Malarial chemoprophylaxis

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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Competing interests:
None declared