Matt Ridley

functions of the body, and a gene whose existence gives the lie to the mind-body dualism that plagues our mental image of the human person. The brain, the body and the genome are locked, all three, in a dance. The genome is as much under the control of the other two as they are controlled by it. That is partly why genetic determinism is such a myth. The switching on and off of human genes can be influenced by conscious or unconscious external action.

Cholesterol — a word pregnant with danger. The cause of heart disease; bad stuff; red meat. You eat it, you die. Nothing could be more wrong than this equation of cholesterol with poison. Cholesterol is an essential ingredient of the body. It lies at the centre of an intricate system of biochemistry and genetics that integrates the whole body. Cholesterol is a small organic compound that is soluble in fat but not in water. The body manufactures most of its cholesterol from sugars in the diet, and could not survive without it. From cholesterol at least five crucial hormones are made, each with a very different task: progesterone, aldosterone, Cortisol, testosterone and oestradiol. Collectively, they are known as the steroids. The relationship between these hormones and the genes of the body is intimate, fascinating and unsettling.

Steroids have been used by living creatures for so long that they probably pre-date the split between plants, animals and fungi. The hormone that triggers the shedding of an insect's skin is a steroid.

So is the enigmatic chemical known in human medicine as vitamin D. Some synthetic, or anabolic, steroids can be manufactured to S T R E S S 149

trick the body into suppressing inflammation, while others can be used for building athletes' muscles. Yet other steroids, derived originally from plants, can mimic human hormones sufficiently well to be used as oral contraceptives. Others still, products of the chemical industry, may be responsible for the ferninisation of male fish in polluted streams and the falling sperm counts of modern men.

There is a gene on chromosome 10 called CYP17. It makes an enzyme, which enables the body to convert cholesterol into Cortisol, testosterone and oestradiol. Without the enzyme, the pathway is blocked and the only hormones that can be made from cholesterol are progesterone and corticosterone. People who lack a working copy of this gene cannot make other sex hormones so they fail to go through puberty; if genetically male, they look like girls.

But put the sex hormones on one side for a moment and consider the other hormone that is made using CYP17. Cortisol. Cortisol is used in virtually every system in the body, a hormone that literally integrates the body and the mind by altering the configuration of the brain. Cortisol interferes with the immune system, changes the sensitivity of the ears, nose and eyes, and alters various bodily functions. When you have a lot of Cortisol coursing through your veins, you are - by definition — under stress. Cortisol and stress are virtually synonymous.

Stress is caused by the outside world, by an impending exam, a recent bereavement, something frightening in the newspaper or the unremitting exhaustion of caring for a person with Alzheimer's disease. Short-term stressors cause an immediate increase in epinephrine and norepinephrine, the hormones that make the heart beat faster, the feet go cold. These hormones prepare the body for 'fight or flight' in an emergency. Stressors that last for longer activate a different pathway that results in a much slower, but more persistent increase in Cortisol. One of Cortisol's most surprising effects is that it suppresses the working of the immune system. It is a remarkable fact that people who have been preparing for an important exam, and have shown the symptoms of stress, are more likely to catch colds and other infections, because one of the effects of Cortisol is to reduce the 1 5 0 G E N O M E

activity, number and lifetime of lymphocytes — white blood cells.

Cortisol does this by switching genes on. It only switches on genes in cells that have Cortisol receptors in them, which have in turn been switched on by some other triggers. The genes that it switches on mostly switch on other genes in turn, and sometimes the genes that they switch on will then switch on other genes and so on. The secondary effects of Cortisol can involve tens, or maybe even hundreds, of genes. But the Cortisol was only made in the first place because a series of genes was switched on in the adrenal cortex to make the enzymes necessary for making Cortisol - among them CYP17. It is a system of mindboggling complexity: if I started to list even the barest outlines of the actual pathways I would bore you to tears. Suffice to say that you cannot produce, regulate and respond to Cortisol without hundreds of genes, nearly all of which work by switching each other on and off. It is a timely lesson that the main purpose of most genes in the human genome is regulating the expression of other genes in the genome.

I promised not to bore you, but let me just take a quick glimpse at one of the effects of Cortisol. In white blood cells Cortisol is almost certainly involved in switching on a gene called TCF, also on chromosome 10, thus enabling TCF to make its own protein, whose job is to suppress the expression of another protein called interleukin 2, and interleukin 2 is a chemical that puts white blood cells on alert to be especially vigilant for germs. So Cortisol suppresses the immune alertness of white blood cells and makes you more susceptible to disease.

The question I want to put in front of you is: who's in charge?

Who ordered all these switches to be set in the right way in the first place, and who decides when to start to let loose the Cortisol?

You could argue that the genes are in charge, because the differentiation of the body into different cell types, each with different genes switched on, was at root a genetic process. But that's misleading, because genes are not the cause of stress. The death of a loved one, or an impending exam do not speak directly to the genes. They are information processed by the brain.

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So the brain is in charge. The hypothalamus of the brain sends out the signal that tells the pituitary gland to release a hormone that tells the adrenal gland to make and secrete Cortisol. The hypothalamus takes its orders from the conscious part of the brain which gets its information from the outside world.

But that's not much of an answer either, because the brain is part of the body. The reason the hypothalamus stimulates the pituitary which stimulates the adrenal cortex is not because the brain decided or learnt that this was a good way to do things. It did not set up the system in such a way that thinking about an impending exam would make you less resistant to catching a cold. Natural selection did that (for reasons I will come back to shortly). And in any case, it is a wholly involuntary and unconscious reaction, which implies that it is the exam, rather than the brain, that is in charge of events.

And if the exam is in charge, then society is to blame, but what is society but a collection of individuals, which brings us back to bodies? Besides, people vary in their susceptibility to stress. Some find impending exams terrifying, others take them in their stride.

What is the difference? Somewhere down the cascade of events that is the production, control and reaction to Cortisol, stress-prone people must have subtly different genes from phlegmatic folk. But who or what controls these genetic differences?

The truth is that nobody is in charge. It is the hardest thing for human beings to get used to, but the world is