Mutants
Page 25
So far, at least a hundred genes have been identified in worms that, when mutated, cause them to live longer. Many of these mutations disable the worm’s insulin-like growth-factor-signalling pathway. As a consequence of doing so, the whole physiology of the worm changes. Mutant worms that are defective for IGF signalling reproduce less, store large amounts of fat and sugars, and activate a whole battery of genes that encode for stress-resistance proteins, among them superoxide dismutase. The result is worms that radiate health even as their normal contemporaries wither in their petri-dishes.
We have come across insulin-like growth factor before. It is the lack of this hormone that makes pygmies small and its excess that makes Great Danes large. It is also one of the hormones that, when inactivated in mice, cause them to be dwarf and long-lived. In worms, IGF does not seem to control body size (something of a surprise since it does so in so many other creatures, including fruit flies). Even so, taking these findings from worms together with what is known about IGF in mice, flies and many other creatures, it is possible to sketch an account of a mechanism, perhaps universal to all animal life, that allows animals to live longer when they need to.
Worms are not frightfully bright. The nervous system of any one worm, including what passes for its brain, contains only 302 neurons; a human brain has around a billion-fold more. Even so, a worm has nous enough to know how much food it has. When a worm perceives that it is about to starve, neuronal signals from sense organs in its head signal the rest of the body and IGF signalling is shut off. A change in environment mimics what many mutants do, and the result is the same: the worm lives longer.
This should sound familiar. It is, in effect, what happens in caloric restriction in mice and rats. And it suggests an interpretation for how and why la vita sobria has its beneficial effects. Far from being an odd laboratory phenomenon of interest only to gerontologists and diet gurus pursuing dreams of immortality, the caloric restriction response is probably a device that has evolved to allow animals to cope with the vicissitudes of life. Perceiving that it is in for hard times, a young animal alters its mode of life. Instead of investing resources in growing large and reproducing soon, it switches to survival mode. It remains small and ceases to reproduce, in effect gambling that sooner or later better times will come. If this view of caloric restriction is correct, then its enthusiasts are attempting nothing less than the revival of devices evolved to cope with the deprivation that was surely our lot for millennia of prehistory (and surely a lot of history too). Though they do not know it, when they calculate their foods to the last calorie, surround themselves with bottled vitamins, and monitor, as they must, their bone density by the month, they are playing the part of civilisation’s most dedicated discontents.
Can longevity genes be found in humans? Many scientists think so. In France, Britain, Holland, Japan, Finland and the United States gerontologists are busily compiling lists of centenarians and analysing their DNA in order to find out why they live so long. They do so not in the expectation that there is any one mutation or polymorphism that all these centenarians have in common – and they fully accept that some centenarians will have made their century by a combination of good luck and virtuous living. Rather, the approach is to scan many genes which, for one reason or another, are believed to contribute to the diseases of old age and to search for those variants that are more common in geriatric survivors relative to the rest of the population.
One of the first longevity genes to be identified in this way was apolipoprotein E (APOE). The protein encoded by this gene comes in several polymorphic variants called ?2, ?3 and ?4. About 11 per cent of Frenchmen and women under the age of seventy carry at least one copy of the ?4 variant, but in French centenarians this number drops to 5 per cent, the difference being made up by the ?2 variant, which becomes more common. This implies that should you wish to see your hundredth birthday, you should hope to have at least one copy of ε2 but none of ε4.
This is because the APOE gene, which encodes a protein involved in cholesterol transport, has been implicated in Alzheimer’s disease. About one in ten people aged sixty-five or over will contract Alzheimer’s, but the odds are skewed drastically if you are an ?4 carrier. One copy of ?4 relative to none increases your risk of Alzheimer’s three-fold; two copies increases your risk eight-fold. Were this not enough, ?4 also predisposes to cardiovascular disease. With this sort of molecular double jeopardy it is easy to see why ?4 carriers rarely survive to a great age.
All this seems to matter less if you are black. Surveys of APOE genes have shown that ?4 is very common in sub-Saharan Africa. Nearly half of African pygmies carry at least one copy. Does this really mean that Alzheimer’s disease is rampant among the Efe? The short answer is that we don’t know. No studies on the epidemiology of Alzheimer’s seem to have been carried out on pygmies, and they would be hard to do since a high rate of death due to infection and accidents means that few pygmies survive to an age when Alzheimer’s might be seen. This, in itself, may explain why ?4 is so common among them, but a more likely explanation is that it is less dangerous to Africans than it is to Europeans. Several studies have sought, and failed, to find an increased risk of Alzheimer’s in Nigerians and African Americans who carry the ?4 variant. Why this should be so is something of a mystery.
In Europeans, at least, the genetics of Alzheimer’s provide a beautiful illustration of the evolutionary theory of ageing that is, if anything, even more persuasive than that of Huntington’s. Even among the clearly susceptible (white) French, ?4 is common for such a lethal variant, and its presence can only be explained by the fact that it has little net effect on the reproductive success of its carriers. The contrast with other genes that cause Alzheimer’s is instructive. Mutations in at least three other genes cause Alzheimer’s but do so at around age thirty. They kill their carriers in their prime and, exposed to the full force of natural selection, are accordingly – thankfully – rare.
These kinds of findings are only the beginning. Within a few years, dozens, if not hundreds, of polymorphisms will be found that add years to our lives or else take them away. Most of these polymorphisms will either hasten or else delay the features of ageing with which we are familiar: senile dementia, arteriosclerosis, kidney failure, prostate failure, menopause, cancer and the like. No single person’s genome will possess all the variants that might be desirable for long life. This much is already apparent from the sheer diversity of ways in which we die. But it will be possible to describe in actuarial terms the relative risk of possessing a given genome. Here is a taste of what is to come. All else being equal, a forty-year-old whose genome has the following variants:
SRY(–/–); APOE(ε2/ε2); ACE(D/D); MTHFR(Ala222/Ala222)
will have a lower risk of cardiovascular disease, and hence a lower yearly risk of death, than someone with the following:
SRYf(+/-); APOE(ε4/ε4); ACE(I/I); MTHFR(Val222/Val222).
The difference between these two lists is quite unmysterious. There are four genes – SRY, APOE, ACE and MTHFR – each of which has two variants known to be associated with a difference in the mortality rates of middle-aged or elderly people. These two lists are, then, a predictive theory of longevity, but one that is no more profound than the assertion than someone who neither smokes, drinks, drives or has sex will generally live longer than someone who does all those things. Only here the risk factors lie in the genome.
Possession of the second genome does not inevitably spell an early death. While it is not possible to diet your way out of Alzheimer’s, much can be done to prevent a heart attack. That these genes confer different risks of death at any given age seems certain, but it is not yet possible to translate those differences into years. To do so requires large population studies of a sort that have not yet been done, but that surely will. There is one exception to this. In the USA, SRY(-/-) individuals live, on average, five years longer than those who are SRY(+/-). This, of course, is rather hard on those of us who are SRY(+/-), but the
re’s not a lot that can be done about it except to give a Gallic shrug and mutter Vive la différence.
EVER UPWARDS
In 1994 a remarkable thing happened. Not a single eight-year-old Swedish girl died. Not one succumbed to the ‘flu; not one was hit by a bus. At the beginning of the year there were 112,521 of them. At the end of the year they were all still there.
It was, of course, a statistical fluke. In that same year some eight-year-old Swedish boys died, so did some seven- and nine-year-old girls, and a few eight-year-olds of both sexes died the following year. But the survival, in that year, of those Swedish girls may be taken as symbolic of the greatest accomplishment of industrial civilisation: the protection of children from death.
Childhood mortality rates in the most advanced economies have become vanishingly small, particularly when death due to accident or violence is excluded. It is this accomplishment, at least 250 years in the making, which has driven the long climb in human life expectancy. Before 1750, a newborn child could expect to live to twenty years of age; today in the wealthiest countries a newborn can expect to live to about seventy-five. Most of this increase can be credited to the elimination of infectious diseases that preferentially strike the young. The curious thing, however, is that even though the protection of the young is largely a completed project – in the wealthiest countries – life expectancy continues to rise.
The 1960s were, it is said, revolutionary. But far from the Sturm und Drang of the cultural and sexual revolutions, something far more important was happening. Mortality rates of the old began to decline. An American woman who turned eighty in 1970 had a 30 per cent chance of surviving another decade; had she turned eighty in 1997 her chance of doing so would have increased to 40 per cent. The same phenomenon can be seen in the progress of maximum longevity in Sweden. Between 1860 and 1960, the age at death of Sweden’s oldest person increased steadily, decade by decade, at rate of about 0.4 years. Between 1969 and 1999, the rate of increase climbed to about 1.1 years per decade. We have been living longer for some time, but since the 1960s we have been living longer ever faster.
These numbers tell us that not only can ageing be cured, but that cures have been coming thick and fast. If ageing is the age-dependent increase in the mortality rate, then anything that ameliorates the mortality rate is, by definition, its cure. The decline of mortality rates among the old is mainly due to a several-decades-long decline in cardiovascular disease and cancer. Cardiovascular disease has been the leading cause of death in the United States since the 1920s, but between 1950 and 1996 its contribution to the death rate declined by half. In Japan, cancer rates began to decline in the 1960s; in the rest of the industrialised world the decline began about twenty years later. Nothing spectacular, then, just the incremental advance of public health.
But incremental advance is all we can reasonably expect. Evolutionary theory and the increasing flow of information about the genetics of ageing, be it premature or postponed, tell us that ageing is many diseases that will have to be cured one by one. At the same time, there is no obvious impediment to that advance; nothing to make us think that human beings have a fixed lifespan. In 1994, 1674 eighty-year-old Swedish women died. It is impossible to predict what medical breakthroughs will be required to ensure that none will die in the future. But when that day comes, it will mark the completion of industrial civilisation’s second great project: the protection of the old from death.
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ANTHROPOMETAMORPHOSIS
[AN EPILOGUE]
The authors of books about genetics – at least books written for the general reader – disagree about many things. What they agree on is the need either to predict the future course of humanity or to moralise about it, or, better yet, to do both. The predictions invariably concern the role that the ‘new genetic technologies’ – mass genetic screening, embryo selection, cloning, germ-line modification and the like – will have in the lives of individuals and societies. Some writers are sanguine, and assure us that these technologies are as nothing compared to the great demographic forces such as birth rates and migrations that shape the gene pool of our species; others contemplate, with surprising equanimity, the transformation of the human species into something resembling a highly intelligent plant. Some – media scientists usually – would like to clone themselves; others would like to restructure the tax system so that people with inherited disorders have a disincentive to reproduce. Others again – soi-disant ethicists, dialectical biologists and bishops – speak portentously of ‘human dignity’, rail against ‘genetic determinism’ or else mutter darkly about the ‘ethical dilemmas that face us all’ – though rarely condescend to explain exactly what these might be.
SKULL OF AN AUSTRALIAN ABORIGINE, ARNHEM LAND. FROM ARMAND DE QUATREFAGES 1882 Crania ethnica: les cranes des races humaines.
I propose to resist the temptation to do any of this. I do not know the future, and my views on the morality of cloning humans, or germ-line engineering, or any other topic, are neither so deeply considered nor so unique as to warrant public exposure – a reticence born not of cowardice, but rather of courtesy, or so I like to think. Instead I will end this book, which has been all about the many things that we know about the construction of the human body, with some thoughts on what we do not know and what we – or at least I – would like to.
I would like to know about variety. Most of this book has been about the rare mutations that damage the body. If I have mentioned variety, I have done so only in passing. By variety I mean the normal variation in human appearance and attributes that we see in healthy people around us. I mean the variety that can be found within the smallest Scottish hamlet, with its brown-, green- and blue-eyed inhabitants. But I also mean the differences in form between populations of people who live near to each other, but are somehow distinct: short pygmies versus taller Bantu farmers, for example. And I also mean the differences in skin colour, hair curliness and eye shape that distinguish – more or less – people who originate from different continents. One of the things, then, that I want to know about is race.
Race has long been under siege. Among scientists, geneticists have led the assault. Their attack has been predicated on two empirical results that have emerged from the study of patterns of genetic variation across the globe. The first was the discovery that most of the variety so abundantly visible in our genomes does not divide humanity along lines that correspond to the races of traditional and folk anthropology. All genes come in different variants, even if most of those variants are ‘silent’ and do not affect the structure of the proteins they encode. Inevitably, some variants are more common in some parts of the world than others. But the ubiquity and rarity of most variant genes across the globe do not correspond to traditional racial boundaries. Racial boundaries are usually held to be sharp; gene variant frequency changes are generally smooth. Changes in variant frequencies are also inconsistent between one gene and another. If there are lines to be drawn through humanity, most genes simply don’t show where they should go.
The second discovery that caused, and causes, geneticists to doubt the existence of races is the ubiquity of genetic variation within even the smallest populations. About ?5 per cent of the global stock of genetic variation can be found within any country or population – Cambodians or Nigerians, say. About another 8 per cent distinguish nations from each other – the Dutch from the Spanish – which leaves only a paltry 7 per cent or so to account for differences between continents or, in the most generous interpretation of the term, ‘races’. To be sure, there are genetic differences between a Dutchman and a Dinka, but not many more than between any two natives of Delft.
These facts about human genetic variation have been known since the 1960s. In each decade since then they have been confirmed, with ever more lavish quantities of data, using ever more sophisticated means of finding and analysing human genetic variation. In the 1960s genetic variation was studied by examining the migration of variant proteins on gels; tod
ay it is studied by sequencing entire genomes. Generations of scientists have expounded these results much as I have here – and asserted that, as far as genetics is concerned, races do not exist. They are reifications, social constructs, or else they are the remnants of discredited ideologies.
Most people have remained unconvinced. They have absorbed the message that races are, somehow, not quite what they used to be. Far better, then, to avoid the word and substitute ‘ethnicity’ or some similar term that comfortably conflates cultural and physical variety. For some, the persistence of the idea of race is a sign of racism’s tenacity. I doubt that this is true. Instead I suspect that the reason the lesson of genetics has been so widely ignored is that it seems to contradict the evidence of our eyes. If races don’t exist, then why does a moment’s glance at a stranger’s face serve to identify the continent, perhaps even the country, from which he or his family came?
The answer to this question must lie in that 7 per cent – paltry though it is – of global genetic variation that distinguishes people in different parts of the world. Seven per cent is a small part of global genetic variation, but it is large enough to imply the existence of hundreds, perhaps thousands, of genetic polymorphisms that are common, even ubiquitous, on one continent but rare, or even absent, on another. In recent years some geneticists have begun searching for such variants. The variants are known as AIMs or ‘Ancestry Informative Markers’ – so called because they can indeed tell you roughly where your ancestors came from, and even sort them out if – the case for so many of us – they came from several different places. The search for AIMs, which initially focused on Africans and Europeans but is already being extended, is prompted by the hope of identifying the genetic basis of several diseases, among them type 2 diabetes, the risk of which differs among Africans and Europeans.