Malaria and sickle cell: "Protection?" Or "No Protection?" - Confusion reigns

In discussing malarial chemoprophylaxis Kelsey D J Jones (Oct 4) was absolutely right in mentioning not only the incomplete protective nature of sickle cell trait [1] but also the risks of malarial illness in children with sickle cell disease (scd). Doctors are confused not only about what constitutes sickle cell trait (one normal adult haemoglobin gene A¦ plus a sickle cell haemoglobin gene S¦ denoted AS phenotype which is supposed to afford protection against malaria, but also about the extreme vulnerability of patients with scd (two sickle cell genes) to malaria. Why, they ask, should one sickle gene be protective but two sickle genes deleterious? I hope the following removes the confusion.

THE PARADOX

The paradox confuses them. Indeed, I once said this: For example, at least one UK family physician has misadvised a Ghanaian patient who was homozygous (SS) for the sickle cell gene and going on holiday to West Africa. The doctor claimed the patient should have no problem with malaria because one S is protective, so SS must be doubly protective. On return to the UK, the patient had a devastating sickle cell crisis precipitated by malaria. [2] So what happened to the haemoglobin S protection? And what really are the facts?

SICKLE CELL TRAIT PROTECTION: HISTORICAL ASPECTS

Dr E A Beet, a British Colonial medical officer in Northern Rhodesia (Zambia) was the first to observe in 1946 that P malaria & P ovale infection rates were considerably less for sicklers than for non-sicklers [3]. A B Raper next suggested in 1949 that sickling was protective against tropical parasites [4]. From the then Congo in 1951 Lambotte-Legrand J & C [5] reported lower infant mortality from malaria and a lower incidence of cerebral malaria in sicklers. Dr P Brain in 1952 made the definite suggestion that the malarial parasites might find the erythrocytes of sicklers a less favourable environment than normal cells [6]. By this time haemoglobin electrophoresis had been discovered by Linus Pauling enabling him to identify and distinguish in the laboratory heterozygote AS (Trait) from homozygote SS disease [7] for which he got the Nobel Prize. Then J V Neel [8] in 1953 thought a balanced polymorphism could exist by which the Trait (heterozygote) enjoyed a selective advantage over either homozygote (ie later called respectively AA and the SS.

WHAT IS BALANCED POLYMORPHISM?

How I defined it: This is a biological phenomenon which occurs when the loss of a particular abnormal gene due to a selective disadvantage in the homozygous state is balanced by a relative superiority in the fitness of the heterozygote over the "normal homozygote" [9, pages 91-108]. For example, the gene for haemoglobin S is considered "abnormal and there is a selective disadvantage of the homozygote SS state, so that over the centuries, most homozygous patients failed to survive to procreative age" [9]. Loss of S¡¦ genes resulted. But non-sickling persons ie AA, did not survive as well over the centuries as the AS sicklers, so that when more of the AA died than the AS the proportion of the AS in the population increased. This is balanced polymporphism the phenomenon, according to Fisher [10], is sufficiently uncommon to suggest that it must always owe its origin to rather special circumstances [9].

CEREBRAL MALARIA THE SPECIAL CICUMSTANCES

Impressed by the clinical evidence of Beet [3 11], Raper [4], Lambotte-Legrand J & C [5] and Brain [6] and by the general correspondence between high malarial incidences in Africa and high sickling rate, Dr A C Allison [12] methodically presented 3 types of indirect evidence in favour of heterozygote survival superiority over normal and abnormal homozygotes, a conclusion that had been arrived at by Mackay and Vivarelli just a month earlier than Allison in the same British Medical Journal when the former stated that in a hyperendemic malarious area like Dar es Salaam the sickler has a better chance of survival to adult life than the non-sickler [13]. I have summarized in detail the early work done to confirm this phenomenon and to stress that the heterozygote survival advantage applies only to babies and toddlers with sickle cell trait, and the extrapolation of this to say that all sickle cell traits (young and old alike) are immune to malaria is a half truth. Cerebral malaria from Plasmodium falciparum is what the trait protects from in childhood. AA children die from this, while SS children die even quicker [14]. I find the work of Professor J O Oliver-Commey on cerebral malaria the most convincing direct evidence of this sickle Cell Trait advantage [15]. One in 5 perfectly healthy Ghanaians in Accra has the sickle cell trait AS [16], therefore if there was no heterozygote protection one would find them represented in any consecutive admissions into hospital. Using Commey criteria for cerebral malaria diagnosis in the Third World [17] this distinguished Ghanaian Paediatrician examined 30 consecutive admissions to his Unit at Korle Bu Teaching Hospital, expecting to find about six sickle cell traits (ie 20%) among them. There was not one AS phenotype among them [18]. Falciparum malaria is naturally selecting sickle cell traits for survival hence the keen interest in the phenomenon as an evolutionary tool.

THE SICKLE CELL GENE AND DARWINIAN EVOLUTION?

In March 1973 in Zurich Professor Alexander Boyo and I were two Africans invited among an international Consultation Group of 30 to prepare a working document on Genetics and the Quality of Life [19]. In the Group were lawyers, parliamentarians, medical physiologists, ethicists, embryologists, clinicians and geneticists under the able chairmanship of the celebrated Dr Robert Edwards. During one of the sessions, quite unprovoked, a professor of Biological Sciences from one Dominion Commonwealth Country turned his guns on Boyo and myself, accusing us of upsetting the course of Darwinian Evolution by seeking to eradicate malaria in Africa through chemoprophylaxis and other means. So sudden and unexpected was this attack that Boyo and I became (quite uncharacteristically) speechless. While Alexander Boyo DPhil (Oxon) MA MD (Cambridge) FRCPath FRCP seethed with anger, before he could explode, Bob Edwards stepped in with his usual Anglo-Saxon finesse and diplomacy to defuse a nasty situation. Boyo was not only a well known and respected malariologist and an authority on sickle cell balanced polymorphism, he also chaired several WHO Expert Panel Groups on the subject [20 21 22 23]. The assault on Boyo and me regarding malarial chemoprophylaxis upsetting the course of evolution was the first time it dawned on me that some intelligent scientists actually believed that the malaria-sickle cell adaptive interaction could be cited as evidence for the kind of natural selection that they said propelled Darwinian Evolution, even though I knew J S Haldane had suggested it before with respect to thalassaemia [24]. In relation to alpha thalassaemia, and to some extent beta thalassaemia The Haldane hypothesis, says Sir David Weatherall FRS, was correct (or almost) [25]. However, looking carefully at the malaria evidence as regards the sickle cell gene I once stated that I became convinced that the proof that evolution did take place must be sought elsewhere, and not in the adaptive processes against P. falciparum, anymore than that the ability of my black black skin to withstand the tropical sun established an evolutionary process starting perhaps with a Big Bang, to unicellular organism then multicellular organism then invertebrates then vertebrates and then man [9, pp 106-108]. But was balanced polymorphism with its Sickle Trait (AS) survival advantage over normal homozygotes (AA) and sickle cell anaemia patients (SS) alone sufficient to explain sickle cell trait huge incidences of 20% in southern Ghana, 30% in northern Nigeria, 43% in certain parts of India? [9, pp 76-82]. ANSWER: Certainly not. And this is where my African Anthropogenetic MPSI comes in.

MALE PROCREATIVE SUPERIORITY INDEX (MPSI)

Go to my tribe (Manya Krobo in South-east Ghana) and phenotype 100 consecutive babies born for beta globin genes. The result follows exactly that predicted by the Hardy-Weinberg Equation for the tribe where beta-S gene frequency is 0.1, beta-C is 0.05 [26]. About 20 of the babies will be sickle cell trait AS, 10 roughly will be Haemoglobin C Trait AC, 1 will be SS and 1 SC [Sickle Cell Haemoglobin C Disease]. Follow them up in a primitive decade without chemoprophylaxis. By procreative age the SS would have died, some of the AA children would die from Falciparum malaria, and the proportion of AS traits in the tribe by and large would increase just in one generation. But imagine a pair of boy/girl sickle cell trait twins who also survive into adulthood. The boy twin had (in the traditional situation) more offspring due to polygamy than his twin sister could ever hope to have, if only because the menopause prevented her. We have quantified the effect of this in different areas of Ghana and shown how this has been enhancing the sickle trait survival advantage and leading to genetic consequences [27 28 29 30], which led me to say that African anthropogenetics needs rethinking more on factual lines than on theoretical evolutionary concepts [27].

CONCLUSIONS

1. Sickle cell disease (scd) patients are not immune to malaria. They die quicker from the disease and need chemoprophylaxis [1 14].

2. Sickle Cell Traits (AS) are not immune to malaria. They get malaria, but they did not die from cerebral malaria as the non-sickler AA and the scd patient SS did before the age of immunity to malaria in the hyperendemic milieu [31 32 33]. The traits also need protecting from attacks of malaria because immunity is not total. My sickle cell trait (AS) mother was for ever suffering from malaria until she died of something else at the age of 89.

3. The sickle cell heterozygote (AS) survival adaptive advantage in the Falciparum malaria environment cannot be justifiably extrapolated to support Darwinian evolutionism.

4 The high sickle cell trait AS incidences (nearly 50% in certain areas of Praja Prajara in India) are better understood by a combination of more traits reaching procreative age to acquire more wives than other phenotypes born at the same time in the same village.

F I D Konotey-Ahulu MD (Lond) FRCP (Lond) DTMH(L'pool)
Kwegyir Aggrey Distinguished Professor of Human Genetics, University of Cape Coast, Ghana & Consultant Physician Genetic Counsellor, 10 Harley Street, London W1G 9PF
felix@konotey-ahulu.com

Competing interests: None declared.

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