Matt Ridley

Steve Fodor, president of Asymetrix

The improvement of any medical technology confronts our species with a moral dilemma. If the technology can save lives, then not to develop it and use it is morally culpable, even if there are attendant risks. In the Stone Age, we had no option but to watch our relatives die of smallpox. After Jenner had perfected vaccination we were derelict in our duty if we did so. In the nineteenth century, we had no alternative to watching our parents succumb to tuberculosis.

After Fleming found penicillin we were guilty of neglect if we failed to take a dying tubercular patient to the doctor. And what applies on the individual level applies with even greater force on the level of countries and peoples. Rich countries can no longer ignore the epidemics of diarrhoea that claim the lives of countless children in poor countries, because no longer can we argue that nothing medically can be done. Oral rehydration therapy has given us a conscience.

Because something can be done, so something must be done.

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This chapter is about the genetic diagnosis of two of the commonest diseases that afflict people, one a swift and merciless killer, the other a slow and relentless thief of memory: coronary heart disease and Alzheimer's disease. I believe we are in danger of being too squeamish and too cautious in using knowledge about the genes that influence both diseases, and we therefore stand at risk of committing the moral error of denying people access to life-saving research.

There is a family of genes called the apolipoprotein genes, or APO

genes. They come in four basic varieties, called A, B, C and - strangely

- E, though there are various different versions of each on different chromosomes. The one that interests us most is APOE, which happens to lie here on chromosome 19. To understand APOE's job requires a digression into the habits of cholesterol and triglyceride fats. When you eat a plate of bacon and eggs, you absorb much fat and with it cholesterol, the fat-soluble molecule from which so many hormones are made (see the chapter on chromosome 10). The liver digests this stuff and feeds it into the bloodstream for delivery to other tissues. Being insoluble in water, both triglyceride fats and cholesterol have to be carried through the blood by proteins called lipoproteins. At the beginning of the journey, laden with both cholesterol and fats, the delivery truck is called V L D L , for very-low-density lipoprotein. As it drops off some of its triglycerides, it becomes low-density lipoprotein, or L D L ('bad cholesterol').

Finally, after delivering its cholesterol, it becomes high-density lipoprotein, H D L ('good cholesterol') and returns to the liver for a new consignment.

The job of APOE's protein (called apo-epsilon) is to effect an introduction between V L D L and a receptor on a cell that needs some triglycerides; APOB's job (or rather apo-beta's) is to do the same for the cholesterol drop-off. It is easy to see therefore that APOE and APOB are prime candidates for involvement in heart disease. If they are not working, the cholesterol and fat stay in the bloodstream and can build up on the walls of arteries as atherosclerosis. Knockout mice with no APOE genes get atherosclerosis even 2 6 0 G E N O M E

on a normal mouse diet. The genes for the lipoproteins themselves and for the receptors on cells can also affect the way in which cholesterol and fat behave in the blood and thereby facilitate heart attacks. An inherited predisposition to heart disease, called familial hypercholesterolaemia, results from a rare 'spelling change' in the gene for cholesterol receptors.1

What marks APOE out as special is that it is so 'polymorphic'.

Instead of us all having one version of the gene, with rare exceptions, APOE is like eye colour: it comes in three common kinds, known as E2, E3 and E4. Because these three vary in their efficiency at removing triglycerides from the blood, they also vary in their susceptibility to heart disease. In Europe, E3 is both the 'best' and the commonest kind: more than eighty per cent of people have at least one copy of E3 and thirty-nine per cent have two copies. But the seven per cent of people who have two copies of E4 are at markedly high risk of early heart disease, and so, in a slightly different way, are the four per cent of people who have two copies of E2.2

But that is a Europe-wide average. Like many such polymorphisms, this one shows geographical trends. The further north in Europe you go, the commoner E4 becomes, at the expense of E3

(E2 remains roughly constant). In Sweden and Finland the frequency of E4 is nearly three times as high as in Italy. So, approximately, is the frequency of coronary heart disease.3 Further afield, there are even greater variations. Roughly thirty per cent of Europeans have at least one copy of E4; Orientals have the lowest frequency at roughly fifteen per cent; American blacks, Africans and Polynesians, over forty per cent; and New Guineans, more than fifty per cent.

This probably reflects in part the amount of fat and fatty meat in the diet during the last few millennia. It has been known for some while that New Guineans have little heart disease when they eat their traditional diet of sugar cane, taro and occasional meals of lean bush meat from possums and tree kangaroos. But as soon as they get jobs at strip mines and start eating western hamburgers and chips, their risk of early heart attacks shoots up - much more quickly than in most Europeans.4

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Heart disease is a preventable and treatable condition. Those with the E2 gene in particular are acutely sensitive to fatty and cholesterol-rich diets, or to put it another way, they are easily treated by being warned off such diets. This is extremely valuable genetic knowledge. How many lives could be saved, and early heart attacks averted, by simple genetic diagnosis to identify those at risk and target treatment at them?

Genetic screening does not automatically lead to such drastic solutions as abortion or gene therapy. Increasingly a bad genetic diagnosis can lead to less drastic remedies: to the margarine tub and the aerobics class. Instead of warning us all to steer clear of fatty foods, the medical profession must soon learn to seek out which of us could profit from such a warning and which of us can relax and hit the ice cream. This might go against the profession's puritanical instincts, but not against its Hippocratic oath.

However, I did not bring you to the APOE gene chiefly to write about heart disease, though I fear I am still breaking my rule by writing about another disease. The reason it is one of the most investigated genes of all is not because of its role in heart disease, but because of its pre-eminent role in a much more sinister and much less curable condition: Alzheimer's disease. The devastating loss of memory and of personality that accompanies old age in so many people — and that occurs in a few people when quite young

- has been attributed to all sorts of factors, environmental, pathological and accidental. The diagnostic