Quote: Lederberg on Haldane

J. B. S. Haldane has typically been assigned credit for the first suggestion that human hemoglobinopathies are adaptations to malaria. In 1999, Joshua Lederberg examined the history of this question Lederberg:Haldane:1999.

Haldane's most often remembered attribution, to malaria, oddly enough does not appear at all in the formal article but in the discussion footnotes. Therein, Montalenti acknowledges a verbal communication from Haldane suggesting that thalassemia heterozygotes may be more resistant to malaria. In his rejoinder, Haldane goes on to suggest that microcythemic heterozygotes may be at an advantage on diets deficient in iron or other substances, thus leading to anemia (HALDANE 1949, p. 76). This has been widely viewed as an anticipation of much later research on heterozygote advantage of blood dyscrasias in relation to malaria.1
In this regard, the work of A. C. ALLISON (1954) is well known. However, he remarks (private e-mail communication, April 26, 1999):
At the time of publication of my finding that sickle-cell heterozygotes have some protection against malaria (1954), I was unaware that J. B. S. Haldane had made a similar suggestion for thalassemia. After my publication I was invited to make a presentation at University College, London, and we had a friendly discussion. Haldane said that he had recognized that heterozygotes for the thalassemia gene are likely to have some advantage to counter-balance selection against homozygotes and suggested several possible candidates, among them malaria and better absorption of iron. He added that to speculate about the problem was one thing and to provide experimental evidence for a solution was altogether another. This was the first evidence that natural selection operates in humans.

Meanwhile, Allison himself Allison:1954 cited the earlier work of Beet, who showed in 1946 and 1947 that the blood of East African peoples with the sickle-cell trait carried a lower incidence of malaria parasites than the blood of normal individuals Beet:1946Beet:sickle:1947. Beet’s articles are of interest because they precede Haldane’s oblique suggestion about the adaptive value of thalassemia. Still, the relatively weak observation that sickle-cell individuals have a slightly lower incidence of parasites was not a sufficient proof that the sickle-cell trait actually protected its carriers.

Allison demonstrated the connection between sickle-cell and malaria resistance in two ways. He undertook an epidemiological survey among children, showing a very strong statistical association between non-sicklers and parasites in the blood. Then, he performed an experiment in which 15 sickle-cell trait and 15 normal individuals were injected with the malaria parasites in a controlled way. These two groups were starkly different in their parasite response, with only two of the sickle-cell trait individuals showing any parasites at all, and then at low blood counts; while 14 out of 15 of the normal individuals had parasite infections. His article is notable not only for this clear demonstration, but because of its direct discussion of the other major arguments in favor of the malaria resistance hypothesis, including the close examination of the geographic distribution of the sickle-cell trait in relation to endemic malaria, and the rejection of alternative hypothesis of high mutation rate. This paragraph is exceptionally clear:

The main problem can be stated briefly: how can the sickle-cell gene be maintained at such a high frequency among so many peoples in spite of the constant elimination of these genes through deaths from the anaemia? Since most sickle-cell anaemia subjects are homozygotes, the failure of each one to reproduce usually means the loss of two sickle-cell genes in every generation. It can be estimated that for the lost genes to be replaced by recurrent mutation so as to leave a balanced state, assuming that the sickle-cell trait -- that is, the heterozygous condition -- is neutral from the point of view of natural selection, it would be necessary to have a mutation rate on the order of 10-1. This is about 3,000 times greater than naturally occurring mutation rates calculated for man and, with rare exceptions, in many other animals.

Interesting: the mechanism by which the sickle-cell trait deters the parasites is even today not fully understood.