So you want to be normal

This essay was written by Iain Robinson and was first published in the 1999 Mill Hill Essays.

Normal. That’s what we all want to be, right? But maybe just a little bit different from everyone else – not too different you understand, just enough to be recognisably individual, that is, different from –well – you know, – the normal population. But what does normal mean, and more to the point, what does it imply? Well, doesn’t that depend on what is being measured, and on our personal assessment of our place in the normal population?

Sometimes we don’t want to be normal. Take death for example. Few healthy people would opt for a lifespan below normal – in fact the opposite is true – there is an increasing obsession with living longer and longer – in extending our lives beyond the normal lifespan. But only provided we can be guaranteed a level of vitality and fitness which is in reality quite abnormal for that extreme age. My grandmother lived to be one hundred and four and enjoyed her active life until the very end – but when I asked her what she thought about living so long, she replied, rather wistfully, that it didn’t seem quite normal – to outlive not only her peers, but many of their children as well. I don’t know what it was in my grandmother’s genes that led to her healthy and long life – unfortunately for me the males in my family die much younger!

If you want a fairly accurate, continuing assessment of normal lifespan in human populations then you can look it up in life insurance company tables. These do not yet contain genetic information that could readily be available and would significantly sharpen their statistical predictive power in an uncomfortable and, at present socially unacceptable, fashion. Whilst measuring death rates by disease category is accepted in order to assess health care priorities in the normal population, other aspects of measuring normality, for example to assess educational priorities, are far more controversial. Intelligence tests, such as the infamous IQ score, attempt to place individuals somewhere in a normal population on the basis of performance in a standardized test. It seems highly improbable that genetic combinations do not contribute to the performance of the brain, since they clearly contribute to the performance of most other organs and tissues. Nevertheless, only the most insensitive molecular geneticist fails to recognize the spectre of eugenics which overshadowed the original exploration of this topic, and continues to make further evaluations and discussions of a genetic contribution to intelligence so emotionally charged.

When schools in a certain country were asked to rate the ability of their children in a survey, the results showed that ninety-nine percent of them were average or above! Perhaps this isn’t so surprising – in this context, “normal” just doesn’t seem to be good enough, and satisfactory has come to mean unsatisfactory – we need to feel we keep on improving the average, or at least reducing the difference between the best and the worst. On the other hand we have to face the unpalatable fact that there will always be a lowest ten percent for any measure in any population, wherever the average is. It’s just that none of us wants to be counted amongst that number.

What about less emotive areas of normality? Those of us that are interested in the biological mechanisms that control body size come to the conclusion that there is a normal target range for this, and that during development from infancy to adulthood we need to stay on the track that eventually results in normal size and body proportion. There are many ups and downs on this path. It seems a curious hormonal design for human development to arrange for puberty and its associated growth spurt to occur around two years earlier in teenage girls than in boys. The girls suddenly seem to grow and develop whilst their male classmates look on in a combination of interest and bewilderment, until belatedly, and at different times, the boys thankfully begin their own growth spurt. Yet it is precisely because puberty occurs later in boys that they have more time to gain extra height in their childhood phase of growth. By delaying that pubertal growth phase, when it finally arrives the boys ultimately benefit from a greater final height – on average, of course!

Here the case for a strong genetic contribution to “normal” height is matter-of-fact. Children with growth problems are identified by comparison with “normal growth charts”, their current height and growth rate and the heights of their parents. Some brave paediatricians then make a carefully calculated prediction, let’s call it guess number 1, of the final height that child would reach if things carry on as now, and, secondly, how much taller the child might get with treatment, guess number 2. In these days of clinical audit and accountability, it is important to assess the cost benefit of such a treatment – the answer is given, in pounds sterling per inch, by the formula:

Cost benefit = Price of the drug / guess 2-guess 1

Societal prejudices have a major influence on our attitude to height, and hence what target height we should try to achieve for children with growth problems. Far more boys than girls are referred for clinical investigation for problems of short stature, and whether claims that success or popularity in business or politics are correlated with height, for instance United States presidential candidates tend to be taller than average, are real or anecdotal, but not forgetting Napoleon, there is clearly a sex bias in the perception of normality of stature. This is even more obvious for tall individuals. There are undoubtedly some problems that can occur in childhood for taller boys, for example being assumed to be older and more mature and treated as such, but eventually being very tall for a man is at worst an inconvenience for buying clothes, and at best, an opportunity to make a good career in basket ball. Even in the normal population, being moderately tall for a girl can be an advantage for a modelling career, but being excessively tall may be considered such a disadvantage that some anxious parents may be driven to ask doctors to intervene to reduce their daughter’s growth rate so that her final height can be nearer the normal range, acceptable for a girl in that society. Should the girl, the parents, or society be the target for treatment in this case?

In extreme cases, the psychological consequences of dissatisfaction with body size or proportion can undoubtedly be very serious. In some individuals, their body image, whether real or imaginary is irrelevant, is so out of kilter with societal norms, again either perceived or imaginary, that the behavioural responses can reach life–threatening proportions at either extreme, as in severe anorexia nervosa, or compulsive eating disorders. To the extent we have control of our energy output by exercising and input by eating we can alter our weight, and there are clearly trends in fashionable body shapes, curiously mostly for women, that will alter the degree of societal pressure on weight norms. In the days when Rubens was painting female figures Kate Moss would certainly have been rejected as a model. Unfortunately, there is very little we can do about our height.

Adults with extremely short stature often differ on what, if anything, one should try to do about it, and rarely get to discuss this anyway with parents of normal stature worried about the growth of their children. Some severely short children who have no possibility of hormonal stimulation of their growth will undergo operations and many months of discomfort involving fracture and gradual lengthening of the healing callouses in their long bones to gain real increments in height, which they really appreciate. Others feel it is up to society to change its attitudes to short stature, rather than force short individuals to try to conform to normality. Political correctness adds confusion to the brew – what is the politically correct attitude to the “vertically–challenged” person who stridently asserts his or her right to participate willingly as the projectile in a dwarf–tossing contest?

What is “normal” height anyway? We can look at growth charts to get height and weight estimates at different ages, based on measurements of, typically, a representative population of children in that country, but there are a number of problems with this approach. Firstly, it is highly dependent on the population. The numbers on an African normal growth chart would look very different for the Bantu and Pygmy populations, and this is not confined to these famous extremes in height. Growth progression charts for Japan, and Norway look similar in shape but the final numbers are very different! Secondly, even within countries with a relatively stable genetic mix, the average heights for both men and women have increased markedly over the years. In some cases this is quite dramatic. Next time you are in Japan, stand in a crowded train station and look at the difference in height between the older and younger Japanese. In Holland, most of the men conscripted into the army one hundred years ago did not reach one metre seventy centimetres in height. Today, Holland boasts one of the tallest populations in Europe and almost all of the men are taller than one metre seventy centimetres. This is known as a secular trend for height, varies in degree markedly from country to country and at different times of the century. Its roots are visible quite early in childhood, and it is probably due in part to improvements in maternal care and nutrition, as well as in the general health of the population. To put it another way, we don’t really understand why!

Another factor affecting population height more recently is the genetic mix. Many countries long isolated for geographical, cultural or political reasons now harbour a much broader population. These factors can pose real problems in practice. What does one do when faced with an orphaned child from Vietnam adopted by Norwegian parents currently living in Spain, who are worried that their child is not growing appropriately? Clearly the genetically-determined final height of the child is difficult to predict in the absence of information about the height of the biological parents, and expectations of an adult’s height differ substantially in Spain and Norway. What is the appropriate target height to aim at for that child? Guess number three?

Body size is clearly genetically programmed within a species, but even here the limits are quite broad. For mammals, the size of the foetus, and its growing nutritional and physical demands on its mother place some constraints on its growth rate throughout pregnancy. Foetal growth is largely determined by nutrition, provided exclusively by the mother, and a few specific growth factors and receptors, where father can make his genetic voice heard. In general, paternal influences tend to increase the size of the baby whilst maternal factors tend to restrain growth rate, and this is emphasized by the phenomenon of genetic imprinting in which either the maternal or paternal copy of several genes are selectively inactivated. It is probably not a coincidence that most of the imprinted genes identified to date seem to be involved in the growth and development of the foetus or placenta.

A successful outcome probably requires a compromise in this battle of the sexes, and whilst the size of the mother and number of foetuses being nurtured does have the most powerful effect on the mass of offspring that can be successfully carried to term, if the battle is too one–sided, for example by artificial insemination of small cows with sperm from huge bulls, the results can be catastrophic at delivery. Recent evidence suggests that the outcome of this compromise determining foetal size and early post–natal growth may have far–reaching consequences and strongly affect our likelihood of developing diabetes or cardiovascular disease much later in adult life.

Selective breeding within domestic species to alter body size and proportion has long been practised, for economic or other reasons. Strain differences even within a species can be enormous. Compare for instance toy poodle dogs with their king–sized relatives. For agricultural purposes, increasing the amount of muscle mass and decreasing fat mass in pigs destined for meat production is more important than overall body size, at least from the economic point of view; it may be less important from the pig’s point of view. As in many other areas of biology, advances in molecular genetics have started to make an impact here, and research to identify those genes that govern commercially important traits like milk yield, milk quality, meat production and muscle size is proceeding apace. What we do with the information is, of course, another issue.

Much current debate centres on the use of growth hormone, a protein which is secreted by the pituitary gland to stimulate normal post–natal growth. Growth hormone works in most tissues to stimulate, directly or indirectly, cell proliferation, development and shape. In older animals and humans, it increases the efficiency with which foodstuffs are converted into body mass, favours the build–up of muscle protein and reduces fat. Whilst it is easy to understand that a lack of normal growth hormone will result in poor growth since it accounts for roughly half the growth we achieve from early childhood onwards, it is less appreciated that the upper limit of our growth potential far exceeds that which we normally achieve. In other words it is possible to overgrow if too much growth hormone is present. But how much is too much? And what would we do if unlimited supplies of extra growth hormone were available?

Until about fifteen years ago this was a purely academic question for the following reason. Growth hormone works by sticking to specific proteins on the surface of many types of cell, thereby sending a signal which activates that cell. Whilst human growth hormone will produce this response in many other species, only the human growth hormone works in humans. Even large doses of growth hormones from other species will have no effect. This meant that the only way to obtain growth hormone to treat children with a deficiency of their own hormone production was to extract it from pituitary glands taken from dead people. This proceeded until, in 1985 it was recognized that Creutzfeld Jacob disease, a now notorious but still extremely rare form of spongiform encephalopathy, TSE, was unwittingly transmitted to some children who had received growth hormone preparations, derived presumably from pituitary glands of one or more cadavers in which the disease had not been recognized. This was a terrible shock to all the doctors and scientists working in the field, and remains a continuing source of concern for those families whose children might have been exposed to a similar risk.

At the same time, advances in molecular biology and genetic engineering meant that the process to make synthetic human growth hormone in bacteria had been developed. Within a few months it was possible to offer this synthetic human growth hormone to these children, free of the risk of contamination. It is interesting to recall the attitudes in those days, which are reminiscent of the current concerns over genetically modified foods. When the first synthetic growth hormone preparations were available for testing in humans, they were viewed with deep suspicion, and a widespread view was expressed that we should refrain from taking risks with a product from a genetically modified organism. After all, who knew what nasty bacterial products might inadvertently slip through. Surely it would be much better to stick with the “safer” natural product from human pituitary glands? There was much pressure to increase the supplies of the pituitary product since the amounts available were so limited that it was carefully rationed in dose to only the most severe cases. With hindsight there is a bitter irony to these arguments. But there is also a remarkable complacency about hindsight.

The same processes were used to generate virtually unlimited quantities of cattle or pig growth hormone, to enable its uses in livestock to be explored. It is now well established that growth hormone will stimulate milk production in cattle and give us leaner pigs. But the consumer in Europe at present is unable, and may perhaps be unwilling, to consume the milk or import the meat, currently consumed on a wide scale in the United States. In the earliest trials in which growth hormone genes were introduced to animals, excess production of the hormone gave entirely predictable results. Large excesses of growth hormone cause unpleasant side effects, just as they do in humans, and there are clear welfare concerns, that remain hotly debated, for the health of hormone–treated animals. We still know very little about the effects of long term exposure to food stuffs from animals exposed to moderately increased growth hormone levels. Many consumer groups have raised legitimate concerns, but there is also a real possibility that in this particular case, the change in food composition induced by growth hormone treatment, reducing fat and increasing protein, could even be beneficial to the human population that consumes it!

Now that we have potentially unlimited quantities of human growth hormone, it is important to define where the upper limit of “normal” is reached and what might constitute excess. If your otherwise normal son wants to grow a few extra inches to be a better basketball player, or even worse, you want him to be a basketball player even more than he does, and you can afford to buy growth hormone for him, is it really any different than feeding him a chronic overdose of steak and eggs if he wanted to be a weight–lifter? To my mind the answer is yes, but mostly because we have very little idea about the damage that might be done with moderate excess of growth hormone, but a very good idea that considerable excess is definitely bad for us. The human condition of acromegaly, which usually arises from a pituitary tumour causing excessive amounts of growth hormone to be secreted, is unpleasant and life-threatening, with increased incidence of diabetes, heart and circulatory diseases and colon cancer. This does not seem to have prevented growth hormone joining the fashionable list of substances abused by athletes in the search for increased performance, since its ability to build muscle and reduce fat is obviously tempting. Only now are legitimate studies being performed to study properly the effects of growth hormone doping in athletes.

And so we come back to the problem of defining “normal” ranges of growth hormone. For athletes, whose physical performance capacities, through training, are clearly abnormal compared with the population at large, it is very difficult to define what is normal. But you don’t have to be an athlete to aspire to increased performance. A search on the Internet will lead you to a remarkable source of a variety of growth hormone stimulants which, the purveyors claim, will take you to a realm of dreams of rejuvenation, regaining potency, vitality, and a zest for life. Before you get too excited, remember you will need to get some needles to inject growth hormone every day as well. This is clearly aimed at those of us who wish to counter the decline in performance that occurs with advancing years. But that’s normal – isn’t it?

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