gallstone formation, and gall bladder disease are unusually common in people with haemoglobin E beta thalassaemia in Sri Lanka. To determine whether this has a genetic basis we compared the bilirubin levels and frequency of gallstones in patients with different alleles of the UGT*1 gene. There was a significantly higher bilirubin level in those with the 7/7 genotypes compared with 6/6 and 6/7 genotype (p=0.032 and 0.0015 respectively), who also appeared more prone to gallstone formation. These results suggest that the UGT*1 genotpe is of importance in the genesis of gallstones in this population of patients.

Weatherall DJ. 2001. Towards molecular medicine; reminiscences of the haemoglobin field, 1960-2000. Br J Haematol, 115 (4), pp. 729-738. | Read more

Weatherall DJ. 2001. Phenotype-genotype relationships in monogenic disease: lessons from the thalassaemias. Nat Rev Genet, 2 (4), pp. 245-255. | Show Abstract | Read more

The remarkable phenotypic diversity of the beta-thalassaemias reflects the heterogeneity of mutations at the beta-globin locus, the action of many secondary and tertiary modifiers, and a wide range of environmental factors. It is likely that phenotype-genotype relationships will be equally complex in the case of many monogenic diseases. These findings highlight the problems that might be encountered in defining the relationship between the genome and the environment in multifactorial disorders, in which the degree of heritability might be relatively low and several environmental agents are involved. They also emphasize the value of an understanding of phenotype-genotype relationships in designing approaches to gene therapy.

Weatherall DJ, Clegg JB. 2001. Inherited haemoglobin disorders: an increasing global health problem. Bull World Health Organ, 79 (8), pp. 704-712. | Show Abstract

Despite major advances in our understanding of the molecular pathology, pathophysiology, and control and management of the inherited disorders of haemoglobin, thousands of infants and children with these diseases are dying through lack of appropriate medical care. This problem will undoubtedly increase over the next 20 years because, as the result of a reduction in childhood mortality due to infection and malnutrition, more babies with haemoglobin disorders will survive to present for treatment. Although WHO and various voluntary agencies have tried to disseminate information about these diseases, they are rarely mentioned as being sufficiently important to be included in setting health care priorities for the future. It takes considerable time to establish expertise in developing programmes for the control and management of these conditions, and the lessons learned in developed countries will need to be transmitted to those countries in which they occur at a high frequency.

Weatherall DJ. 2000. Science, medicine, and the future: Single gene disorders or complex traits: lessons from the thalassaemias and other monogenic diseases BMJ, 321 (7269), pp. 1117-1120. | Read more

Weatherall D. 2000. A passion for DNA - Genes, genomes, and society SCIENCE, 289 (5479), pp. 554-555. | Read more

Ledingham JGG, Warrell DA, Weatherall D. 2000. Asymptomatic haematuria - Oxford Textbook of Medicine might have helped author BRITISH MEDICAL JOURNAL, 320 (7249), pp. 1599-1599.

Weatherall D. 2000. Academia and industry: increasingly uneasy bedfellows. Lancet, 355 (9215), pp. 1574. | Read more

Provan D, Weatherall D. 2000. Red cells II: acquired anaemias and polycythaemia. Lancet, 355 (9211), pp. 1260-1268. | Show Abstract | Read more

Iron deficiency affects 30% of the world's population. Iron metabolism is tightly regulated, with both gut transport and storage being coordinated. Hereditary haemochromatosis due to mutations in the HFE gene leads to increased absorption of iron and multiple end-organ damage. Myelodysplastic disorders are acquired clonal stem-cell disorders that cause ineffective erythropoiesis. Aplastic anaemia is caused by an intrinsic defect of haemopoietic stem cells; both inherited and acquired forms occur. Primary polycythaemia is a myeloproliferative disorder, a non-malignant stem-cell disease.

de Silva S, Fisher CA, Premawardhena A, Lamabadusuriya SP, Peto TE, Perera G, Old JM, Clegg JB, Olivieri NF, Weatherall DJ. 2000. Thalassaemia in Sri Lanka: implications for the future health burden of Asian populations. Sri Lanka Thalassaemia Study Group. Lancet, 355 (9206), pp. 786-791. | Show Abstract | Read more

BACKGROUND: Thalassaemias pose an increasing problem for the Indian subcontinent and many Asian countries. We analysed the different types of thalassaemia in the Sri Lankan population, surveyed gene frequencies in schoolchildren, and estimated the burden of disease and requirements for its control. METHODS: We analysed blood samples from patients attending clinics in nine hospitals and defined the different types of beta thalassaemia by high-performance liquid chromatography (HPLC) and DNA analysis. The range of mutations was obtained by analysis of beta-globin genes. Capillary blood was obtained from schoolchildren from different parts of the island and analysed by HPLC to provide an approximate assessment of the carrier frequency of beta thalassaemia and haemoglobin E (HbE). To estimate the frequency of alpha thalassaemia the alpha-globin genotypes were also analysed when it was possible. FINDINGS: Blood samples were obtained from 703 patients with beta thalassaemia and from 1600 schoolchildren. The thalassaemia mutations were unevenly spread. Although 23 different beta-thalassaemia mutations were found, three accounted for the thalassaemia phenotype in about 70% of the patients, most whom are homozygotes or compound heterozygotes for IVS1-5 (G-->C) or IVS1-1 (G-->A). The third common mutation, codon 26 (G-->A), which produces HbE, interacts with one or other of these mutations to produce HbE/beta thalassaemia; this comprises 13.0-30.9% of cases in the main centres. Samples from 472 patients were analysed to determine the alpha-globin genotype. Overall, 15.5% patients were carriers for deletion forms of alpha+ thalassaemia. Average gene frequencies showed that there will be more than 2000 patients requiring treatment at any one time, in the future, of whom those with HbE/beta thalassaemia will account for about 40%. INTERPRETATION: In Sri Lanka, interactions of the two common beta-thalassaemia alleles will nearly always result in a transfusion-dependent disorder. However, about 40% of patients will have HbE/beta thalassaemia, which has a variable course. The management of these disorders could require about 5% of the total health budget. We need to learn more about the natural history and appropriate management of HbE/beta thalassaemia if resources are to be used effectively.

Liu YT, Old JM, Miles K, Fisher CA, Weatherall DJ, Clegg JB. 2000. Rapid detection of alpha-thalassaemia deletions and alpha-globin gene triplication by multiplex polymerase chain reactions. Br J Haematol, 108 (2), pp. 295-299. | Show Abstract | Read more

We describe a sensitive, reliable and reproducible method, based on three multiplex PCR assays, for the rapid detection of seven common alpha-thalassaemia deletions and one alpha-globin gene triplication. The new assay detects the alpha0 deletions - -SEA, - (alpha)20.5, - -MED, - -FIL and - -THAI in the first multiplex PCR, the second multiplex detects the -alpha3.7 deletion and alphaalphaalphaanti3.7 variant, the third multiplex detects the -alpha4.2 deletion. This simple multiplex method should greatly facilitate the genetic screening and molecular diagnosis of these determinants in populations where alpha-thalassaemias are prevalent.

Weatherall DJ, Provan AB. 2000. Red cells I: inherited anaemias. Lancet, 355 (9210), pp. 1169-1175. | Show Abstract | Read more

Examination of the genetic mechanisms underlying the thalassaemias has led to a clearer understanding of the control of eukaryotic genes in general. Inherited disorders of haemoglobin synthesis are an important cause worldwide of morbidity and mortality, and place a large burden on patients, families, and ultimately communities. The haemoglobin disorders can be controlled, by counselling and prenatal diagnosis. Treatment is usually symptomatic, though bone-marrow transplantation for beta-thalassaemia may be successful in suitable patients.

Pippard MJ, Weatherall DJ. 2000. Oral iron chelation therapy for thalassaemia: an uncertain scene. Br J Haematol, 111 (1), pp. 2-5. | Read more

Weatherall DJ. 2000. Introduction to the problem of hemoglobin E-beta thalassemia. J Pediatr Hematol Oncol, 22 (6), pp. 551. | Read more

Weatherall DJ. 2000. Internal medicine in the 21st century. Introduction. J Intern Med, 247 (1), pp. 3-5. | Read more

Weatherall DJ. 2000. Haematology in the new millennium. Br J Haematol, 108 (1), pp. 1-5. | Read more

Pippard MJ, Weatherall DJ. 2000. Deferiprone for thalassaemia. Lancet, 356 (9239), pp. 1444-1445. | Read more

Weatherall D. 1999. From genotype to phenotype: genetics and medical practice in the new millennium Philosophical Transactions of the Royal Society B: Biological Sciences, 354 (1392), pp. 1995-2010. | Read more

Fisher CA, Premawardhena A, De Silva S, Perera G, Lamabadasuriya SP, Peto TEA, Clegg JB, Olivieri NF, Weatherall DJ, Old JM, Study SLT. 1999. Thalassaemia in Sri Lanka: A molecular basis. BLOOD, 94 (10), pp. 424A-424A.

Clegg JB, Weatherall DJ. 1999. Thalassemia and Malaria: New Insights into an Old Problem Proceedings of the Association of American Physicians, 111 (4), pp. 278-282. | Read more

Allen SJ, O'Donnell A, Alexander ND, Mgone CS, Peto TE, Clegg JB, Alpers MP, Weatherall DJ. 1999. Prevention of cerebral malaria in children in Papua New Guinea by southeast Asian ovalocytosis band 3. Am J Trop Med Hyg, 60 (6), pp. 1056-1060. | Show Abstract | Read more

Southeast Asian ovalocytosis (SAO) occurs at high frequency in malarious regions of the western Pacific and may afford a survival advantage against malaria. It is caused by a deletion of the erythrocyte membrane band 3 gene and the band 3 protein mediates the cytoadherence of parasitized erythrocytes in vitro. The SAO band 3 variant may prevent cerebral malaria but it exacerbates malaria anemia and may also increase acidosis, a major determinant of mortality in malaria. We undertook a case-control study of children admitted to hospital in a malarious region of Papua New Guinea. The SAO band 3, detected by the polymerase chain reaction, was present in 0 of 68 children with cerebral malaria compared with six (8.8%) of 68 matched community controls (odds ratio = 0, 95% confidence interval = 0-0.85). Median hemoglobin levels were 1.2 g/dl lower in malaria cases with SAO than in controls (P = 0.035) but acidosis was not affected. The remarkable protection that SAO band 3 affords against cerebral malaria may offer a valuable approach to a better understanding of the mechanisms of adherence of parasitized erythrocytes to vascular endothelium, and thus of the pathogenesis of cerebral malaria.

Williams TN, Maitland K, Rees DC, Peto TE, Bowden DK, Weatherall DJ, Clegg JB. 1999. Reduced soluble transferrin receptor concentrations in acute malaria in Vanuatu. Am J Trop Med Hyg, 60 (5), pp. 875-878. | Show Abstract | Read more

Soluble transferrin receptor (sTfR) concentration is a sensitive index of iron deficiency when used in conjunction with ferritin measurements in adults. One advantage of this assay is that unlike ferritin it does not appear to be affected by a range of infectious and inflammatory conditions or by pregnancy, rendering it a promising adjunct to the diagnosis of iron deficiency in tropical populations. We have measured plasma sTfR concentrations in a group of malaria patients (n = 21) and asymptomatic (18) and aparasitemic (76) controls in Vanuatu. Plasma sTfR concentration was significantly reduced in individuals with acute malaria (P = 0.003). While this observation provides evidence that erythropoeitic suppression may be an important etiologic component in malarial anemia, it also suggests that malaria may be a confounding factor when interpreting sTfR concentrations in such populations. The role of sTfR in the diagnosis of iron deficiency in tropical populations remains to be established.

Rochette J, Pointon JJ, Fisher CA, Perera G, Arambepola M, Arichchi DSK, De Silva S, Vandwalle JL, Monti JP, Old JM et al. 1999. Multicentric Origin of Hemochromatosis Gene (HFE) Mutations The American Journal of Human Genetics, 64 (4), pp. 1056-1062. | Read more

Nathan DG, Weatherall DJ. 1999. Academia and industry: lessons from the unfortunate events in Toronto The Lancet, 353 (9155), pp. 771-772. | Read more

1998. Iron Chelation with Oral Deferiprone in Patients with Thalassemia New England Journal of Medicine, 339 (23), pp. 1710-1714. | Read more

Rees DC, Williams TN, Maitland K, Clegg JB, Weatherall DJ. 1998. Alpha thalassaemia is associated with increased soluble transferrin receptor levels. Br J Haematol, 103 (2), pp. 365-369. | Show Abstract | Read more

Although alpha+ thalassaemia is the commonest haemoglobinopathy in the world, it is not known if it is associated with significant ineffective erythropoiesis, a fact of importance in interpreting its complex interaction with malaria. To study this problem, we have measured the concentrations of soluble transferrin receptor (sTIR) and ferritin in 181 children from Vanuatu with heterozygous (68) and homozygous (46) alpha+ thalassaemia, and normal controls (67). sTfR concentrations were significantly higher in both homozygotes (mean 3.1 mg/l, range 2.8-3.4) and heterozygotes (2.86 mg/l, 2.6-3.2) compared to the normal controls (2.48 mg/l, 2.3-2.7), suggesting that although globin chain imbalance is minimal, there is ineffective erythropoiesis in both these conditions. Age was also shown to significantly affect sTfR, with peak levels occurring in the 5-9 years age group. Ferritin concentrations showed a similar trend, being higher in the thalassaemic groups, although this did not reach statistical significance. No individuals had low ferritin concentrations, although two had significantly elevated sTfR levels. These observations suggest that the alpha+ thalassaemia phenotype includes an expansion of the erythron, and may suggest possible mechanisms for the increased susceptibility in babies with alpha thalassaemia to both P. falciparum and P. vivax malaria.

Olivieri N. 1998. The therapeutic reactivation of fetal haemoglobin Human Molecular Genetics, 7 (10), pp. 1655-1658. | Read more

Weatherall DJ. 1998. Gene therapy: Repairing haemoglobin disorders with ribozymes Current Biology, 8 (19), pp. R696-R698. | Read more

O'donnell, Allen, Mgone, Martinson, Clegg, Weatherall. 1998. Red cell morphology and malaria anaemia in children with Southeast-Asian ovalocytosis band 3 in Papua New Guinea British Journal of Haematology, 101 (3), pp. 407-412. | Read more

REES DC, STYLES L, VICHINSKY EP, CLEGG JB, WEATHERALL DJ. 1998. The Hemoglobin E Syndromes Annals of the New York Academy of Sciences, 850 (1 COOLEY'S ANEM), pp. 334-343. | Read more

HO PJ, HALL GW, LUO LY, WEATHERALL DJ, THEIN SL. 1998. Phenotypic Prediction in beta-Thalassemia Annals of the New York Academy of Sciences, 850 (1 COOLEY'S ANEM), pp. 436-441. | Read more

Williams TN, Maitland K, Martin PM, Weatherall DJ, Clegg JB. 1998. Splenic size in homozygous alpha+ thalassaemia. Br J Haematol, 100 (3), pp. 611-612. | Read more

Weatherall DJ. 1998. 4 Pathophysiology of thalassaemia Baillière's Clinical Haematology, 11 (1), pp. 127-146. | Read more

Ho, Hall, Luo, Weatherall, Thein. 1998. Beta-thalassaemia intermedia: is it possible consistently to predict phenotype from genotype? British Journal of Haematology, 100 (1), pp. 70-78. | Read more

Weatherall D. 1998. The future role of molecular and cell biology in medical practice in the tropical countries British Medical Bulletin, 54 (2), pp. 489-501. | Read more

Allen SJ, O'Donnell A, Alexander ND, Alpers MP, Peto TE, Clegg JB, Weatherall DJ. 1997. alpha+-Thalassemia protects children against disease caused by other infections as well as malaria. Proc Natl Acad Sci U S A, 94 (26), pp. 14736-14741. | Show Abstract | Read more

In the South West Pacific region, the striking geographical correlation between the frequency of alpha+-thalassemia and the endemicity of Plasmodium falciparum suggests that this hemoglobinopathy provides a selective advantage against malaria. In Vanuatu, paradoxically, alpha+-thalassemia increases the incidence of contracting mild malaria in the first 2 years of life, but severe disease was too uncommon to assess adequately. Therefore, we undertook a prospective case-control study of children with severe malaria on the north coast of Papua New Guinea, where malaria transmission is intense and alpha+-thalassemia affects more than 90% of the population. Compared with normal children, the risk of having severe malaria was 0.40 (95% confidence interval 0.22-0.74) in alpha+-thalassemia homozygotes and 0.66 (0.37-1.20) in heterozygotes. Unexpectedly, the risk of hospital admission with infections other than malaria also was reduced to a similar degree in homozygous (0. 36; 95% confidence interval 0.22-0.60) and heterozygous (0.63; 0. 38-1.07) children. This clinical study demonstrates that a malaria resistance gene protects against disease caused by infections other than malaria. The mechanism of the remarkable protective effect of alpha+-thalassemia against severe childhood disease remains unclear but must encompass the clear interaction between this hemoglobinopathy and both malarial and nonmalarial infections.




Williams TN, Maitland K, Phelps L, Bennett S, Peto TEA, Viji J, Timothy R, Clegg JB, Weatherall DJ, Bowden DK. 1997. Plasmodium vivax: a cause of malnutrition in young children QJM-MONTHLY JOURNAL OF THE ASSOCIATION OF PHYSICIANS, 90 (12), pp. 751-7U2. | Read more

Maitland K, Williams TN, Peto TE, Day KP, Clegg JB, Weatherall DJ, Bowden DK. 1997. Absence of malaria-specific mortality in children in an area of hyperendemic malaria. Trans R Soc Trop Med Hyg, 91 (5), pp. 562-566. | Show Abstract | Read more

We conducted a prospective community-based malaria surveillance study on a cohort of children < 10 years old living in an area of hyperendemic malaria (spleen rates > 50% in children aged 2-9 years) in Vanuatu, Melanesia, supported by a concurrent prospective descriptive study of malaria admissions to the local hospital. The incidence of clinical malaria in children < 10 years old was 1.9 episodes/year. The annual incidence of severe malaria (severe malarial anaemia and cerebral malaria) was only 2/1000 in children aged < 5 years. The only manifestation of severe malaria seen in indigenous children was anaemia. No death could be attributed to malaria. While the incidence of uncomplicated clinical malaria in this population was comparable to that in many parts of Africa, the incidence of severe forms of the disease was significantly lower. This could not be attributed to differing rates of malaria transmission, chloroquine resistance, or to host protective or behavioural factors. These findings suggest that studies which compare disease patterns in geographically disparate populations may be instrumental in developing a better understanding of the determinants of clinical outcome in Plasmodium falciparum malaria and that such regional differences must be considered when planning or interpreting the effects of malaria interventions.

Olivieri NF, Rees DC, Ginder GD, Thein SL, Brittenham GM, Waye JS, Weatherall DJ. 1997. Treatment of thalassaemia major with phenylbutyrate and hydroxyurea The Lancet, 350 (9076), pp. 491-492. | Read more

Weatherall DJ. 1997. Fortnightly review: The thalassaemias BMJ, 314 (7095), pp. 1675-1675. | Read more

Weatherall DJ. 1997. ABC of clinical haematology: The hereditary anaemias BMJ, 314 (7079), pp. 492-492. | Read more

Maitland K, Williams TN, Bennett S, Newbold CI, Peto TE, Viji J, Timothy R, Clegg JB, Weatherall DJ, Bowden DK. 1996. The interaction between Plasmodium falciparum and P. vivax in children on Espiritu Santo island, Vanuatu. Trans R Soc Trop Med Hyg, 90 (6), pp. 614-620. | Show Abstract | Read more

Studies of the prevalence and incidence of malaria were conducted in children < 10 years old living in 10 rural villages on the island of Espiritu Santo, Vanuatu, south-west Pacific. Malaria prevalence remained stable at 30% throughout the year but the relative contributions of the 2 major species were highly dependent on season. Plasmodium falciparum predominated in the long wet season (November-May) and P. vivax in the dry season (June-October). Case definitions for malaria, derived using a multiple logistic regression method, showed that parasite densities associated with clinical disease were low; case definitions for P. falciparum (> 1000 parasites/microL in children > 1 year old and > 500 microL in infants) and P. vivax (> 500 parasites/microL at all ages) were both associated with a specificity and sensitivity of > 90%. Like prevalence data, malaria morbidity was highly seasonal; 80% of clinical P. falciparum infections occurred in the wet season and 66% of clinical P. vivax in the dry season. Mixed infections were rare. Malaria was important cause of morbidity with children < 5 years old experiencing 1.3-3.0 episodes of clinical malaria per year and 23% of fevers being attributable to malaria in this age group. Children aged 5-9 years continued to suffer one episode of clinical malaria per year. The peak incidence of P. vivax malaria occurred earlier in life than the peak incidence of P. falciparum malaria. The possible interactions between these 2 parasite species are discussed.

Williams TN, Maitland K, Ganczakowski M, Peto TE, Clegg JB, Weatherall DJ, Bowden DK. 1996. Red blood cell phenotypes in the alpha + thalassaemias from early childhood to maturity. Br J Haematol, 95 (2), pp. 266-272. | Show Abstract | Read more

The alpha+ thalassaemias are the most common single gene disorders of humans, yet little is known about their haematological characteristics in childhood. Blood samples have been collected randomly from more than 2000 individuals in village communities in Vanuatu in the South West Pacific and analysed for alpha thalassaemia and associated haematological changes. Here we describe the haematological effects of the alpha+ thalassaemias from early childhood through to maturity in this population. Mean cell volume (MCV) and mean cell haemoglobin (MCH) levels in individuals of normal, heterozygous and homozygous genotype differed significantly from one another throughout the entire age range (2P < 0.05). In contrast, haemoglobin levels in heterozygous and homozygous individuals were well maintained throughout development. Adults of normal genotype attain Hb levels which are indistinguishable from Caucasian reference values, a finding made all the more remarkable given the high frequency of clinical malaria in this population. It is clear from these findings that haematological data are valuable in screening for carriers of alpha+ thalassaemia in this population. MCH is clearly the most sensitive discriminator. None of the homozygous adults tested had an MCH of > 27 pg, whereas < 10% of normals had a value of < 27 pg. These data provide reference values for areas in which the alpha+ thalassaemias are common and often confused with iron-deficiency anaemia.

1996. Pitfalls of Genetic Testing New England Journal of Medicine, 335 (16), pp. 1235-1237. | Read more

Williams TN, Maitland K, Bennett S, Ganczakowski M, Peto TE, Newbold CI, Bowden DK, Weatherall DJ, Clegg JB. 1996. High incidence of malaria in alpha-thalassaemic children. Nature, 383 (6600), pp. 522-525. | Show Abstract | Read more

The alpha+-thalassaemias are the commonest known human genetic disorders, affecting up to 80 per cent of some populations. Although there is good evidence from both epidemiological and clinical studies that these gene frequencies reflect selection by, and protection from, malaria, the mechanism is unknown. We have studied the epidemiology of malaria in childhood on the southwestern Pacific island of Espiritu Santo in Vanuatu and here we report that, paradoxically, both the incidence of uncomplicated malaria and the prevalence of splenomegaly, an index of malaria infection, are significantly higher in young children with alpha+-thalassaemia than in normal children. Furthermore, this effect is most marked in the youngest children and for the non-lethal parasite Plasmodium vivax. The alpha+-thalassaemias may have been selected for their ability beneficially to increase susceptibility to P. vivax, which, by acting as a natural vaccine in this community, induces limited cross-species protection against subsequent severe P. falciparum malaria.

Weatherall DJ, Clegg JB. 1996. Thalassemia — a global public health problem Nature Medicine, 2 (8), pp. 847-849. | Read more

Warrell DA, White NJ, Nosten F, Day N. 1996. Tropical medicine in and out of the tropics. Lancet, 347 (9008), pp. 1111-1112. | Read more

Craig JE, Rochette J, Fisher CA, Weatherall DJ, Marc S, Lathrop GM, Demenais F, Thein S. 1996. Dissecting the loci controlling fetal haemoglobin production on chromosomes 11p and 6q by the regressive approach Nature Genetics, 12 (1), pp. 58-64. | Read more

Weatherall DJ, Ledingham JG, Warrell DA. 1995. On dinosaurs and medical textbooks. Lancet, 346 (8966), pp. 4-5. | Read more

Weatherall DJ. 1995. Teaching ethics to medical students. Journal of Medical Ethics, 21 (3), pp. 133-134. | Read more

WEATHERALL DAVIDJ. 1995. The Molecular Basis for Phenotypic Diversity of Genetic Disease Annals of the New York Academy of Sciences, 758 (1 DNA), pp. 245-260. | Read more

Weatherall D. 1995. The molecular basis for phenotypic variability of the common thalassaemias Molecular Medicine Today, 1 (1), pp. 15-20. | Read more

Ganczakowski M, Bowden DK, Maitland K, Williams TN, O'Shaughnessy D, Viji J, Lucassen A, Clegg JB, Weatherall DJ. 1995. Thalassaemia in Vanuatu, south-west Pacific: frequency and haematological phenotypes of young children. Br J Haematol, 89 (3), pp. 485-495. | Show Abstract | Read more

The archipelago of Vanuatu situated in the South-West Pacific has a high frequency of alpha + thalassaemia and additionally on some of the islands there is a high frequency of beta thalassaemia. As part of a large cohort study to investigate the clinical effect of thalassaemia on malaria on the islands of Espiritu Santo and Maewo in Vanuatu, the gene frequencies of the thalassaemias were determined and blood counts were performed on a cohort of infants from birth to 3 years. The haematological phenotypes of the different thalassaemic genotypes are compared, providing a detailed description of the clinical manifestations of alpha + thalassaemia during early development. In addition, cross-sectional surveys of the population of the two islands were performed to establish the frequency of thalassaemia and other red cell polymorphisms and their geographical distribution.

Weatherall DJ. 1994. The inhumanity of medicine BMJ, 309 (6970), pp. 1671-1672. | Read more

Stone C, Pointon JJ, Jazwinska EC, Halliday JW, Powell LW, Robson KJ, Monaco AP, Weatherall DJ. 1994. Isolation of CA dinucleotide repeats close to D6S105; linkage disequilibrium with haemochromatosis. Hum Mol Genet, 3 (11), pp. 2043-2046. | Show Abstract

The gene for hereditary haemochromatosis (HC) is linked to HLA-A and D6S105 on chromosome 6p. Both markers have also been reported to display linkage disequilibrium with the disease. However, their physical localization relative to one another has not been established. We demonstrate by fluorescent in situ hybridisation that D6S105 lies at least 1-2 Mb telomeric of HLA-A. The haemochromatosis critical region extending from proximal of HLA-A to distal of D6S105 is therefore large. To improve the genetic resolution in this region more highly polymorphic markers are required. We have therefore isolated three novel CA dinucleotide repeats close to D6S105. A linkage disequilibrium study, with two of these microsatellites, in HC patients and controls lends support to the conclusion that D6S105 is a close marker to the haemochromatosis gene.

Weatherall DJ. 1993. The Treatment of Thalassemia -- Slow Progress and New Dilemmas New England Journal of Medicine, 329 (12), pp. 877-879. | Read more

Weatherall DJ. 1993. Molecular medicine — towards the millennium Trends in Genetics, 9 (4), pp. 102-102. | Read more

Weatherall DJ. 1991. Examining undergraduate examinations The Lancet, 338 (8758), pp. 37-39. | Read more

Weatherall DJ. 1991. The physician scientist: an endangered but far from extinct species. BMJ, 302 (6783), pp. 1002-1005. | Read more

Luzzi GA, Merry AH, Newbold CI, Marsh K, Pasvol G, Weatherall DJ. 1991. Surface antigen expression on Plasmodium falciparum-infected erythrocytes is modified in alpha- and beta-thalassemia. J Exp Med, 173 (4), pp. 785-791. | Show Abstract | Read more

In an attempt to determine the mechanism whereby thalassemia in its milder forms may protect against malaria, we have examined the expression of neoantigen at the surface of Plasmodium falciparum-parasitized thalassemic red cells. Neoantigen expression was estimated by measurement of antibody bound after incubation in serum from adults living in a malaria-endemic area, using a quantitative radiometric antiglobulin assay. We found that P. falciparum-parasitized alpha- and beta-thalassemic red cells bind greater levels of antibody from endemic serum than controls: mean binding ratios (+/- SE), respectively, for alpha- and beta-thalassemia compared with controls were 1.69 +/- 0.12 and 1.23 +/- 0.06 on a cell for cell basis, and 1.97 +/- 0.11 and 1.47 +/- 0.08 after a correction for surface area differences. Binding of antibody increased exponentially during parasite maturation. In addition, we found a small but significant degree of binding of naturally occurring antibody to parasitized red cells, the extent of which was also greater in thalassemia. The apparent protective effect of thalassemia against malaria may be related to enhanced immune recognition and hence clearance of parasitized erythrocytes.

Weatherall DJ. 1991. Gene therapy in perspective Nature, 349 (6307), pp. 275-276. | Read more

Gibbons RJ, Wilkie AO, Weatherall DJ, Higgs DR. 1991. A newly defined X linked mental retardation syndrome associated with alpha thalassaemia. J Med Genet, 28 (11), pp. 729-733. | Read more

PETROU MARY, MODELL BERNADETTE, DARR AAMRA, OLD JOHN, KIN EI, WEATHERALL DAVID. 1990. Antenatal Diagnosis How to Deliver a Comprehensive Service in the United Kingdom Annals of the New York Academy of Sciences, 612 (1 Sixth Cooley'), pp. 251-263. | Read more

FRIEDLAND JS, WEATHERALL DJ, LEDINGHAM JGG. 1990. A Chronic Granulomatous Syndrome of Unknown Origin Medicine, 69 (6), pp. 325-331. | Read more

Thein SL, Hesketh C, Taylor P, Temperley IJ, Hutchinson RM, Old JM, Wood WG, Clegg JB, Weatherall DJ. 1990. Molecular basis for dominantly inherited inclusion body beta-thalassemia. Proceedings of the National Academy of Sciences, 87 (10), pp. 3924-3928. | Read more

O'Shaughnessy DF, Hill AV, Bowden DK, Weatherall DJ, Clegg JB. 1990. Globin genes in Micronesia: origins and affinities of Pacific Island peoples. Am J Hum Genet, 46 (1), pp. 144-155. | Show Abstract

DNA polymorphisms and copy-number variants of alpha-, zeta-, and gamma-globin genes have been studied in seven Micronesian island populations and have been compared with those in populations from Southeast Asia, Melanesia, and Polynesia. Micronesians are not significantly different from Polynesians at these loci and appear to be intermediate between Southeast Asians and Melanesians. There is evidence of significant Melanesian input into the Micronesian gene pool and of substantial proto-Polynesian contact with Melanesia.

Wilkie AO, Zeitlin HC, Lindenbaum RH, Buckle VJ, Fischel-Ghodsian N, Chui DH, Gardner-Medwin D, MacGillivray MH, Weatherall DJ, Higgs DR. 1990. Clinical features and molecular analysis of the alpha thalassemia/mental retardation syndromes. II. Cases without detectable abnormality of the alpha globin complex. Am J Hum Genet, 46 (6), pp. 1127-1140. | Show Abstract

We have identified five unrelated patients, all of north European origin, who have hemoglobin H (Hb H) disease and profound mental handicap. Surprisingly, detailed molecular analysis of the alpha globin complex is normal in these subjects. Clinically, they present with a rather uniform constellation of abnormalities, notably severe mental handicap, microcephaly, relative hypertelorism, unusual facies and genital anomalies. Hematologically, their Hb H disease has subtly but distinctly milder properties than the recognized Mendelian forms of the disease. These common features suggest that these five "nondeletion" patients have a similar underlying mutation, quite distinct from the 16p13.3 deletion associated with alpha thalassemia and mild to moderate mental retardation described in the accompanying paper. We speculate that the locus of this underlying mutation is not closely linked to the alpha globin complex and may encode a trans-acting factor involved in the normal regulation of alpha globin expression.

Lee SH, Looareesuwan S, Wattanagoon Y, Ho M, Wuthiekanun V, Vilaiwanna N, Weatherall DJ, White NJ. 1989. Antibody-dependent red cell removal during P. falciparum malaria: the clearance of red cells sensitized with an IgG anti-D. Br J Haematol, 73 (3), pp. 396-402. | Show Abstract | Read more

The clearance of autologous red cells sensitized with an IgG anti-D has been studied in patients during and after an attack of P. falciparum malaria, and in 11 uninfected control subjects. In most patients with P. falciparum malaria there was evidence of increased clearance of sensitized red cells, compared to controls. Clearance half-times of IgG sensitized red cells were significantly decreased (P less than 0.01) in 16 patients with acute falciparum malaria (median 21 min, range 11-53 min) compared to 11 control subjects (median 37 min, range 20-60 min). This difference was independent of the degree of IgG sensitization of red cells. In patients with acute falciparum malaria, clearance half-times were positively correlated with venous haematocrit (P less than 0.05). In 11 patients studied between 1 and 9 weeks after the attack, clearance half-times (median 17 min, range 11-56 min) were also significantly decreased compared to controls (P less than 0.01). In the majority of acute and convalescent patients, there was further evidence for early destruction of an additional substantial proportion of sensitized red cells. Our data indicate that in most patients with uncomplicated P. falciparum malaria, IgG sensitized red cells are rapidly removed from the peripheral circulation by the spleen, and that rapid clearance persists during recovery.

Monteiro C, Rueff J, Falcao AB, Portugal S, Weatherall DJ, Kulozik AE. 1989. The frequency and origin of the sickle cell mutation in the district of Coruche/Portugal Human Genetics, 82 (3), pp. 255-258. | Read more

Higgs DR, Vickers MA, Wilkie AO, Pretorius IM, Jarman AP, Weatherall DJ. 1989. A review of the molecular genetics of the human alpha-globin gene cluster. Blood, 73 (5), pp. 1081-1104.

Lamb J, Wilkie AO, Harris PC, Buckle VJ, Lindenbaum RH, Barton NJ, Reeders ST, Weatherall DJ, Higgs DR. 1989. Detection of breakpoints in submicroscopic chromosomal translocation, illustrating an important mechanism for genetic disease. Lancet, 2 (8667), pp. 819-824. | Show Abstract

A 3-year-old boy presented with alpha-thalassaemia, dysmorphic features, and mental handicap. His younger sister is also mentally retarded, but haematologically normal. High resolution cytogenetic analysis revealed a normal karyotype in all family members. However, a combination of DNA analysis and in situ hybridisation demonstrated that the mother has a previously unsuspected balanced reciprocal translocation between the tips of the short arms of chromosomes 1 and 16, and that the alpha-globin gene complex (which maps to the tip of chromosome 16) is included in the translocated segment. Both of her children have inherited one of the translocation chromosomes in an unbalanced fashion: the boy has the derived chromosome 16, and therefore has alpha-thalassaemia, whilst the girl has the derived chromosome 1. Such cytogenetically invisible subtelomeric translocations are probably an important and hitherto unrecognised cause of genetic disease.

Vyas P, Higgs DR, Weatherall DJ, Dunn D, Serjeant BE, Serjeant GR. 1988. The interaction of alpha thalassaemia and sickle cell-beta zero thalassaemia. Br J Haematol, 70 (4), pp. 449-454. | Show Abstract | Read more

The effects of alpha thalassaemia on sickle cell-beta zero thalassaemia have been studied by comparing haematological and clinical features in four subjects homozygous for alpha thalassaemia 2 (2-gene group), 27 heterozygotes (3-gene group), and 55 with a normal alpha globin gene complement (4-gene group). Alpha thalassaemia was associated with significantly higher haemoglobin levels and lower reticulocyte counts independent of the presence of splenomegaly. Contrary to expectation, alpha thalassaemia was associated with small but significant increases in mean cell volume and mean corpuscular haemoglobin concentration. Splenomegaly at age 5 years and episodes of acute splenic sequestration were significantly more frequent in the 4-gene group. There were no significant differences in painful crises, acute chest syndrome, or other clinical features.

Weatherall DJ, Bell JI, Clegg JB, Flint J, Higgs DR, Hill AV, Pasvol G, Thein SL. 1988. Genetic factors as determinants of infectious disease transmission in human communities. Philos Trans R Soc Lond B Biol Sci, 321 (1207), pp. 327-348. | Show Abstract | Read more

Genetic factors may play an important role in individual susceptibility to infection. Hitherto this problem has been investigated by attempting to relate the distribution of genetic polymorphisms in populations to present or past infection, or by analysing specific infections by classical twin studies or group comparisons. There is reasonable evidence that the common red-cell polymorphisms involving haemoglobin, enzymes or membrane have been maintained by relative resistance to malaria. Blood-group heterogeneity, including secretor status, may reflect varying susceptibility to bacterial, virus and yeast infection. There is increasing evidence that the HLA-DR system may be involved in modifying the clinical course of bacterial, virus and parasitic infection. So far no specific resistance or susceptibility loci similar to those found in murine models have been found in man. DNA analysis, particularly involving restriction fragment length polymorphism associations with candidate genes, offers a valuable new approach to this problem.

Thein SL, Hesketh C, Wallace RB, Weatherall DJ. 1988. The molecular basis of thalassaemia major and thalassaemia intermedia in Asian Indians: application to prenatal diagnosis British Journal of Haematology, 70 (2), pp. 225-231. | Read more

Robson KJ, Hall JR, Jennings MW, Harris TJ, Marsh K, Newbold CI, Tate VE, Weatherall DJ. 1988. A highly conserved amino-acid sequence in thrombospondin, properdin and in proteins from sporozoites and blood stages of a human malaria parasite. Nature, 335 (6185), pp. 79-82. | Show Abstract | Read more

As a consequence of gene cloning and DNA sequencing several gene families are emerging in the field of cell-cell recognition. These include immunoglobulins, integrins, certain extracellular glycoproteins and a family of functionally unrelated proteins which include factor B. We report here the cloning and sequencing of a gene from Plasmodium falciparum, coding for a protein we call thrombospondin related anonymous protein (TRAP), which shares certain sequence motifs common to other well-characterized proteins. The most significant homology is based around the sequence Trp-Ser-Pro-Cys-Ser-Val-Thr-Cys-Gly (WSPCSVTCG), present in three copies in region I of thrombospondin (TSP), six copies in properdin (P) and one copy in all the circumsporozoite (CS) proteins sequenced so far. TRAP also shares with certain extracellular glycoproteins, including TSP, the cell-recognition signal Arg-Gly-Asp (RGD), which has been shown to be crucial in the interaction of several extracellular glycoproteins with members of the integrin superfamily. Unlike the CS protein, TRAP is expressed during the erythrocytic stage of the parasite life cycle.

Hill AV, Bowden DK, O'Shaughnessy DF, Weatherall DJ, Clegg JB. 1988. Beta thalassemia in Melanesia: association with malaria and characterization of a common variant (IVS-1 nt 5 G----C). Blood, 72 (1), pp. 9-14. | Show Abstract

Data on the distribution of beta thalassemia among over 6,000 Melanesians reveals a major difference in the carrier rates between populations in the malarious coastal regions of New Guinea and those living in the historically malaria-free Highlands. The island of Maewo in Vanuatu has a particularly high incidence of beta + thalassemia associated with a single restriction enzyme haplotype. Direct cloning into a plasmid vector and sequence analysis demonstrate that the mutation is a G to C transversion at position 5 of intron 1 of the beta-globin gene. Oligonucleotide probe surveys indicate that this variant accounted for all cases of beta thalassemia studied from Maewo. It is also common in coastal Papua New Guinea where haplotype and oligonucleotide probe data suggest that the molecular basis of beta thalassmia is more heterogeneous.

Romeo G, Costa G, Catizone L, Germino GG, Weatherall DJ, Devoto M, Roncuzzi L, Zucchelli P, Keith T, Reeders ST. 1988. A SECOND GENETIC LOCUS FOR AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE The Lancet, 332 (8601), pp. 8-11. | Read more

Weatherall DJ, Old JM, Thein SL, Wainscoat JS, Sharma H, Emery AEH, Modell B. 1988. The Role of Cloned Genes in the Prevention of Genetic Disease [and Discussion] Philosophical Transactions of the Royal Society B: Biological Sciences, 319 (1194), pp. 249-261. | Read more

Hershko C, Peto TE, Weatherall DJ. 1988. Iron and infection. Br Med J (Clin Res Ed), 296 (6623), pp. 660-664. | Show Abstract | Read more

Because iron is needed in essential biochemical reactions and in oxygen transport living organisms have developed efficient mechanisms for its acquisition, transport, and storage. In man, transferrin and lactoferrin are responsible for binding ferric iron and transporting it in plasma and secretions, whereas non-functional iron is stored in the cells as ferric oxohydroxy crystals within ferritin molecules.1 To compete with these powerful iron conserving systems microorganisms have developed their own chelating compounds, the siderophores, which enable them to make iron soluble and assimilate it from their environment.23 This function is closely related to their virulence. © 1988, British Medical Journal Publishing Group. All rights reserved.

Weatherall DJ. 1988. The slow road to gene therapy Nature, 331 (6151), pp. 13-14. | Read more

Hershko C, Weatherall DJ, Finch C. 1988. Iron-Chelating Therapy CRC Critical Reviews in Clinical Laboratory Sciences, 26 (4), pp. 303-345. | Read more

Sacks SH, Old JM, Reeders ST, Weatherall DJ, Douglas AS, Winter JH, Rizza CR. 1988. Evidence linking familial thrombosis with a defective antithrombin III gene in two British kindreds. Journal of Medical Genetics, 25 (1), pp. 20-24. | Read more

Buckle VJ, Higgs DR, Wilkie AO, Super M, Weatherall DJ. 1988. Localisation of human alpha globin to 16p13.3----pter. J Med Genet, 25 (12), pp. 847-849. | Show Abstract

A female child with alpha thalassaemia trait, moderate mental retardation, and dysmorphic features has inherited an abnormal chromosome 16 complement as a result of the unbalanced segregation of a maternal balanced translocation. Cytogenetic analysis indicates that the patient is monosomic for 16p13.3----pter and trisomic for 10q26.13----qter. DNA studies show that the patient has not inherited either maternal alpha globin allele. This accounts for the alpha thalassaemia trait in the child and places the human alpha globin complex in band 16p13.3----pter.

Hill AV, Thein SL, Mavo B, Weatherall DJ, Clegg JB. 1987. Non-deletion haemoglobin H disease in Papua New Guinea. J Med Genet, 24 (12), pp. 767-771. | Show Abstract | Read more

Analysis of DNA from members of a Melanesian family from Papua New Guinea with haemoglobin (Hb) H disease revealed that all four alpha globin genes are intact in affected subjects. Study of restriction enzyme site and length polymorphisms and the use of oligonucleotide probes indicated that the molecular basis of this Papuan form of non-deletion Hb H disease differs from the previously described Middle Eastern and Mediterranean types.

Looareesuwan S, Merry AH, Phillips RE, Pleehachinda R, Wattanagoon Y, Ho M, Charoenlarp P, Warrell DA, Weatherall DJ. 1987. Reduced erythrocyte survival following clearance of malarial parasitaemia in Thai patients. Br J Haematol, 67 (4), pp. 473-478. | Show Abstract | Read more

Erythrocyte survival times were measured in healthy Thai controls and in patients following clearance of asexual P. falciparum or P. vivax parasitaemia. In five controls the mean cell life (MCL) of compatible donor erythrocytes was 89.6 d (mean range 73-101 d) compared with a mean MCL of 56.8 d (range 30-66 d) for autologous erythrocytes in 12 falciparum patients. In one of these patients the survival curve was biphasic with a rapid loss of some labelled cells. The survival of compatible donor erythrocytes was also studied in 10 patients and two types of survival curve could be distinguished. In five patients the cells had a mean MCL of 64.4 d (range 42-90 d). In the others survival curves were curvilinear, suggesting a complex mechanism of cell clearance or the presence of more than one cell population. There was initially a more rapid rate of destruction. In P. vivax malaria the MCL of autologous erythrocytes in seven patients was a mean of 67.2 d (range 34-74 d) and that of compatible donor cells in six patients was 66.8 d (range 54-76 d). In all except one of these patients both autologous and donor cell survival curves could be fitted to straight lines. No increase in cell-bound IgG or C3 was evident in 12 patients tested. The differences between the mean MCL in all the groups of patients and the controls were statistically significant at the 5% level. This indicates an increased rate of erythrocyte destruction following clearance of P. falciparum or P. vivax parasites which is not antibody or complement mediated. The mechanism is unknown, but appears to be extrinsic to the erythrocytes themselves and may result from nonspecific activation of the reticuloendothelial function associated with the parasitic infection.

Wainscoat JS, Thein SL, Weatherall DJ. 1987. Thalassaemia intermedia Blood Reviews, 1 (4), pp. 273-279. | Read more

1987. Bone Marrow Transplantation for Thalassemia New England Journal of Medicine, 317 (15), pp. 964-964. | Read more

Weatherall D. 1987. Molecular and cell biology in clinical medicine: introduction. BMJ, 295 (6598), pp. 587-589. | Read more

Weatherall DJ. 1987. Molecular pathology of single gene disorders. Journal of Clinical Pathology, 40 (9), pp. 959-970. | Read more

Reeders ST, Breuning MH, Ryynanen MA, Wright AF, Davies KE, King AW, Watson ML, Weatherall DJ. 1987. A study of genetic linkage heterogeneity in adult polycystic kidney disease. Hum Genet, 76 (4), pp. 348-351. | Show Abstract | Read more

The mutation for adult polycystic kidney disease (APKD) has previously been localised to chromosome 16 by the demonstration of genetic linkage with the loci for the alpha-chain of haemoglobin and phosphoglycolate phosphatase. These studies were carried out, however, on only nine families so that the possibility remained that mutations at other genetic loci might produce the disease. Such genetic heterogeneity of linkage would invalidate the general use of chromosome 16 markers for the purposes of detection of the disease, and complicate the characterisation of APKD at the molecular level. Therefore further families were studied to address this question. A total of 28 northern European pedigrees were analysed, all apparently unrelated, and with origins in England, Scotland, Holland and eastern Finland. No evidence was found to suggest heterogeneity of genetic linkage between alpha-globin and the APKD locus in this population.

Bowden DK, Hill AV, Weatherall DJ, Clegg JB. 1987. High frequency of beta thalassaemia in a small island population in Melanesia. J Med Genet, 24 (6), pp. 357-361. | Show Abstract | Read more

A study of the causes of anaemia in the south west Pacific archipelago of Vanuatu has identified one island, Maewo, where the carrier rate for beta thalassaemia exceeds 20%, one of the highest recorded incidences in the world. Homozygous beta thalassaemia is a major cause of infant mortality and a serious drain on health resources on this island. Interactions of beta thalassaemia with various forms of alpha + thalassaemia were common in this population. Coexistent alpha + thalassaemia leads to better haemoglobinised and larger red cells than are seen in simple beta thalassaemia heterozygotes and screening for the latter can only be reliably carried out by Hb A2 estimation.

Hill AV, Gentile B, Bonnardot JM, Roux J, Weatherall DJ, Clegg JB. 1987. Polynesian origins and affinities: globin gene variants in eastern Polynesia. Am J Hum Genet, 40 (5), pp. 453-463. | Show Abstract

Analysis of copy number variants of the duplicated alpha-, zeta-, and gamma-globin genes in eastern Polynesians revealed a high frequency of both triplicated-zeta-gene chromosomes and a specific alpha thalassemia deletion. This deletion and a novel restriction-enzyme-site polymorphism associated with a zeta zeta zeta chromosome are found only in Melanesians and Polynesians. Analysis of alpha-globin restriction-enzyme haplotypes indicated further similarities to Melanesians but suggested an additional non-Melanesian genetic component in eastern Polynesia. Several globin gene alleles showed evidence of marked frequency fluctuations due to genetic drift.

Thein SL, Jeffreys AJ, Gooi HC, Cotter F, Flint J, O'Connor NT, Weatherall DJ, Wainscoat JS. 1987. Detection of somatic changes in human cancer DNA by DNA fingerprint analysis. Br J Cancer, 55 (4), pp. 353-356. | Show Abstract | Read more

Minisatellite DNA probes which can detect a large number of autosomal loci dispersed throughout the human genome were used to examine the constitutional and tumour DNA of 35 patients with a variety of cancers of which eight were of gastrointestinal origin. Somatic changes were seen in the tumour DNA in ten of the 35 cases. The changes included alterations in the relative intensities of hybridising DNA fragments, and, in three cases of cancers of gastrointestinal origin, the appearance of novel minisatellite fragments not seen in the corresponding constitutional DNA. The results of this preliminary study suggests that DNA fingerprint analysis provides a useful technique for identifying somatic changes in cancers.

Thein SL, Wainscoat JS, Sampietro M, Old JM, Cappellini D, Fiorelli G, Modell B, Weatherall DJ. 1987. Association of thalassaemia intermedia with a beta-globin gene haplotype British Journal of Haematology, 65 (3), pp. 367-373. | Read more

Thein SL, Lynch JR, Old JM, Weatherall DJ. 1987. Direct detection of haemoglobin E with MnlI. Journal of Medical Genetics, 24 (2), pp. 110-111. | Read more

Thein SL, Weatherall DJ. 1987. Approach to the Diagnosis of β-Thalassaemia by DNA Analysis Acta Haematologica, 78 (2-3), pp. 159-167. | Read more

Hill AV, Flint J, Weatherall DJ, Clegg JB. 1987. Alpha-thalassaemia and the malaria hypothesis. Acta Haematol, 78 (2-3), pp. 173-179. | Show Abstract | Read more

Recent population genetic studies of the distribution of alpha+-thalassaemia in Melanesia using DNA analysis have provided strong support for the hypothesis that high frequencies of this genetic disorder are the result of natural selection by malaria.

Weatherall DJ. 1987. Has Haemoglobin a Future? Acta Haematologica, 78 (2-3), pp. 74-74. | Read more

Hill AV, Whitehouse DB, Bowden DK, Hopkinson DA, Draper CC, Peto TE, Clegg JB, Weatherall DJ. 1987. Ahaptoglobinaemia in Melanesia: DNA and malarial antibody studies. Trans R Soc Trop Med Hyg, 81 (4), pp. 573-577. | Show Abstract | Read more

To assess the relative contributions of genetic and acquired factors, particularly malaria, to the high frequencies of ahaptoglobinaemia found in Melanesia we have performed DNA and malarial antibody studies in a population from Vanuatu. No gene deletion or rearrangement was found on gene mapping in any ahaptoglobinaemic individual and the frequencies of the Hp1 and Hp2 alleles in the ahaptoglobinaemic group were similar to controls. However, antibodies to Plasmodium falciparum were significantly elevated in the ahaptoglobinaemics. These data suggest that malaria rather than genetic factors is the major cause of ahaptoglobinaemia in Melanesia.

Bowden DK, Hill AV, Higgs DR, Oppenheimer SJ, Weatherall DJ, Clegg JB. 1987. Different hematologic phenotypes are associated with the leftward (-alpha 4.2) and rightward (-alpha 3.7) alpha+-thalassemia deletions. J Clin Invest, 79 (1), pp. 39-43. | Show Abstract | Read more

We have compared the phenotypes of the two common deletion forms of alpha+-thalassemia by analysis of umbilical cord blood samples from Melanesia. Homozygotes for the leftward, 4.2-kilobase, deletion (-alpha 4.2) had significantly higher levels of Hb Bart's at birth than homozygotes for the rightward, 3.7-kilobase, deletion (-alpha 3.7). Compound heterozygotes for each deletion had intermediate values. Although deletion forms of alpha 0 thalassemia were not found in this survey, nondeletion alpha-thalassemia was present at low frequency. Since the predominant rightward deletion in this population, -alpha 3.7III, entirely removes the alpha 1-gene and the 4.2-kilobase deletion deletes the alpha 2-gene, these data indicate that the alpha 2-globin gene has a higher output than the alpha 1-gene, on single alpha-gene chromosomes.


Old JM, Heath C, Fitches A, Thein SL, Weatherall DJ, Warren R, Mckenzie C, Rodeck CH, Modell B, Petrou M, Ward RHT. 1986. FIRST-TRIMESTER FETAL DIAGNOSIS FOR HAEMOGLOBINOPATHIES: REPORT ON 200 CASES The Lancet, 328 (8510), pp. 763-767. | Read more

Merry AH, Looareesuwan S, Phillips RE, Chanthavanich P, Supanaranond W, Warrell DA, Weatherall DJ. 1986. Evidence against immune haemolysis in falciparum malaria in Thailand. Br J Haematol, 64 (1), pp. 187-194. | Show Abstract | Read more

Evidence of immune mediated haemolysis was sought in 83 patients with P. falciparum malaria in eastern Thailand. Amongst 73 patients with uncomplicated infection 12 (16.4%) had a weakly positive direct antiglobulin test (DAT). The incidence in 32 children aged 8-16 years was similar to that in adults. Of 10 patients with cerebral malaria, six adults, all of whom were in unrousable coma, had a positive DAT. Erythrocyte-bound IgG1 accounted for the positive DAT in all cases; sensitization with complement or other IgG subclasses was not found. Patients with uncomplicated malaria had a median value of 70 IgG molecules per erythrocyte compared with 65 molecules per cell in 67 healthy controls. This difference was not statistically significant but could account for the lower incidence of a positive DAT in control subjects (4.5%). There was no correlation between the number of IgG molecules per cell and the degree of anaemia during the acute or convalescent phases of the infection. There is no evidence from this study that an immunohaemolytic process contributes to the anaemia of falciparum malaria in eastern Thailand.

Flint J, Hill AV, Weatherall DJ, Clegg JB, Higgs DR. 1986. Alpha globin genotypes in two North European populations. Br J Haematol, 63 (4), pp. 796-797. | Read more

Reeders ST, Gal A, Propping P, Waldherr R, Davies KE, Zerres K, Hogenkamp T, Schmidt W, Dolata MM, Weatherall DJ. 1986. PRENATAL DIAGNOSIS OF AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE WITH A DNA PROBE The Lancet, 328 (8497), pp. 6-8. | Read more

Tate VE, Hill AV, Bowden DK, Sadler JR, Weatherall DJ, Clegg JB. 1986. A silent deletion in the beta-globin gene cluster. Nucleic Acids Res, 14 (12), pp. 4743-4750. | Show Abstract | Read more

A survey of the gamma-globin gene region of over 1000 normal individuals revealed a novel 2.5 kb deletion which removes the 5' end of the A gamma-globin gene. Unusually, this deletion in the beta-globin gene cluster is not associated with increased fetal haemoglobin production. Sequence analysis of the deletion endpoints revealed no significant homology at the breakpoint and failed to support a role for a proposed recombination hotspot in IVS-2 in the generation of this illegitimate recombination event. The existence of small "silent" deletions in the beta-globin gene cluster emphasizes the importance of deletion size in altering expression of the fetal globin genes.

Weatherall DJ. 1986. Molecular biology at the bedside. BMJ, 292 (6534), pp. 1505-1508. | Read more

Hill AV, Bowden DK, Weatherall DJ, Clegg JB. 1986. Chromosomes with one, two, three, and four fetal globin genes: molecular and hematologic analysis. Blood, 67 (6), pp. 1611-1618. | Show Abstract

Analysis of DNA from 852 Island Melanesians has revealed a high frequency of single- and triple-gamma-globin genes in this population. Homozygotes for triple- and single-gamma genes have normal hematologic findings, normal hemoglobin F (HbF) levels, and when there is coexisting alpha thalassemia, appropriate levels of Bart's Hb (gamma 4) at birth. In addition, we have identified an individual with a quadruple-gamma gene chromosome who also has a normal HbF level. All single-gamma genes were A gamma, all triple-gamma genes G gamma G gamma A gamma, and the quadruple-gamma gene G gamma G gamma G gamma A gamma. Analysis of G gamma:A gamma ratios in cord bloods and HbF levels in adults showed that these additional gamma genes are expressed and are down regulated appropriately by the fetal to adult Hb switch. Analysis of the restriction enzyme haplotypes of these various chromosomes indicates that intrachromosomal cross-overs are more likely to have produced these variants than interchromosomal recombination events.

Simpkins H, Hill AV, Derry S, Clegg JB, Weatherall DJ. 1986. Interaction of five globin gene abnormalities in a Cambodian family. Br J Haematol, 63 (1), pp. 7-15. | Show Abstract | Read more

Members of a Cambodian family with an undiagnosed hypochromic, microcytic anaemia were found by haemoglobin and DNA analysis to have five interacting globin gene abnormalities. One child has Hb E and typical Hb H disease, while his mother has the form of Hb H disease associated with Hb Constant Spring interacting with Hb E. Quantitation of Hbs E and A2 by globin chain separation and triton/urea gel electrophoresis support the concept that Hb H/Constant Spring disease is a more severe form of alpha thalassaemia than Hb H disease. This family illustrates how the remarkably high prevalence of globin gene abnormalities in Southeast Asians can give rise to a series of atypical thalassaemic phenotypes, and how they can be defined by direct globin gene analysis.

Reeders ST, Breuning MH, Corney G, Jeremiah SJ, Meera Khan P, Davies KE, Hopkinson DA, Pearson PL, Weatherall DJ. 1986. Two genetic markers closely linked to adult polycystic kidney disease on chromosome 16. BMJ, 292 (6524), pp. 851-853. | Read more

Phillips RE, Looareesuwan S, Warrell DA, Lee SH, Karbwang J, Warrell MJ, White NJ, Swasdichai C, Weatherall DJ. 1986. The importance of anaemia in cerebral and uncomplicated falciparum malaria: role of complications, dyserythropoiesis and iron sequestration. Q J Med, 58 (227), pp. 305-323. | Show Abstract | Read more

Ninety-four per cent of 169 patients with cerebral malaria developed anaemia (haematocrit less than 35 per cent) and 30 per cent required blood transfusion to maintain the haematocrit at more than 21 per cent. Anaemia was at its worst on admission in 58 patients (34 per cent); in the rest the haematocrit fell further, reaching its nadir one to 17 days later (mean 2.3 days). The mean lowest haematocrit was 24.3 +/- 7.2 per cent (+/- 1 SD) and the mean maximum fall was 7.9 +/- 5.6 per cent. Anaemia was more severe in patients with bacterial infection, retinal haemorrhages, schizontaemia and in pregnancy. The lowest haematocrit correlated with admission parasitaemia (r = -0.33, p less than 0.001), total serum bilirubin (r = -0.25, p less than 0.01) and serum creatinine (r = -0.22, p less than 0.01). In 23 patients with uncomplicated falciparum malaria the mean serum iron on admission was 53 micrograms/dl (range 16-157) and the mean serum ferritin 1773 ng/ml (range 170-10 000). There was a significant (p less than 0.001) rise in serum iron 96 h after starting antimalarial treatment; the serum ferritin declined slowly over several weeks. Stainable iron was present in all marrows examined and in eight patients the characteristic pattern of the anaemia of chronic disorders was seen. Seventy-three per cent of patients had dyserythropoiesis which was moderate to gross in 36 per cent. Dyserythropoiesis and erythrophagocytosis were often present on admission but sometimes appeared after the parasitaemia had cleared and persisted for at least three weeks into convalescence. These disturbances in iron metabolism and haemopoiesis are not completely explicable by red blood cell parasitisation. They may contribute more to the anaemia than has previously been recognised.

Wainscoat JS, Hill AV, Boyce AL, Flint J, Hernandez M, Thein SL, Old JM, Lynch JR, Falusi AG, Weatherall DJ. 1986. Evolutionary relationships of human populations from an analysis of nuclear DNA polymorphisms. Nature, 319 (6053), pp. 491-493. | Show Abstract | Read more

The genetic relationships of human populations have been studied by comparing gene frequency data for protein and blood-group loci of different populations. DNA analysis now promises to be more informative since not only do the DNA coding sequences have more variation than their corresponding proteins but, in addition, noncoding DNA sequences display more extensive polymorphism. We have now studied the frequency of a group of closely linked nuclear DNA polymorphisms (haplotypes) in the beta-globin gene cluster of normal (beta A) chromosomes of individuals from eight diverse populations. We have found that all non-African populations share a limited number of common haplotypes whereas Africans have predominantly a different haplotype not found in other populations. Genetic distance analysis based on these nuclear DNA polymorphisms indicates a major division of human populations into an African and a Eurasian group.

Old JM, Heath C, Fitches A, Thein SL, Jeffreys AJ, Petrou M, Modell B, Weatherall DJ. 1986. Meiotic recombination between two polymorphic restriction sites within the beta globin gene cluster. Journal of Medical Genetics, 23 (1), pp. 14-18. | Read more

WEATHERALL DJ. 1986. The Regulation of the Differential Expression of the Human Globin Genes During Development Journal of Cell Science, 1986 (Supplement 4), pp. 319-336. | Read more

Thein SL, Lynch JR, Weatherall DJ, Wallace RB. 1986. DIRECT DETECTION OF HAEMOGLOBIN E WITH SYNTHETIC OLIGONUCLEOTIDES The Lancet, 327 (8472), pp. 93-93. | Read more

Weatherall DJ, Old JM, Thein SL, Wainscoat JS, Clegg JB. 1985. Prenatal diagnosis of the common haemoglobin disorders. Journal of Medical Genetics, 22 (6), pp. 422-430. | Read more

O'Connor NT, Wainscoat JS, Weatherall DJ, Gatter KC, Feller AC, Isaacson P, Jones D, Lennert K, Pallesen G, Ramsey A. 1985. Rearrangement of the T-cell-receptor beta-chain gene in the diagnosis of lymphoproliferative disorders. Lancet, 1 (8441), pp. 1295-1297. | Show Abstract | Read more

The arrangement of the T-cell-receptor and immunoglobulin genes has been analysed in 77 cases of lymphoproliferative disorder. All 6 T-cell leukaemias and 16 of 19 T-cell lymphomas showed rearrangement of the gene coding for the beta chain of the T-cell receptor, associated in all cases with a germline arrangement of the immunoglobulin genes. All 36 B-cell leukaemias and all 16 B-cell lymphomas showed rearrangement of immunoglobulin genes; the T-cell-receptor gene was in the germline configuration in most of these cases but showed a rearranged pattern in 3 cases (2 chronic lymphatic leukaemias and 1 immunoblastic lymphoma). The combined use of T-cell-receptor and immunoglobulin gene probes promises to be a valuable means of identifying and classifying T-cell neoplasms.

JENNINGS MW, WOOD WG, JONES RW, WEATHERALL DJ. 1985. Analysis of Globin Gene Inversion Reveals Similarities with Immunoglobulin Rearrangement Annals of the New York Academy of Sciences, 445 (1 Fifth Cooley'), pp. 212-217. | Read more

OLD JM, WEATHERALL DJ, WARD RHT, PETROU M, MODELL B, RODECK CH, WARREN R, MORSMAN JM. 1985. First Trimester Diagnosis of the Hemoglobin Disorders Annals of the New York Academy of Sciences, 445 (1 Fifth Cooley'), pp. 349-356. | Read more

Hatton CS, Bunch C, Weatherall DJ. 1985. Hepatic sequestration in sickle cell anaemia. BMJ, 290 (6470), pp. 744-745. | Read more

Jennings MW, Jones RW, Wood WG, Weatherall DJ. 1985. Analysis of an inversion within the human beta globin gene cluster Nucleic Acids Research, 13 (8), pp. 2897-2906. | Read more

Hill AV, Bowden DK, Trent RJ, Higgs DR, Oppenheimer SJ, Thein SL, Mickleson KN, Weatherall DJ, Clegg JB. 1985. Melanesians and Polynesians share a unique alpha-thalassemia mutation. Am J Hum Genet, 37 (3), pp. 571-580. | Show Abstract

Several genetic markers that provide information on population migrations and affinities have been detected by studies of proteins and cellular antigens in blood. Analysis of DNA polymorphisms promises to yield many further population markers, and we report here the distribution of a new alpha-globin gene deletion (-alpha 3.7 III) detected by a restriction enzyme mapping. This is found frequently in Melanesians and Polynesians but not in five other populations in which alpha-thalassemia is prevalent. We used restriction enzyme haplotype analysis to support a single origin for this mutation and propose that it is a useful population marker. Its geographical distribution supports a route through Island Melanesia for the colonizers of Polynesia.

Higgs DR, Ayyub H, Clegg JB, Hill AV, Nicholls RD, Teal H, Wainscoat JS, Weatherall DJ. 1985. Alpha thalassaemia in British people. Br Med J (Clin Res Ed), 290 (6478), pp. 1303-1306. | Show Abstract | Read more

Although alpha thalassaemia is rare in north Europeans, it has been identified in British people with no known foreign ancestry. Twelve such patients were studied, of whom eight shared a distinctive molecular defect, which was clearly different from defects seen in subjects of Mediterranean or South East Asian origin. A rare but specific form of alpha thalassaemia is therefore present in the British population. In addition, two patients from families of mixed racial origin were encountered who had a moderately severe form of thalassaemia (HbH disease) due to the inheritance of one form of alpha thalassaemia from the British parent and another type from the foreign parent. This shows the importance of careful genetic counselling of British patients with haematological findings of thalassaemia.

Athanasou NA, Hatton C, McGee JO, Weatherall DJ. 1985. Vascular occlusion and infarction in sickle cell crisis and the sickle chest syndrome. J Clin Pathol, 38 (6), pp. 659-664. | Show Abstract | Read more

A young adult with homozygous sickle cell anaemia (Hb SS) suffered a fatal sickle cell crisis complicated by the sickle chest syndrome. At necropsy multiple large infarcts of the lung, bone marrow, and pituitary gland were found. The large majority of pulmonary infarcts were not associated with either gross or microscopic vaso-occlusion. These findings are discussed and correlated with past and current opinions of sickle cell crisis and the sickle chest syndrome.

Bowden DK, Hill AV, Higgs DR, Weatherall DJ, Clegg JB. 1985. Relative roles of genetic factors, dietary deficiency, and infection in anaemia in Vanuatu, South-West Pacific. Lancet, 2 (8463), pp. 1025-1028. | Show Abstract | Read more

Hypochromic anaemia is very common among the island populations of Vanuatu in the South-West Pacific. Results of a large-scale survey show that, unexpectedly, this form of anaemia is seldom due to iron deficiency or coexistent parasitic disease. Rather, it results from a previously unsuspected high incidence of alpha-thalassaemia which has been identified only by application of DNA analysis to the populations studied. These findings suggest that hypochromic anaemia in tropical or subtropical populations should not necessarily be attributed to iron deficiency; detailed studies of iron status should be carried out before major dietary changes or fortification of food with iron are implemented.

Higgs DR, Hill AV, Nicholls R, Goodbourn SE, Ayyub H, Teal H, Clegg JB, Weatherall DJ. 1985. Molecular rearrangements of the human alpha-globin gene cluster. Ann N Y Acad Sci, 445 (JUN), pp. 45-56. | Read more

Weatherall D. 1984. Gene transfection: A step nearer gene therapy? Nature, 310 (5977), pp. 451-451. | Read more

Derry S, Wood WG, Pippard M, Clegg JB, Weatherall DJ, Wickramasinghe SN, Darley J, Fucharoen S, Wasi P. 1984. Hematologic and biosynthetic studies in homozygous hemoglobin Constant Spring. Journal of Clinical Investigation, 73 (6), pp. 1673-1682. | Read more

Weatherall DJ. 1984. Prenatal diagnosis of thalassaemia. BMJ, 288 (6427), pp. 1321-1322. | Read more

Abdalla SH, Wickramasinghe SN, Weatherall DJ. 1984. The deoxyuridine suppression test in severe anaemia following Plasmodium falciparum malaria Transactions of the Royal Society of Tropical Medicine and Hygiene, 78 (1), pp. 60-63. | Read more

Potter CG, Bunch C, Potter AC, Buckle V, Derry S, Wood WG, Weatherall DJ. 1984. Erythroid differentiation in CGL cells from a patient with blast crisis Leukemia Research, 8 (4), pp. 713-721. | Read more

Higgs DR, Hill AV, Bowden DK, Weatherall DJ, Clegg JB. 1984. Independent recombination events between the duplicated human alpha globin genes; implications for their concerted evolution. Nucleic Acids Res, 12 (18), pp. 6965-6977. | Show Abstract | Read more

We have examined the molecular structure of the human alpha globin gene complex from individuals with a common form of alpha thalassaemia in which one of the duplicated pair of alpha genes (alpha alpha) has been deleted (-alpha 3-7). Restriction mapping and DNA sequence analysis of the mutants indicate that different -alpha 3.7 chromosomes are the result of at least three independent events. In each case the genetic crossover has occurred within a region of complete homology between the alpha 1 and alpha 2 genes. Since the -alpha chromosomes may reflect the processes of crossover fixation and gene conversion between the two genes, their structures may provide some insight into the mechanism by which the concerted evolution of the human alpha globin genes occurs.

Weatherall DJ, Higgs DH, Wood WG, Clegg JB. 1984. Genetic Disorders of Human Haemoglobin as Models for Analysing Gene Regulation Philosophical Transactions of the Royal Society B: Biological Sciences, 307 (1132), pp. 247-259. | Read more

Petrou M, Ward RHT, Modell B, Karagozlu F, Ozunlu VA, Hunt K, Old J, Weatherall DJ. 1983. OBSTETRIC OUTCOME IN FIRST TRIMESTER FETAL DIAGNOSIS FOR THE HAEMOGLOBINOPATHIES The Lancet, 322 (8361), pp. 1251-1251. | Read more

Wainscoat JS, Bell JI, Thein SL, Higgs DR, Sarjeant GR, Peto TE, Weatherall DJ. 1983. Multiple origins of the sickle mutation: evidence from beta S globin gene cluster polymorphisms. Mol Biol Med, 1 (2), pp. 191-197. | Show Abstract

Restriction site polymorphisms of the beta globin gene cluster of 244 Jamaican beta S chromosomes have been studied. Various patterns of restriction site polymorphisms (haplotypes) both 5' and 3' to the beta gene have been found. These two groups of haplotypes were found to be non-randomized with respect to each other. This is in contrast to normal beta A chromosomes where the 5' and 3' haplotypes are randomized. These findings together with the large number (18) of different beta S haplotypes found indicate that the beta S mutation probably has multiple origins.

Peto TE, Rutherford TR, Thompson JL, Weatherall DJ. 1983. Iron metabolism in murine erythroleukaemic cells. Br J Haematol, 54 (4), pp. 623-631. | Show Abstract | Read more

In an attempt to develop a model system for analysing iron metabolism in a relatively homogeneous population of early red cell precursors, the intracellular distribution of 59Fe was examined in Friend murine erythroleukaemic cells after induction of haemoglobin synthesis with dimethylsulphoxide. After incubation of the cells with 59Fe-labelled transferrin, 59Fe was incorporated into haemoglobin, various ferritin fractions, and into the pellet obtained by centrifugation. No intracellular transferrin or low molecular weight compounds were found. In a series of 'chase' experiments 59Fe accumulated in haem, and some of this radioactivity appeared to be derived from the ferritin fraction. Extra iron could be mobilized from ferritin during chase experiments using iron deficient incubation medium. These studies indicated that, at least under these experimental conditions, ferritin iron in early red cell precursors can be utilized for haemoglobin synthesis.

Duncan JR, Cappellini MD, Anderson MJ, Potter CG, Kurtz JB, Weatherall DJ. 1983. APLASTIC CRISIS DUE TO PARVOVIRUS INFECTION IN PYRUVATE KINASE DEFICIENCY The Lancet, 322 (8340), pp. 14-16. | Read more


Jungery M, Boyle D, Patel T, Pasvol G, Weatherall DJ. 1983. Lectin-like polypeptides of P. falciparum bind to red cell sialoglycoproteins Nature, 301 (5902), pp. 704-705. | Read more

Peto TE, Pippard MJ, Weatherall DJ. 1983. Iron overload in mild sideroblastic anaemias. Lancet, 1 (8321), pp. 375-378. | Show Abstract | Read more

Life-threatening iron overload may occur without severe anaemia in patients with sideroblastic disorders. Assessment of erythroid expansion in bone-marrow aspirates may be as useful as ferrokinetic studies in predicting both the risk of iron loading and the need for prophylactic phlebotomy or iron-chelation therapy.

Bell JI, Wainscoat JS, Old JM, Chlouverakis C, Keen H, Turner RC, Weatherall DJ. 1983. Maturity onset diabetes of the young is not linked to the insulin gene. BMJ, 286 (6365), pp. 590-592. | Read more

Abdalla SH, Kasili EG, Weatherall DJ. 1983. The Coombs direct antiglobulin test in Kenyans Transactions of the Royal Society of Tropical Medicine and Hygiene, 77 (1), pp. 99-102. | Read more

Jungery M, Pasvol G, Newbold CI, Weatherall DJ. 1983. A lectin-like receptor is involved in invasion of erythrocytes by Plasmodium falciparum. Proc Natl Acad Sci U S A, 80 (4), pp. 1018-1022. | Show Abstract | Read more

Glycophorin both in solution and inserted into liposomes blocks invasion of erythrocytes by the malaria parasite Plasmodium falciparum. Furthermore, one sugar, N-acetyl-D-glucosamine (GlcNAc), completely blocks invasion of the erythrocyte by this parasite. GlcNAc coupled to bovine serum albumin to prevent the sugar entering infected erythrocytes was at least 100,000 times more effective than GlcNAc alone. Bovine serum albumin coupled to lactose or bovine serum albumin alone had no effect on invasion. These results suggest that the binding of P. falciparum to erythrocytes is lectin-like and is determined by carbohydrates on glycophorin.

Clegg JB, Weatherall DJ, Bodmer WF. 1983. 5-azacytidine for beta-thalassemia? Lancet, 1 (8323), pp. 536. | Read more

Higgs DR, Goodbourn SE, Lamb J, Clegg JB, Weatherall DJ, Proudfoot NJ. 1983. Alpha-thalassaemia caused by a polyadenylation signal mutation. Nature, 306 (5941), pp. 398-400. | Show Abstract | Read more

Most eukaryotic messenger RNAs have the sequence AAUAAA 11-30 nucleotides from the 3'-terminal poly(A) tract. Since this is the only significant sequence homology in the 3' non-coding region it has been suggested that it may be a recognition site for enzymes involved in polyadenylation and/or termination of polymerase II transcription. This idea is strengthened by observations on the effect of deletion mutations in or around the AATAAA sequence on polyadenylation of late simian virus 40 (SV40) mRNA; removal of this sequence prevents poly(A) addition. Naturally occurring variants of this hexanucleotide are rare and hitherto their functional significance has not been assessed. We have now identified a human alpha 2-globin gene which contains a single point mutation in this hexanucleotide (AATAAA leads to AATAAG). The paired alpha 1 gene on the same chromosome is completely inactivated by a frame-shift mutation. This unique combination has enabled the expression of the mutant alpha 2 gene to be studied in vivo where it has been found that the accumulated level of alpha 2-specific mRNA in erythroid cells is reduced. Furthermore, readthrough transcripts extending beyond the normal poly(A) addition site are detected in mRNA obtained from HeLa cells transfected with cloned DNA from the mutant alpha 2 gene, suggesting that the single nucleotide change in the AATAAA sequence is the cause of its abnormal expression.

Krishna S, Shoubridge EA, White NJ, Weatherall DJ, Radda GK. 1983. Plasmodium yoelii: blood oxygen and brain function in the infected mouse. Exp Parasitol, 56 (3), pp. 391-396. | Show Abstract | Read more

The carriage of oxygen by the blood and the in vivo response of the brain were investigated in mice infected with a lethal strain of Plasmodium yoelii. All mice with parasitaemia exceeding 70% were severely anaemic (Hb 3.5 +/- 1.8 g/dl; mean +/- 1 SD), acidotic (blood pH 7.04 +/- 0.06) and hypoglycaemic (blood glucose 0.6 +/- 0.76 mumol/ml). The oxyhaemoglobin dissociation curve (ODC) of blood from heavily infected mice was shifted right as compared to controls, but the increase in p50 was less than expected from the accompanying acidosis. The reduced shift right was due to a decrease in the 2,3-DPG/Hb ratio in infected animals (0.72 +/- 0.12, n = 17 vs 1.10 +/- 0.09, n = 12 in controls). Despite the severity of terminal infection, the cerebral pH and the relative steady-state concentrations of PCr, ATP and Pi measured in vivo by nuclear magnetic resonance (31P NMR) were normal. Alterations in brain energy status and pH cannot account for cerebral signs or death in this proposed mouse model of cerebral malaria.


Pasvol G, Jungery M, Weatherall DJ, Parsons SF, Anstee DJ, Tanner MJA. 1982. GLYCOPHORIN AS A POSSIBLE RECEPTOR FOR PLASMODIUM FALCIPARUM The Lancet, 320 (8305), pp. 947-950. | Read more

Wickramasinghe SN, Abdalla S, Weatherall DJ. 1982. Cell Cycle Distribution of Erythroblasts in P. falciparum Malaria Scandinavian Journal of Haematology, 29 (1), pp. 83-88. | Read more

Abdalla S, Weatherall DJ. 1982. The direct antiglobulin test in P. falciparum malaria British Journal of Haematology, 51 (3), pp. 415-425. | Read more

Weatherall DJ, Clegg JB. 1982. Thalassemia Revisited Cell, 29 (1), pp. 7-9. | Read more

Wood WG, MacRae IA, Darbre PD, CLegg JB, Weatherall DJ. 1982. The British type of non-deletion HPFH: characterization of developmental changes in vivo and erythroid growth in vitro British Journal of Haematology, 50 (3), pp. 401-414. | Read more

Modell B, Letsky EA, Flynn DM, Peto R, Weatherall DJ. 1982. Survival and desferrioxamine in thalassaemia major. Br Med J (Clin Res Ed), 284 (6322), pp. 1081-1084. | Show Abstract | Read more

A small randomised trial and observation of all patients homozygous for beta-thalassaemia in Britain born in or before 1963 indicated that those patients who had received average weekly doses of more than 4 g of desferrioxamine over the previous few years were less likely to die in the near future than were patients of similar ages who had received less, or no, desferrioxamine.

Hunt DM, Higgs DR, Winichagoon P, Clegg JB, Weatherall DJ. 1982. Haemoglobin Constant Spring has an unstable alpha chain messenger RNA. Br J Haematol, 51 (3), pp. 405-413. | Show Abstract | Read more

Haemoglobin Constant Spring (Hb CS) is a variant with an elongated alpha-chain associated with an alpha + thalassaemia phenotype. The amount of alpha mRNA relative to beta mRNA in reticulocytes was reduced in carriers of Hb CS by an amount equivalent to the reduction observed in carriers of alpha + thalassaemia. In a patient with Hb CS-H disease there was greater alpha/beta mRNA ratio in bone marrow nuclear RNA than in the peripheral blood. Furthermore, all the alpha mRNA in the patient's peripheral blood was derived from the alpha 1 (alpha A) gene. The data suggest that alpha CS mRNA is unstable and degraded in the cytoplasm. This instability may be due to destabilization of a specific sequence in the 3' non-coding region during translation.

Bunch C, Wood WG, Weatherall DJ, Robinson JS, Corp MJ. 1981. Haemoglobin Synthesis by Fetal Erythroid Cells in an Adult Environment British Journal of Haematology, 49 (3), pp. 325-336. | Read more

POTTER CG, ROWELL AC, WEATHERALL DJ. 1981. Continuous long-term culture of human bone marrow Clinical & Laboratory Haematology, 3 (3), pp. 245-255. | Read more

Darbre PD, Lauckner SM, Adamson JW, Wood WG, Weatherall DJ. 1981. Haemoglobin Synthesis in Human Erythroid Bursts during Ontogeny: Reproducibility and Sensitivity to Culture Conditions British Journal of Haematology, 48 (2), pp. 237-250. | Read more

Weatherall DJ. 1981. Tropical medicine in British clinical schools: the Oxford experiment Transactions of the Royal Society of Tropical Medicine and Hygiene, 75 pp. 27-28. | Read more

Weatherall DJ, Higgs DR, Bunch C, Old JM, Hunt DM, Pressley L, Clegg JB, Bethlenfalvay NC, Sjolin S, Koler RD et al. 1981. Hemoglobin H disease and mental retardation: a new syndrome or a remarkable coincidence? N Engl J Med, 305 (11), pp. 607-612. | Show Abstract | Read more

Each of three families of northern European origin contains a mentally retarded son with hemoglobin H (Hb H) disease. One parent is a carrier of mild alpha-thalassemia and the other is normal, suggesting that this form of Hb H disease results from the interaction between an inherited defect of alpha-chain production and one member of the pair in chromosome 16 and a new mutation on the other. Restriction-enzyme analysis indicated that the new mutation was not the same in the other three patients, and demonstrated at least two hitherto undescribed lesions involving the alpha-globin gene cluster. Unless the association between the Hb H disease and mental retardation is fortuitous, the new mutations may also be related to the development changes in these children. Since the mutations only came to light because there was concurrent inheritance of an additional alpha-thalassemia determinant, this type of mutation of chromosome 16 may have been overlooked in other mentally retarded patients.

Pasvol G, Weatherall DJ. 1980. THE RED CELL AND THE MALARIAL PARASITE British Journal of Haematology, 46 (2), pp. 165-170. | Read more

Callender S, Weatherall DJ. 1980. IRON CHELATION WITH ORAL DESFERRIOXAMINE The Lancet, 316 (8196), pp. 689-689. | Read more

Wood WG, Pembrey ME, Serjeant GR, Perrine RP, Weatherall DJ. 1980. Hb F Synthesis in Sickle Cell Anaemia: a Comparison of Saudi Arab Cases with those of African Origin British Journal of Haematology, 45 (3), pp. 431-445. | Read more

Pasvol G, Weatherall DJ, Wilson RJM. 1980. The Increased Susceptibility of Young Red Cells to Invasion by the Malarial Parasite Plasmodium falciparum British Journal of Haematology, 45 (2), pp. 285-295. | Read more

Rutherford TR, Clegg JB, Weatherall DJ. 1980. EMBRYONIC HEMOGLOBIN SYNTHESIS IN HUMAN ERYTHROLEUKEMIA CELLS Annals of the New York Academy of Sciences, 344 (1 Fourth Cooley), pp. 233-239. | Read more

Weatherall DJ, Clegg JB, Wood WG, Old JM, Higgs DR, Pressley L, Darbre PD. 1980. THE CLINICAL AND MOLECULAR HETEROGENEITY OF THE THALASSEMIA SYNDROMES Annals of the New York Academy of Sciences, 344 (1 Fourth Cooley), pp. 83-100. | Read more

Higgs DR, Hunt DM, Drysdale HC, Clegg JB, Pressley L, Weatherall DJ. 1980. The genetic basis of Hb Q-H disease. Br J Haematol, 46 (3), pp. 387-400. | Show Abstract | Read more

A Chinese family has been studied in which two siblings have haemoglobin Q-H disease. Using a combination of haematological and haemoglobin analysis, globin chain synthesis, analysis of alpha/beta globin messenger RNA ratios and restriction endonuclease mapping, it has been shown that each of these siblings has received one chromosome on which both alpha chain genes have been deleted and another on which there is only a single alpha chain locus which carries the alpha Q mutation. Their genotype is thus --/-alpha Q. Despite the fact that the haemoglobin Q mutation in this family is carried on a chromosome with a single alpha chain locus, heterozygous carriers for the variant have only 25% or less haemoglobin Q. Our observations indicate that the molecular basis for haemoglobin Q-alpha thalassaemia is similar to that for the common form of haemoglobin H disease in Orientals. Furthermore, they provide clear evidence that the level of an alpha chain variant in heterozygous carriers is not a reliable reflection of the number of alpha globin genes.


Weatherall DJ. 1979. Mapping haemoglobin genes. BMJ, 2 (6186), pp. 352-354. | Read more

RUTHERFORD TR, CLEGG JB, WEATHERALL DJ. 1979. K562 human leukaemic cells synthesise embryonic haemoglobin in response to haemin Nature, 280 (5718), pp. 164-165. | Read more

Bunch C, Wood WG, Weatherall DJ, Adamson JW. 1979. CELLULAR ORIGINS OF THE FETAL-HÆMOGLOBIN-CONTAINING CELLS OF NORMAL ADULTS The Lancet, 313 (8127), pp. 1163-1165. | Read more

Rutherford TR, Weatherall DJ. 1979. Deficient heme synthesis as the cause of noninducibility of hemoglobin synthesis in a friend erythroleukemia cell line Cell, 16 (2), pp. 415-423. | Read more





Pembrey ME, Wood WG, Weatherall DJ, Perrine RP. 1978. Fetal Haemoglobin Production and the Sickle Gene in the Oases of Eastern Saudi Arabia British Journal of Haematology, 40 (3), pp. 415-429. | Read more

PASVOL G, WEATHERALL DJ, WILSON RJM. 1978. Cellular mechanism for the protective effect of haemoglobin S against P. falciparum malaria Nature, 274 (5672), pp. 701-703. | Read more

Old JM, Proudfoot NJ, Wood WG, Longley JI, Clegg JB, Weatherall DJ. 1978. Characterization of beta-globin mRNA in the beta0 thalassemias. Cell, 14 (2), pp. 289-298. | Show Abstract | Read more

A number of cases of beta0 thalassemia have been examined for the presence or absence of beta-globin mRNA. Total RNA extracted from peripheral blood was hybridized to purified complementary DNA specific for beta-globin mRNA, and to beta-cDNA probes specific for the 5' and 3' noncoding regions of beta-globin mRNA. Three clear-cut categories of beta0 thalassemia were identified. The first type had no detectable beta-globin mRNA. A second typed had beta-globin mRNA sequences which hybridized incompletely to the cDNA probes and probably represented mRNAs with grossly altered structures. A third type appeared to have essentially intact, though untranslatable, beta-globin mRNA. Depurination products from 5' and 3' beta-cDNAs synthesized from this latter mRNA were identical to those from normal beta-globin mRNA, but the relative yields were different, suggesting a possible defect near the initiation codon.

Pippard MJ, Letsky EA, Callender ST, Weatherall DJ. 1978. PREVENTION OF IRON LOADING IN TRANSFUSION-DEPENDENT THALASSÆMIA The Lancet, 311 (8075), pp. 1178-1181. | Read more

Fairweather DV, Modell B, Berdoukas V, Alter BP, Nathan DG, Loukopoulos D, Wood W, Clegg JB, Weatherall DJ. 1978. Antenatal diagnosis of thalassaemia major. BMJ, 1 (6109), pp. 350-353. | Read more

Pippard MJ, Callender ST, Weatherall DJ. 1978. Intensive Iron-Chelation Therapy with Desferrioxamine in Iron-Loading Anaemias Clinical Science, 54 (1), pp. 99-106. | Read more

PASVOL G, WEATHERALL DJ, WILSON RJM. 1977. Effects of foetal haemoglobin on susceptibility of red cells to Plasmodium falciparum Nature, 270 (5633), pp. 171-173. | Read more

OLD J, LONGLEY J, WOOD WG, CLEGG JB, WEATHERALL DJ. 1977. Molecular basis for acquired haemoglobin H disease Nature, 269 (5628), pp. 524-525. | Read more

Pippard MJ, Warner GT, Callender ST, Weatherall DJ. 1977. IRON ABSORPTION IN IRON-LOADING ANÆMIAS: EFFECT OF SUBCUTANEOUS DESFERRIOXAMINE INFUSIONS The Lancet, 310 (8041), pp. 737-739. | Read more

Weatherall DJ, Pippard MJ, Callender ST. 1977. Iron Loading and Thalassemia — Experimental Successes and Practical Realities New England Journal of Medicine, 297 (8), pp. 445-446. | Read more

Wood WG, Clegg JB, Weatherall DJ, Gyde OH, Obeid DA, Tarlow MJ, Brown MJ, Hewitt S. 1977. G gamma delta beta thalassaemia and g gamma HPFH (Hb Kenya type): comparison of 2 new cases. Journal of Medical Genetics, 14 (4), pp. 237-244. | Read more

Haghshenass M, Ismail-Beigi F, Clegg JB, Weatherall DJ. 1977. Mild sickle-cell anaemia in Iran associated with high levels of fetal haemoglobin. Journal of Medical Genetics, 14 (3), pp. 168-171. | Read more

Pippard MJ, Callender ST, Weatherall DJ. 1977. CHELATION REGIMENS WITH DESFERRIOXAMINE The Lancet, 309 (8021), pp. 1101-1101. | Read more

Weatherall DJ. 1977. The Molecular Basis for Abnormal Gene Action: Recent Lessons from the Thalassaemia Model Clinical Science, 52 (3), pp. 223-227. | Read more

WOOD WG, PEARCE K, CLEGG JB, WEATHERALL DJ, ROBINSON JS, THORBURN GD, DAWES GS. 1976. Switch from foetal to adult haemoglobin synthesis in normal and hypophysectomised sheep Nature, 264 (5588), pp. 799-801. | Read more

CHARACHE S, CLEGG JB, WEATHERALL DJ. 1976. The Negro Variety of Hereditary Persistence of Fetal Haemoglobin is a Mild Form of Thalassaemia British Journal of Haematology, 34 (4), pp. 527-534. | Read more

CHALEVELAKIS G, CLEGG JB, WEATHERALL DJ. 1976. Globin Synthesis in Normal Human Bone Marrow British Journal of Haematology, 34 (4), pp. 535-557. | Read more

Pritchard J, Longley J, Clegg JB, Weatherall DJ. 1976. Assay of Thalassaemic Messenger RNA in the Wheat Germ System British Journal of Haematology, 32 (4), pp. 473-486. | Read more

Weatherall DJ, Clegg JB, Milner PF, Marsh GW, Bolton FG, Serjeant GR. 1976. Linkage relationships between beta- and delta-structural loci and African forms of beta thalassaemia. Journal of Medical Genetics, 13 (1), pp. 20-26. | Read more

Bunch C, Callender ST, Emerson PM, Sharp AA, Weatherall DJ. 1976. Letter: Isolation of patients with bone marrow depression. BMJ, 1 (6000), pp. 40-40. | Read more

Sheridan BL, Weatherall DJ, Clegg JB, Pritchard J, Wood WG, Callender ST, Durrant IJ, McWhirter WR, Ali M, Partridge JW, Thompson EN. 1976. The patterns of fetal haemoglobin production in leukaemia. Br J Haematol, 32 (4), pp. 487-506. | Show Abstract | Read more

Elevated levels of haemoglobin F (Hb F) have been foudn in a wide range of haematological malignancies, but very high levels were found only in juvenile chronic myeloid leukaemia (JCML), and erythroleukaemia occurring in infancy. In both these disorders a reversion to a fetal form of erythropoiesis may occur, as judged by both the structure of the Hb F and by the disappearance of Hb A2 and the carbnoic-anhydrase isozymes during the course of the illness. The clinical picture of JCML is not always associated with a reversion to fetal erythropoiesis; there appears to be a heterogeneity of conditions with this clinical label. Thus the reversion to a completely fetal pattern of erythropoiesis seems to occur in a variety of leukaemias which start in early life. This change is associated with a uniformly bad prognosis. Of a group of 17 patients with acute myeloid leukaemia 15 developed an increase in the level of Hb F about 60 days after the commencement of treatment; significantly greater increases were observed in those achieving a clinical remission. The level of Hb F usually declined during remission but high levels persisted in a few cases. Increased levels of Hb F were found also in patients with other haematological malignancies who had undergone periods of marrow aplasia during treatment. In all cases the Hb F was heterogeneously distributed throughout the red cells. Analysis of gamma15 or gammaCB3 peptides of Hb F from a variety of leukaemias gave glycine compositions ranging from 0.20 to 0.85 residues with many values in the fetal range; all cases with a reversion to fetal erythropoiesis had values in the fetal range. Attempts to confirm the 'fetal' origin of the cells containing Hb F by means of other markers was possible only in the cases of JCML and in one child with erythroleukaemia. These studies indicate that in some forms of leukaemia there may be a genuine reversion to fetal erythropoiesis while in others the emergence of cells containing Hb F appears to be part of a rapid regeneration process occurring after a period of marrow aplasia. The diagnostic and prognostic value of these observations is discussed.

WEATHERALL DJ, CLEGG JB, WOOD WG, CALLENDER ST, SHERIDAN BL, PRITCHARD J. 1975. Foetal erythropoiesis in human leukaemia Nature, 257 (5528), pp. 710-712. | Read more

Chalevelakis G, Clegg JB, Weatherall DJ. 1975. Imbalanced globin chain synthesis in heterozygous beta-thalassemic bone marrow. Proceedings of the National Academy of Sciences, 72 (10), pp. 3853-3857. | Read more

Weatherall DJ, Clegg JB. 1975. The <latex>$\alpha$</latex>-Chain-Termination Mutants and Their Relation to the <latex>$\alpha$</latex>-Thalassaemias Philosophical Transactions of the Royal Society B: Biological Sciences, 271 (913), pp. 411-455. | Read more

Weatherall DJ, Clegg JB. 1975. Molecular Basis of Thalassaemia British Journal of Haematology, 31 (s1), pp. 133-141. | Read more

Ottolenghi S, Lanyon WG, Williamson R, Weatherall DJ, Clegg JB, Pitcher CS. 1975. Human globin gene analysis for a patient with beta-o/delta beta-thalassemia. Proceedings of the National Academy of Sciences, 72 (6), pp. 2294-2299. | Read more

Willcox MC, Weatherall DJ, Clegg JB. 1975. Homozygous beta thalassaemia in Liberia. Journal of Medical Genetics, 12 (2), pp. 165-173. | Read more

Shchory M, Weatherall DJ. 1975. Haemoglobin Synthesis in Human Fetal Liver Maintained in Short-Term Tissue Culture British Journal of Haematology, 30 (1), pp. 9-20. | Read more

Weatherall DJ, Clegg JB. 1975. HEREDITARY PERSISTENCE OF FETAL HAEMOGLOBIN British Journal of Haematology, 29 (2), pp. 191-198. | Read more

Weatherall DJ. 1974. Molecular Basis for Some Disorders of Haemoglobin Synthesis--I BMJ, 4 (5942), pp. 451-454. | Read more

Weatherall DJ. 1974. THE POTENTIAL MOLECULAR MECHANISM OF THALASSEMIAS AND RELATED DISORDERS Annals of the New York Academy of Sciences, 241 (1 Hemoglobins), pp. 132-141. | Read more

Weatherall DJ. 1974. The genetic control of protein synthesis: The haemoglobin model Journal of Clinical Pathology, s3-8 (1), pp. 1-11. | Read more

Weatherall DJ. 1974. The genetic control of protein synthesis: The haemoglobin model Journal of Clinical Pathology, 27 (Suppl 8), pp. 1-11. | Read more

Whittaker JA, Parry DH, Bunch C, Weatherall DJ. 1973. Coma Associated with Vincristine Therapy BMJ, 4 (5888), pp. 335-337. | Read more

ROBERTS AV, CLEGG JB, WEATHERALL DJ, OHTA Y. 1973. Synthesis in vitro of Anti-Lepore Haemoglobin Nature New Biology, 245 (140), pp. 23-24. | Read more

WOOD WG, WEATHERALL DJ. 1973. Haemoglobin Synthesis during Human Foetal Development Nature, 244 (5412), pp. 162-165. | Read more

Weatherall DJ, Clegg JB, Knox-Macaulay HHM, Bunch C, Hopkins CR, Temperley IJ. 1973. A Genetically Determined Disorder with Features both of Thalassaemia and Congenital Dyserythropoietic Anaemia British Journal of Haematology, 24 (6), pp. 681-702. | Read more

Pembrey ME, Weatherall DJ, Clegg JB. 1973. MATERNAL SYNTHESIS OF HÆMOGLOBIN F IN PREGNANCY The Lancet, 301 (7816), pp. 1350-1355. | Read more

CLEGG JB, WEATHERALL DJ. 1972. Haemoglobin Synthesis during Erythroid Maturation in β-Thalassaemia Nature New Biology, 240 (101), pp. 190-192. | Read more

Perrine RP, Brown MJ, Clegg JB, Weatherall DJ, May A. 1972. BENIGN SICKLE-CELL ANÆMIA The Lancet, 300 (7788), pp. 1163-1167. | Read more

Cochrane P, Weatherall DJ. 1972. THE VARIATION OF NEUTROPHIL ALKALINE PHOSPHATASE DURING THE MENSTRUAL CYCLE BJOG: An International Journal of Obstetrics and Gynaecology, 79 (11), pp. 1002-1008. | Read more

Pembrey ME, McWade P, Weatherall DJ. 1972. Reliable routine estimation of small amounts of foetal haemoglobin by alkali denaturation. Journal of Clinical Pathology, 25 (8), pp. 738-740. | Read more

Wood WG, Whittaker JH, Clegg JB, Weatherall DJ. 1972. Haemoglobin synthesis in human bone marrow culture Biochimica et Biophysica Acta (BBA) - Nucleic Acids and Protein Synthesis, 277 (2), pp. 413-420. | Read more

Beresford CH, Clegg JB, Weatherall DJ. 1972. Haemoglobin Ocho Rios ( beta52 (D3) aspartic acid leads to alanine): a new beta-chain variant of haemoglobin A found in combination with haemoglobin S. Journal of Medical Genetics, 9 (2), pp. 151-153. | Read more

Fessas P, Luan Eng L-I, Na-Nakorn S, Todd D, Clegg JB, Weatherall DJ. 1972. IDENTIFICATION OF SLOW-MOVING HÆMOGLOBINS IN HÆMOGLOBIN H DISEASE FROM DIFFERENT RACIAL GROUPS The Lancet, 299 (7764), pp. 1308-1310. | Read more

Knox-Macaulay HHM, Weatherall DJ, Clegg JB, Bradley J, Brown MJ. 1972. The Clinical and Biosynthetic Characterization of αβ-Thalassaemia British Journal of Haematology, 22 (4), pp. 497-512. | Read more

Weatherall DJ, Clegg JB. 1972. α-Thalassaemia due to a structural haemoglobin variant Biochimie, 54 (5-6), pp. 665-667. | Read more

CLEGG JB, WEATHERALL DJ, MILNER PF. 1971. Haemoglobin Constant Spring—A Chain Termination Mutant ? Nature, 234 (5328), pp. 337-340. | Read more

Clegg JB, Weatherall DJ, Eunson CE. 1971. The distribution of nascent globin chains on human reticulocyte polysomes Biochimica et Biophysica Acta (BBA) - Nucleic Acids and Protein Synthesis, 247 (1), pp. 109-112. | Read more

Bailey CC, Israëls MCG, Brown MT, Geary CG, Whittaker JA, Weatherall DT. 1971. CYTOSINE ARABINOSIDE IN THE TREATMENT OF ACUTE MYELOBLASTIC LEUKÆMIA The Lancet, 297 (7712), pp. 1268-1271. | Read more

Critchley EMR, Nicholson JT, Betts JJ, Weatherall DJ. 1970. Acanthocytosis, normolipoproteinaemia and multiple tics Postgraduate Medical Journal, 46 (542), pp. 698-701. | Read more

Weatherall DJ, Clegg JB. 1970. Haemoglobin synthesis in thalassaemia Biochemical Journal, 119 (5), pp. 68P.2-68P. | Read more

Weatherall DJ, Pembrey ME, Hall EG, Sanger R, Tippett P, Gavin J. 1970. FAMILIAL SIDEROBLASTIC ANÆMIA: PROBLEM OF Xg AND X CHROMOSOME INACTIVATION The Lancet, 296 (7676), pp. 744-748. | Read more

Weatherall DJ, Brown MJ. 1970. JUVENILE CHRONIC MYELOID LEUKÆMIA The Lancet, 295 (7645), pp. 526-526. | Read more

Weatherall DJ, Clegg JB. 1969. DISORDERED GLOBIN SYNTHESIS IN THALASSEMIA Annals of the New York Academy of Sciences, 165 (1 Second Confer), pp. 242-252. | Read more

CAUCHI MN, CLEGG JB, WEATHERALL DJ. 1969. Haemoglobin F(Malta): a New Foetal Haemoglobin Variant with a High Incidence in Maltese Infants Nature, 223 (5203), pp. 311-313. | Read more

CLEGG JB, WEATHERALL DJ, BOON WONGHOCK, MUSTAFA DAOUD. 1969. Two New Haemoglobin Variants involving Proline Substitutions Nature, 222 (5191), pp. 379-380. | Read more

Weatherall DJ. 1969. Polycythemia Resulting from Abnormal Hemoglobins New England Journal of Medicine, 280 (11), pp. 604-606. | Read more

Weatherall DJ, Clegg JB, Na-Nakorn S, Wasi P. 1969. The Pattern of Disordered Haemoglobin Synthesis in Homozygous and Heterozygous β-Thalassaemia British Journal of Haematology, 16 (3), pp. 251-268. | Read more

CLEGG JB, WEATHERALL DJ, NA-NAKORN SUPA, WASI PRAWASE. 1968. Haemoglobin Synthesis in β-Thalassaemia Nature, 220 (5168), pp. 664-668. | Read more

Weatherall DJ. 1968. THE BIOCHEMICAL LESION IN THALASSAEMIA British Journal of Haematology, 15 (1), pp. 1-6. | Read more

McCarthy GM, Temperley IJ, Clegg JB, Weatherall DJ. 1968. Thalassaemia in an Irish family Irish Journal of Medical Science, 1 (7), pp. 303-309. | Read more

Weatherall DJ, Edwards JA, Donohoe WT. 1968. Haemoglobin and red cell enzyme changes in juvenile myeloid leukaemia. BMJ, 1 (5593), pp. 679-681. | Read more

CLEGG JB, WEATHERALL DJ. 1967. Haemoglobin Synthesis in α-Thalassaemia (Haemoglobin H Disease) Nature, 215 (5107), pp. 1241-1243. | Read more

Weatherall DJ, McIntyre PA. 1967. Developmental and Acquired Variations in Erythrocyte Carbonic Anhydrase Isozymes British Journal of Haematology, 13 (1), pp. 106-114. | Read more

Charache S, Weatherall DJ, Clegg JB. 1966. Polycythemia associated with a hemoglobinopathy. Journal of Clinical Investigation, 45 (6), pp. 813-822. | Read more

WEATHERALL DJ, CLEGG JB, NAUGHTON MA. 1965. Globin Synthesis in Thalassaemia: An in vitro Study Nature, 208 (5015), pp. 1061-1065. | Read more

Weatherall DJ. 1964. Biochemical Phenotypes of Thalassemia in the American Negro Population* Annals of the New York Academy of Sciences, 119 (2), pp. 450-462. | Read more

RIEDER RONALDF, WEATHERALL DAVIDJ. 1964. A Variation in the Electrophoretic Pattern of Human Erythrocyte Carbonic Anhydrase Nature, 203 (4952), pp. 1364-1366. | Read more

Forshaw J, Harwood L, Weatherall DJ. 1964. Folic-acid Deficiency and Megaloblastic Erythropoiesis in Myelofibrosis BMJ, 1 (5384), pp. 671-672. | Read more

Huehns ER, Weatherall DJ, De Bellis RH, Luzzatto L, Smithies O. 1964. General Discussion: Human Proteins Cold Spring Harbor Symposia on Quantitative Biology, 29 pp. 387-390. | Read more

Weatherall DJ. 1963. Abnormal Haemoglobins in the Neonatal Period and their Relationship to Thalassaemia British Journal of Haematology, 9 (3), pp. 265-277. | Read more

Weatherall DJ. 1960. ENZYME DEFICIENCY IN HÆMOLYTIC DISEASE OF THE NEWBORN The Lancet, 276 (7155), pp. 835-837. | Read more

Weatherall DJ, Vella F. 1960. Thalassaemia in a Gurkha Family BMJ, 1 (5187), pp. 1711-1713. | Read more

Weatherall DJ, Wilkie AO. 1996. Genetics of disease. Curr Opin Genet Dev, 6 (3), pp. 271-274. | Read more