Fat, Fate, and Disease : Why we are losing the war against obesity and chronic disease (16 page)

And as we have seen we are living these lives in very different ways, with much greater access to dietary calories and fat. It is this combination of living longer and in different ways that makes it no surprise that modern humans develop various types of chronic disease in middle and older age—indeed, it seems inevitable.

This is all very well but it does not really explain why one person develops a particular type of disease and another does not, even though they appear to live in the same environment and have no other obvious differences. After all, they are both the outcome of the same evolutionary process, aren’t they? To understand this we have to address the ultimate
why
question from an ultimate perspective.

A famous demonstration of the power of doing this was the study of growth of children in families who migrated from eastern Europe to the USA in the early 20th century. The distinguished anthropologist Franz Boas made the critical observation that the children who were raised in the USA grew to be several inches taller than their parents, who had grown up in Europe. The same finding has been observed many times—the children of Mayans who had migrated from poor rural Mexico to be, for example, golf course keepers in modern Gainesville, Florida are, within a generation, much taller. What these observations tell us is that our biology, in this case our height, is influenced by more than just our genes. It is influenced by the way we have grown up and in particular by our environment as we were growing up. The parental generation of the eastern Europeans and the Mayans were stunted in childhood by chronic under-nutrition and infection. Their children knew no such constraints.

Let us take an even more telling example. Identical twins have the same genes because they started life when a fertilized egg split into two identical cells. This is a different type of twinning to non-identical twins, when two separate eggs are released in the same menstrual cycle by the mother’s ovaries; both are fertilized by two separate
sperm, so they have different genetic material. But despite their identical genetic material, identical twins are not really identical. They will not have the same birth weights and in most cases their growth and behaviour and personalities will differ, even if only subtly. But it is when we measure the ways their genes are switched on and off that we see that there are other differences in how their gene control systems are set. These differences accumulate over time after conception so that, as they grow, they become more and more different. These switches will be discussed in more detail in the next chapter but here we only need to say that they are influenced by environmental events which may be experienced by one twin differently from the other. And of course, as they accumulate these genetic switch differences, they are more likely to respond differently even to the same stimulus.

A series of experiments conducted in Canada in the 1990s by the distinguished obesity researcher Claude Bouchard and his colleagues demonstrates this point very neatly. They took two groups of identical male twins and exposed both members of the pair to a regime of weight gain or weight loss. Some twin pairs were overfed and were put into positive energy balance for a number of weeks. Other pairs were put into negative energy balance by increasing exercise levels while restricting their food intake. The experiments were very well controlled. Not surprisingly all the twins in the first group gained weight and all those in the second group lost weight. But what was striking was that there were enormous differences in how much weight the members of the pairs gained or lost. For example, over 100 days of overfeeding a pair of twins, one twin gained 12 kg, while his sibling only gained 4 kg. Similar variation in weight loss was observed between twins. Clearly, even identical twins, with the same genes, had very different ways of handling a challenge to their metabolism.

Modern medicine does not find such observations very easy to deal with. Doctors, like so many of us, have been seduced by a simple working model—how well you control your weight depends simply on your genes and your behaviour—what you eat, what you choose
to do. But clearly it is not as simple as that. If the identical twins studied by Bouchard, who had identical genetic make-up and were made to live in the same way for some weeks, showed such enormous variation in weight control, how can we explain it and what does it mean for the rest of us?

Medicine too often ignores such individual variation and focuses on the average. Medical textbooks describe typical cases of disease rather than explaining the full range of ways in which the disease might manifest itself. And medicine tends to assume that we are either sick or we are healthy, with no in-between states. The emphasis of medicine is usually on spotting the definitely abnormal rather than on understanding subtle and not so subtle variations in normality. Typically the latter has been the interest of anthropologists, but there has been surprisingly little interchange between the anthropological and medical communities even though they both study the human condition.

In Bouchard’s experiment all of the twins appeared normal yet some of them clearly put on more weight than others when given excess food. So were those rapid weight gainers actually not as healthy as they appeared? Then again, some twins seemed to lose more weight during the negative energy programme than others. Were they in fact unhealthy because they could lose weight too easily? Or might it be the other way around? Perhaps the twins that did not lose very much weight during the exercise programme were the unhealthy ones who might have trouble regulating their body weight later in their lives. Sorting out what is normal starts to become a bit of headache.

In recent years, medicine has taken this concept of the normal versus the abnormal further—we now screen young adults and middle-aged people to determine who already has the early signs of disease—insulin resistance or high blood pressure, for
example. But this is really too late in that the person singled out for treatment is already on the pathway to disease; disease is inevitable, and all that can be done is to slow down the journey. Such screening has value but it will not prevent anyone getting the disease, nor indeed will it give us any insights into why we are on a high-risk or low-risk path in the first place. Focusing on the dichotomous approach of early categorization as normal or abnormal does not deal with the key issue, which is understanding why there is variation in the biology of individuals which sets them off on different paths—it seems that there is something in their biology that allows apparently normal people to progress very differently through the risky journey of life.

There are many biological processes that might vary subtly between individuals and affect this journey, yet this variation cannot be considered abnormal even though it may have long-term consequences. The variation could be in appetite control; in food preference; digestion and absorption; in liver or muscle metabolism; in their number of fat cells; how efficiently their hormones work; and so forth. When all is said and done, it is quite difficult to get fat unless we have ready access to food and eat lots of it. It is also quite difficult to become fat if we indulge in intense exercise or intense manual labour on a daily basis. But this does not mean that the reverse is true, and herein lies the problem. Not everyone gets fat despite an indulgent lifestyle. We have seen that there are enormous differences between people. Some of these differences are genetic but the failure of the genetic association studies suggests that most differences are intrinsic in some other way. They are independent of any conscious lifestyle decisions about what to eat and when to exercise. And the complexities pile up: while being obese does lead to a greater risk of heart disease and diabetes, there is not a one-to-one correspondence between being fat and suffering from one of these diseases. Indeed, individual variation confuses the picture at every level. And that leads to the next question: where does this variation come from, if it is not all simply genetic? We address this question in the next chapter.

The Gambia in West Africa is a poor country and most Gambians still depend on subsistence farming for their food supply. It has very consistent weather patterns that lead to dramatic seasonal changes in food supply, so much so that the year can be divided into the ‘harvest’ season and the ‘hungry’ season. Pregnant women have had to get used to living on an average of 1,400 calories day through several months of the hungry season but when the harvest comes they can eat about 1,800 calories every day for the next few months. The cycle then starts again. Children, of course, can be born in either season. But what happens to these children as they grow up has been the subject of considerable research. Because The Gambia is so poor, many children die before they are five years old, but there is no difference in the death rates of those born in either of the two very different seasons. Indeed nothing looks very different in terms of mortality until the children reach the age of about 20, when something
surprising seems to happen. Those who had been born in the hungry season start to look more fragile, and they become more likely to die of various illnesses than those who had been born in the harvest season. And over time the difference between these two groups of people gets larger and larger—so much so that the average life expectancy of those born in the hungry season is about 15 years shorter than that of those born in the harvest season.

This is an enormous difference. What can be going on? The only explanation must be that something about the conditions at the time they were born or during their early life as a fetus has made them vulnerable—vulnerable in a way that does not affect them obviously in childhood but starts making an enormous difference, literally the difference between life and death, as they reach adulthood. The latency of the effect is revealing. Something in the underlying biology of these babies is influencing the way they will go through life. Something in their biology is being set for life by their mother’s nutrition before they are born.

This difference in life expectancy in The Gambia is not the only example we have that suggests a remarkable link between our life before we are born and our journey through life. We have already described the Dutch winter famine of 1944–5 when the Nazis reduced the rations available to the people of the western Netherlands from about 2,000 to about 700 calories per day. The women who were pregnant during the famine gave birth to babies whose birth size was not greatly affected (except for those who were in late pregnancy when the famine started) but those children have grown up to be more at risk of diabetes and cardiovascular disease. The same thing is true of children born at the time of the horrific famine in China in 1958–61, during the so-called Great Leap Forward, when Mao Zedong imposed incredibly destructive policies on the Chinese economy. They too grew up to have a higher risk of diabetes.

These experiments of history and nature are both disturbing and instructive. They are examples of how extreme conditions at the
start of life have echoes for the whole of our lives. But this is also true of much less extreme situations. After all, every pregnancy is different—mothers vary in what they eat, how stressed they get, how much exercise they do—and they differ during pregnancy and before. Do these variations in normal pregnancies have long-term consequences for the next generation as well, and if so why?

Over the past two decades, a large amount of research has led us to realize that an individual’s biological destiny is indeed heavily influenced by what happens to them as an embryo, as a fetus, and as an infant, even in the most unremarkable of pregnancies or infancies. Before we explain that evidence and its implications, it is worth asking why an emphasis on early life should turn out to be so important in the pathway to chronic disease. The simplest answer is a chain of cause and effect: the events in early life change our biology in such a way as to make us respond differently to what we confront later in life.

It is like building a house. If the foundations are not properly laid, no matter what is done after that, problems will emerge sooner or later. A subtle defect in the composition of the concrete used in the foundations may not matter at the beginning but in time it will start to crumble and if there is an earthquake the consequences will be much worse. This is the concept of ‘path dependency’—little things at the beginning can have much greater consequences later, in the context of some other event. The analysis of aeroplane crashes and other tragedies shows how disastrously the consequences of path dependency can play out. The space shuttle Challenger was destroyed as a consequence of a very small defect in an O-ring which led to a series of failures on take-off; an event which diminished the thrill of the space age.

So, if path dependency matters in our biology, and if the risk of disease is affected by subtle events that happen early in our lives,
our passage through life could be very different if we were able to identify those early changes and the factors causing them. And the evidence for this is accumulating. Indeed, we now know that many of the processes which influence whether or not we are likely to succumb to chronic disease are not only influenced by events in early life but actually start during early life. For example, the number of muscle cells in the heart is definitively set during fetal life. We are all born with our full complement of beating heart muscle cells and these must function for (hopefully) at least two billion heartbeats during our lives. They cannot stop contracting, relaxing, and then contracting again, whether we are reading, exercising intensely, or asleep.

In the same way, the number of filtering units in our kidneys is established before we are born. These will continue to filter our blood every day, removing excess fluid, toxins, and metabolic by-products, and excreting them in the urine. The filtering task is enormous—they do not just secrete urine; they have to filter many litres of blood and in doing so extract much fluid out of our bodies, and then to reabsorb most of that fluid again, because we only pass about 1–2 litres of urine each day. These kidney units, called nephrons, are tremendously active units—they receive about a quarter of the blood pumped by the heart every minute throughout our lives. But as we get older they slowly fail. In most people this is not a problem because we start life with spare capacity, but in some susceptible individuals the rate of decline may be too fast or, more importantly, they started out with a smaller number of filtering units as babies. Either way this deficiency in functioning nephrons is more likely to trigger a rise in blood pressure, because the only way to filter fluid with a smaller number of units is to force blood into them at higher pressure—and this will then have longer-term consequences. If the number of effective units falls too much then only dialysis or a kidney transplant can save us.