Science: A skier with gold medals in his blood: In endurance sports, a plentiful supply of oxygen to the muscles is vital to success. Ruth McKernan on a family blessed by a mutant gene
Monday 02 August 1993
Athletes who push themselves to the limits of performance, such as long-distance runners, cyclists and cross-country skiers, rely heavily on the blood's ability to deliver a plentiful supply of oxygen to their muscles. High-altitude training is a legitimate way of increasing the number of oxygen-carrying red cells in the blood. Some athletes, however, supplement their blood with concentrated red cells, a procedure known as blood doping.
Red blood cell production is normally controlled in the body by the hormone erythropoietin, which can be used as a drug to increase the red blood count of sufferers from renal failure, or anaemia as a consequence of Aids. Some athletes have illicitly taken erythropoietin, an action that is difficult, if not impossible, to detect.
The Finnish gold medallist skier, however, comes from a family whose unusual blood profile was puzzling doctors long before any gold medals were won. All members of the family are descended from one couple, born in the 1850s.
'Typically, members of the family are healthy, go to a doctor for something else, and as part of a routine blood test, doctors find levels of haemoglobin and red blood cells that to them are incomprehensible,' says Albert de la Chapelle, professor of medical genetics at the University of Helsinki and leader of the group that solved the mystery.
Dr Eeva Juvonen, a haematologist from the Department of Medicine at the University of Helsinki, has studied blood from many of the 100 or so family members. She finds that all the affected individuals have high levels of haemoglobin, the oxygen-carrying molecule in red blood cells, averaging 200gm per litre (a normal person would have about 150gm per litre). Such levels are a consequence of having more red blood cells. In all other respects, as far as the doctors can see, members of the group have no negative symptoms except perhaps a ruddy complexion.
Dr Juvonen and her colleagues found that this haemoglobin molecule carries oxygen in exactly the same way as normal blood, and the level of erythropoietin is also normal. Dr Juvonen even took cells from the bone marrow, the precursors of red blood cells, grew them in the laboratory and searched for anything unusual, but nothing turned up.
More than 15 years after the first study, however, one experiment pointed the researchers in the right direction. Dr Juvonen took more bone marrow cells from three affected individuals and found that smaller amounts of erythropoietin produced more red blood cells than usual.
The researchers then realised that the abnormality lay in how juvenile cells responded to the hormone. From that point, the search moved to the field of molecular genetics and the laboratory of Professor de la Chapelle.
Earlier this year, Professor de la Chapelle and his colleagues found the gene responsible for the syndrome. All affected members of the family have one normal and one abnormal gene. The latter contains the genetic prescription for making the erythropoietin 'receptor'. The hormone homes in on this target molecule, which lies on the surface of young bone marrow cells, and by locking on to the receptor, stimulates the production of red blood cells.
The tiniest error in the DNA coding for the receptor is enough to produce an obvious change in the blood's characteristics. The mutation is the equivalent of a typographical error in a page of text, where the letter 'a' three-quarters of the way down the page is replaced by the letter 'e'. Instead of reading the word 'and', the cell's machinery in effect reads the word 'end', and ignores the rest of the instructions. Consequently the cell makes an erythropoietin receptor that has the final 20 per cent of its structure missing.
According to Dr Gregory Longmore, assistant professor of medicine and cell biology at Washington University, the receptor molecule spans the cell's wall: the outermost part responds to circulating erythropoietin, and a second region, inside the cell, regulates the response.
When activated, the receptor instructs the cell to develop into a red blood cell and make haemoglobin. The regulatory domain acts as a brake. But in members of this Finnish family, the inner domain is absent. The brake has been removed in individuals with the disorder, Professor de la Chapelle says.
Scientists still have to find out what might happen if both chromosomes carried the mutation. 'We have been speculating about this,' Professor de la Chapelle says. 'With members of the family three or four generations apart, it could happen, but so far we haven't found anyone.'
The modest increase in the number of red blood cells experienced by the Finnish family is beneficial, but Dr Longmore warns that 'with too much, you can get sludging of the blood, which makes you more prone to strokes and bleeding complications, headaches and other disturbances'.
Heavy smokers have more red blood cells than non-smokers. Carbon monoxide from cigarette smoke binds tightly to haemoglobin, compromising the oxygen-carrying capacity of the blood. The body adapts by making many more red blood cells.
As the athletic record book shows, carriers of the mutant erythropoietin gene who take part in endurance sports find themselves blessed with a natural talent. But the scientists' findings do not undermine the skier's achievements.
A genetic advantage is not enough in itself to make a supreme athlete out of anyone. Tall, long-legged people do not all make good high jumpers, and sturdy, muscle-bound individuals do not necessarily become champion weightlifters. There is much more to being a champion sportsman or woman than the sum of the biological properties of the person's body.
With the recent advances in genetics, the discovery of rare mutations is becoming commonplace. Scientists have found more than 100 dominantly inherited mutations that are linked to diseases, but the erythropoietin gene is the first that bodes well, rather than ill, for the recipient.
'Certain widespread mutations are mildly advantageous when recessive - for example, sickle-cell anaemia, which is protective against malaria - but an autosomal dominant mutation like this is unique,' Professor de la Chapelle says. It has been possible to track down this particular mutation only because it causes obvious physical changes in the blood. Other mutations with more subtle consequences may never be identified.
The mutant erythropoietin receptor could be regarded as contemporary evidence for Darwin's theory of natural selection.
In times when long-distance travel was governed more by personal fitness than by the performance of a combustion engine, the inheritance of a mutant erythropoietin receptor could have made the difference between life and death. Today, it may just make the difference between gold, silver and bronze.
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