Could our genes be a vaccine for Aids?

December 6, 2002

Can we use evolution to our advantage in the fight against disease? Martin Ince speaks to Sir David Weatherall (pictured) about the potential of molecular medicine

Evolution by natural selection is meant to be about the survival of the fittest. Exactly what that means is the subject of constant debate and discovery. But any organism that is felled by disease before it can reproduce is one that looks likely to fail the test of fitness.

This link will be explored in detail today by the Academy of Medical Sciences scientific meeting on evolution and disease. According to Sir David Weatherall, former director of the Weatherall Institute of Molecular Medicine in Oxford and a participant in the conference, the subject is an established one that produces much solid knowledge with potential clinical use, and one open to wild speculation.

He dates the field to 1948, when the British biologist J. B. S. Haldane pointed out the high frequency of genetic blood diseases - sickle-cell disease and thalassaemia - in some human populations in the tropics. "This was a big leap because he thought that the presence of the disease might bring some advantage and suggested that it could involve resistance to malaria," Weatherall says. "It took a long time to validate this but it turned out to be true. Sickle-cell disease itself is very severe but people who are carriers of the disease, and do not have it actively, live normal lives and are far less likely to develop malaria." Two years ago a study of children in Papua New Guinea showed that thalassaemia carriers were 60 per cent less likely than other children in the same villages to develop severe malaria.

It is not clear how long these adaptations have been at work, but Weatherall suggests that they date back about 5,000 years. This is the period of time over which settled human populations practising agriculture have been in contact with the malaria parasite and have participated in its transmission. "The malarial parasite has been in existence longer than this but was not in contact with people before then," he says. "Malaria kills people, and therefore resistance to it is selected severely in the carriers: in other words, in people." The health advantage conferred by adaptations such as sickle-cell disease is very large and enough time has passed for it to become entrenched in the population of malarial regions.

This kind of genetic variation is called a polymorphism, as the genes concerned can appear in one of a number of forms. A polymorphism that has arisen in the human population, and gives its carriers a slight advantage in reproduction over inhabitants of malarial areas who do not have it, will build up until there is a balance between the advantage it confers on the population and the loss being caused by the disease it brings.

Thalassaemia and sickle-cell disease are only the best-known adaptations to malaria. The disease is such a danger across the tropical world that a wide range of genetic countermeasures have sprung up to fight it. Weatherall says that there are millions of children with an enzyme defect that makes their red blood cells more likely to break up, which is doubtless malaria-related.

Malaria is not the only such case, however. There are people whose genes make them more resistant to HIV/Aids. Over time this polymorphism might be expected to spread, as those against malaria have in the tropics, although, Weatherall says, nobody knows how this particular polymorphism came to be there in the first place. HIV has not been in contact with the human population long enough for resistance to it to convey a reproductive advantage, which would let it spread by natural selection. Instead, it may in the past have conveyed resistance to virus infections that are no longer problematic.

One of the issues being addressed in a number of guises at today's conference is how fast evolution works. Weatherall says that the process can be very fast indeed when the pressure is strong - it may take just tens of years for the proportion of people with innate resistance to increase in a case such as Aids, for example. This kind of rapid effect is also likely to be the cause of a large amount of human diversity, such as the existence of different blood groups. These involve different blood proteins and different patterns of susceptibility to disease.

The prevalence of genetic effects varies with the severity of the disease they guard against. For example, the great European plagues had a rapid effect on the genetic make-up of Europeans. "If you look at cystic fibrosis, one of the few common single-gene diseases, you find it is very common in northern Europe but its frequency declines to the east and south," Weatherall says. "It is possible that carriers of the gene are protected from cholera and other plagues of the bowel and gut."

Weatherall says that more such examples will emerge because of the technology for analysing genes and their variability is advancing fast. We can now say that there has been heavy selection for the genes that convey some reproductive advantage, for example. He describes it as "an emerging story" in which it might be possible to have complete gene screening because of our knowledge of the genomes of important parasites and pathogens, and of humans and mice, a much-used model for human disease.

Knowing about the different forms of relative resistance to a disease might also lead to new ways of managing it. And if a new vaccine is being tested for its ability to attenuate malaria attacks, for example, it would help to know what percentage of the population is already immune before testing it.

Weatherall describes developments such as these as the "hard end" of the debate on evolution and disease. Among the more interesting examples of the "softer side" is what he terms "the extraordinary epidemic of diabetes" in the modern world. The disease is on the rise planet-wide, but he is especially interested in the steep increase of type 2, adult-onset diabetes in the tropical world. It is at its most severe among the indigenous populations of Asia and South America, such as the Pima people of Peru, where 70 per cent of the adult population has the disease, and the Nauru islanders of the Pacific, where the rate has reached up to 80 per cent. In India, rates can reach 30-40 per cent, similar to the incidence among Australian Aborigines.

Weatherall points to the work of the late James Neel, a US scientist at the University of Michigan who developed the "thrifty genotype" theory to explain such anomalies. The ancestors of many of the populations where type 2 diabetes is on the rise made their way from Asia to North America and the Pacific Islands during the last ice age. To do this, they must have faced immense hardship. "Neel suggested that the ancestors of today's populations had been selected for a thrifty genotype that was adapted to a very low-energy diet," Weatherall says. "People with such a genotype would be unsuited to the high-energy diets of the modern world." He says this is an attractive hypothesis, although there are other options. For example, there is a link between low birthweight, heart disease and type 2 diabetes, which reflects the interuterine environment before birth rather than genes.

Evolutionary medicine is also contributing to thought on the production and mutation of cancer cells. While childhood cancers exist, most cancers affect older people, and there has been speculation that they tend to appear when people have become old enough to have reproduced. At this stage the repair mechanisms that protect younger people run out.

This link between evolution and ageing has long been the subject of speculation. From the point of view of genes, why should people, and other animals, stick around once their offspring have become self-supporting? In the past, the answer has been thought to be social. Grandparents are useful, especially for childcare. But Weatherall says this is speculation. If it were true, there would be a selection effect, with grandparents living longer than others, which has not been observed.

Weatherall regards the evolutionary perspective as a counterbalance to the belief of some scientists who think that the safe modern world is one in which most diseases are under control and evolution by natural selection is no longer operating. "In Africa, where malaria kills a million people a year and Aids even more, very rapid selection is still going on," he says. And even in the developed world the evolutionary approach has something to offer. The connection between tobacco and cancer is clear. But work on diet and cancer has been less successful, while cancer risks from ionising radiation and other hazards such as the oxidants that result from our own metabolism also need more work. "In time our knowledge of the genetic makeup of the population is likely to be reflected in public health and in treatment protocols," Weatherall says. "Just to say that we are maladapted to the modern world is a little self-evident. After all, Europeans have only been exposed to tobacco for 500 years." So saying, Weatherall goes off for "a puff of my pipe".

The Academy of Medical Sciences' scientific meeting on evolution and disease is being held today at the Institute of Child Health in London. Sir David Weatherall will speak about the evolutionary legacy of infectious disease.

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