One day in early 1996 I stumbled across a way of helping immune cells fight cancer. Aged twenty-five, I had recently obtained my PhD in physics in Glasgow, and had arrived in a lab in Harvard University to study the immune system. The lab head, Jack Strominger, had, in the 1950s, helped discover how penicillin works and had since then turned his attention to how T cells detect signs of disease in the body, work which made him a candidate for a Nobel Prize.1 His team was chock-full of driven and talented scientists, about twenty in the main Harvard campus where I worked and another twenty in a second lab he ran a couple of miles away at the Harvard Medical School campus, all of whom knew far more about the immune system than I had gleaned from my education in physics. It felt like I’d been let in through some kind of administrative error.
At the time I arrived, Strominger’s lab was focused on understanding how and to what extent our white blood cells called Natural Killer cells can attack cancer cells. To study this, Natural Killer cells were isolated from blood – blood taken from researchers down the corridor – and mixed with different kinds of cancer cells. The cancer cells had been loaded with a radioactive isotope, so that if they were killed, radioactivity would spill out from the broken-apart cancer cells into the broth that the cells were in. Then by measuring the radioactivity of the liquid broth, we could infer what fraction of cancer cells had been killed by Natural Killer cells. One day, perhaps because of my background in physics rather than biology, I wondered what would happen if we heated the cells a bit. I didn’t have any hypothesis to test or any prediction as to what would result, I just wondered. So I briefly heated the cancer cells to around 41°C and found out that they were destroyed much more efficiently.
I never pursued this observation, but a few years later other scientists made a breakthrough by understanding why this happens: heat can induce some types of cancer cells to exhibit at their surface ‘stress-inducible proteins’, so-called because cells display these proteins when they are in a state of stress. Not stressed in the everyday sense of the word but cells undergo what is called a stress response when they are damaged by, for example, exposure to high temperature, toxins or UV light. Protein molecules become misshaped by heat while UV light can break up a cell’s genetic material, and if a cell has these problems it will put up at its surface protein molecules which are not found on healthy cells. These proteins act as a hallmark of cells that are damaged and when Natural Killer cells detect them on a cell, they attack it.2 My own exploration was not at all important here – the big discovery was made by those who understood the process – but it illustrates how science sometimes moves forward when someone asks a question sideways on. It’s why many heads of labs like to hire people from different backgrounds. Having become a lab head myself, I now know it was no mistake that I was let into a top-flight biology lab with a PhD in physics. Professors at Harvard know how to get ahead.
The idea of using heat to treat cancer is far from new. In fact, it can be found in the oldest known description of cancer we have: the Edwin Smith papyrus from around 3,000 years ago.3 Likely a copy of an ancient Egyptian medical textbook, the Edwin Smith papyrus details how hot blades and sticks could be used to tackle breast cancer. This was probably more to do with trying to burn cancer cells than anything more subtle. Modern experiments show, however, that beyond the burning of diseased cells, heat may indeed help treat some types of cancer. In mice with a type of lung cancer, for example, a feverish temperature lowered the chance of the cancer spreading.4 And keeping mice in cages warmed to 30°C can boost the numbers of T cells that infiltrate and target a tumour.5 (That’s not to say this proves a direct effect; mice kept in a warm environment tend to be less active, drink more, and so on, and any of these effects could feasibly underlie a boost to their immune response.)
In medicine today, temperatures above 50°C are sometimes used to destroy cancer cells directly, through the application of radio waves, for example. And temperatures akin to a fever are sometimes induced locally or in the whole body to boost the effectiveness of chemical agents given at the same time – a treatment known as hyperthermia therapy.6 But heat is not used to treat cancer routinely. A reason for this is that the relationship between heat, stress-inducible proteins, inflammation and cancer has turned out to be far more complex than anyone could have known at the time I performed my own heat experiment.
For a start, while our immune system can often suppress or destroy cancer, it can also do the opposite, and there are at least two ways in which cancers can benefit from an immune response, problems that may then be made worse by heat. First, many cancer cells co-opt features of immune cells – by expressing sets of protein molecules used by immune cells – so that they themselves respond to cytokines and other secretions produced during inflammation. This allows cancer cells to hijack the cues immune cells use to multiply and move around the body, so that they too grow, expand and spread. Second, solid tumours sometimes benefit from local inflammation because this can increase the tumour’s supply of nutrients and oxygen. In fact, immune cells can be so beneficial to cancer cells that instead of evading an immune attack, some tumours secrete protein molecules specifically to attract immune cells to live inside them.7 These tumours often secrete hormones to alter the nature of the immune response at the site of the tumour, switching off the immune cells’ capability to attack while maintaining a tumour-promoting local inflammation.8 A tumour that maintains a local inflammation is sometimes thought of as a wound that never heals.
Another complication is that cancer cells which display stress-inducible proteins at their surface – the proteins detected by Natural Killer cells as a hallmark of disease – can sometimes secrete soluble versions of these same proteins into their surroundings. These secretions can act as a decoy, sticking to the receptor proteins on immune cells, blocking them from being able to detect the actual cancer cells.9 But again, the complete opposite can also happen. Some experiments have found that soluble secretions of stress-inducible proteins from tumours prime Natural Killer cells to be even more alert and even better at attacking tumours.10 In other words, secretions from tumour cells can, in some circumstances, switch off an immune attack and in other situations amplify the attack. This is at the cutting edge of current knowledge where our understanding becomes fuzzy, which explains why it is so hard to know if, when, and for which types of cancer it could be useful to increase or decrease the production of stress-inducible proteins, either by heat or any other way.
Leaving aside the special case of cancer for now, though, the fact that all warm-blooded animals are able to raise their core body temperature during an infection – which we call a fever – indicates that this ability must provide a hugely important survival advantage, especially as it requires a lot of energy; an increase in body temperature of 1°C requires an increase in the body’s metabolism of around 10–12%.11 Even more wondrous is that cold-blooded animals – reptiles, fish and insects – raise their temperature during an infection too. Unable to change their temperature from within, they do this by moving into a warmer environment. Amazingly, the heat-seeking behaviour of an infected iguana or tuna fish can be reduced with medicines which lower a fever in us, such as aspirin.12 This means that at least some of the chemical and biological processes causing a reptile or fish to seek a warmer habitat during an infection are similar to those within us during a fever. Even plants might be capable of something akin to a fever, as the temperature of bean-plant leaves can increase during a fungal infection.13
For most of human history, a fever was seen to be demonic or supernatural, a problem to be cured. Throughout the eighteenth and nineteenth centuries, people were often said to have died of a fever: yellow fever, scarlet fever, dengue fever, typhoid fever, and so on.14 Doctors used gruesome methods to try to cure a fever, inducing sweating or vomiting, or blood-letting. Now we know that a fever is part of the body’s response to disease, not an illness in itself. Fevers punctuate all our lives; a periodic reminder that so much of how we feel is down to our body’s basic physiology.
Raising temperature helps the body fight infections in all kinds of ways, affecting germs directly and increasing the activity of our immune system. Most germs that afflict us have evolved to thrive at normal body temperature. As a result, the replication rate of a virus, for example, decreases 200-fold when the temperature is increased to 40–41°C.15 A fever also helps the immune system by increasing the number of immune cells entering the bloodstream from bone marrow, where they are produced. As a result of this, and because heat also causes immune cells to make receptor proteins which direct them to sites of inflammation, a fever increases the flow of immune cells to where they’re needed.16 Once the cells are in the right place, all kinds of immune-cell activity can be boosted by an increase in temperature: macrophages are better at engulfing bacteria; B cells produce more antibodies; dendritic cells, those discovered by Steinman, are better at switching on T cells, and so on. But like everything to do with the immune system, the process can overshoot. Though rarely truly dangerous, a fever can sometimes lead to seizures. Far more common is the sense that your mind and your body are no longer your own.17
The mental ache of a fever makes plain the bond between our immune system and our mind. It’s a feeling that’s hard to express in words, even for Virginia Woolf: ‘English, which can express the thoughts of Hamlet and the tragedy of Lear, has no words for the shiver and the headache. It has all grown one way. The merest schoolgirl, when she falls in love, has Shakespeare, Donne, Keats to speak her mind for her; but let a sufferer try to describe a pain in his head to a doctor and language at once runs dry.’18
The trigger for the body to raise its temperature – in us and probably all animals – is the detection of telltale signs of germs by the immune system’s pattern-recognition receptors. These are the receptors, discussed in Chapter One, whose existence Janeway predicted and which were later discovered in flies, then humans. When these receptors lock onto, for example, the outside coat of bacteria or a virus, an immune response begins and as part of this response, cytokines are secreted. As we discussed in Chapter Three, cytokines call into action different types of immune cells. But cytokines also affect the behaviour of many other types of cells in the body, including neurons. In fact, one of the reasons why blocking cytokines proved to be so effective at treating some rheumatoid arthritis patients is that, as well as stopping the inflammation and thereby increasing the mobility of a patient’s joints, blocking cytokines also limits the impact of the inflammation on the nervous system, so that patients often feel a lot better quickly.19
As well as cytokines, the detection of germs by pattern-recognition receptors also triggers the production of the hormone prostaglandin E2. Prostaglandin E2 can be produced by nearly all types of cells in the body, but during an immune response it is mainly produced by immune cells as well as other cells responding to the cytokines produced by immune cells.20 The production of cytokines and the hormone prostaglandin E2 is essentially how the immune system warns the brain of danger and triggers a fever.21 Aspirin reduces a fever by stopping prostaglandin E2 from being made.22 (You may have come across the hormone prostaglandin E2 as the active ingredient in gels or tablets given to pregnant women to induce labour. Its ability to induce labour isn’t directly related to its role in a fever; it’s just that every hormone and every cytokine has a multitude of effects in the body, and the ability of prostaglandin E2 to relax muscles can help start contractions of the uterus for birth.)
In a fever, these cytokines and hormones act on a region of the brain called the hypothalamus. In response, the hypothalamus signals for the body to produce another hormone, noradrenaline, which constricts blood vessels in the body’s extremities and triggers brown fat cells to burn up energy and produce heat (the specialist job for this type of fat cell), as well as acetylcholine, which acts on muscles to cause shivering, for example, all of which serves to increase the body’s temperature. The hypothalamus also controls our feelings of hunger, thirst and sleep, as well as more complex emotions such as seeking closeness with others and our sex drive. Because of this, as well as feeling sleepy and losing appetite, secretions from immune cells affect all sorts of behaviours and emotions. Although this is not very well understood in detail, our immune system undoubtedly shapes our moods and feelings. Some of this might just be a chance outcome of the way in which hormones and cytokines are interconnected, but some of this is likely to have evolved for a reason. There’s an advantage in, for example, seeking comfort from others who may care for you when ill. Music, it seems, is not the only food of love; caring affections can be fired up by the chemical reaction of immune cells detecting germs.
Broadly, the immune system and our nervous system are in constant dialogue, each affecting the other through the body’s flux of cytokines and hormones. Many hormones affect our immune system, including the sex hormones oestrogen and testosterone, but it is stress hormones that have the greatest impact. We all know what stress is, though it’s hard to define. It can be as all-encompassing as a fever or as fleeting as butterflies in the stomach. What is clear is that stress can have major effects on our health, because of its connection with the immune system. Reducing stress may boost immunity, for example. And our knowledge of the connection between stress, hormones and the immune system has led to one of humankind’s greatest ever medical triumphs – as we shall now see.
On 1 April 1929, American physician Philip Hench had a routine appointment with one of his patients at the Mayo Clinic, Rochester, Minnesota. This sixty-five-year-old patient happened to mention that the pain he suffered from rheumatoid arthritis lessened while he had jaundice (a yellowing of the skin usually caused by a problem in a person’s liver). The patient told Hench that a day after jaundice appeared, he could painlessly walk a mile, something that he couldn’t have done before. Hench, a fan of Arthur Conan Doyle’s detective Sherlock Holmes,23 seized on his patient’s comments as a clue. He wondered if something in the body, induced when a person had jaundice, could alleviate rheumatoid arthritis. He called it substance X.
Over the next few years Hench came across others with a similar experience and noted that patients with jaundice were often relieved from all kinds of problems, not just rheumatoid arthritis, but hay fever and severe asthma too.24 He also began to record anecdotes from pregnant women with rheumatoid arthritis who said that they too gained relief from arthritic pain while pregnant. By trial and error, Hench set out to identify substance X. He injected or gave orally liver extracts, diluted bile, even blood, to try to help arthritic patients. Everything failed.
Elsewhere at the Mayo Clinic, biochemist Edward Kendall was on a different mission: to isolate the hormones produced by the adrenal gland – the term ‘hormones’ having been first used relatively recently, in 1905, by London-based physiologist Ernest Starling, to describe ‘the chemical messengers which speeding from cell to cell along the bloodstream, may coordinate the activities and growth of different parts of the body’.25 At the University of Basel, Polish-born chemist Tadeusz Reichstein independently worked towards this same goal.26 To give a sense of the effort this required, a tonne of adrenal tissue from cattle, received from a slaughter house, would yield about twenty-five grams of active hormones.27 Kendall had separated out a number of them, which he simply designated A through to F. One, which Kendall had named compound E and Reichstein called substance Fa, was especially biologically active, based on experiments in animals. The breakthrough happened after Hench and Kendall discussed their seemingly different lines of research in January 1941.28
Hench knew nothing about compound E and Kendall knew nothing about rheumatoid arthritis, but chatting with one another over coffee and sharing their separate experiences, an idea hatched.29 Hench and Kendall decided that it would be worth testing whether or not the adrenal compound E could be substance X. Even if it wasn’t, the results would probably be interesting. Hench noted the plan in his notebook but it took almost eight years before enough of compound E was available to test the idea.30 On 21 September 1948, a twenty-nine-year-old woman from Indiana with debilitating rheumatoid arthritis was treated with compound E, which, in the end, Kendall had obtained from the pharmaceutical company Merck. Two days later she could walk again, and to celebrate, she left the hospital for a three-hour shopping spree.31
Luck had played its role. Hench happened to have guessed a dose of the hormone which worked well – a dose higher than most physicians would have thought OK to try – and used crystals of it which happened to be the right size to be dissolved in the body at an appropriate rate.32 Luck helped in less scientific ways too: when the precious sample of compound E first arrived in the hospital, the glass vial fell to the marble floor, but didn’t smash.33
When Kendall was invited to meet the patient, she rose from bed and said ‘Let me shake your hand.’34 As a chemist, he seldom met patients and the moment was hugely significant for him, the culmination of eighteen years’ work. Hench also understood the magnitude of their success – so much so that he insisted they rename the compound as compound H, and that nothing should ever be discussed about it over the phone, in case someone else would scoop their discovery.35
Over the next few months Hench treated other patients. Many had been confined to a wheelchair but were soon on their feet. Hench presented the results for the first time at a meeting primarily for his fellow staff at the Mayo Clinic on 20 April 1949.36 Rumours had already spread that something big was going to be announced and the room was packed. Probably because he had a speech impediment, Hench was one of the first lecturers at the Mayo Clinic to use slides and other visual aids.37 On this occasion, he showed a flickering colour film of patients before and after their treatment, at a time when most film and photography was black and white and TV was a novelty. Changes in the patients were remarkable, and the moment was made all the more emotive because many in the audience knew the patients personally. The film sparked resounding applause even before it finished. After showing the film, Hench approached the lectern and received a standing ovation.38 Kendall spoke next, and emphasised how basic chemistry underlies new medicines.39 Soon after, in 1950, Hench, Kendall and Reichstein won a Nobel Prize. Never before or since has a Nobel Prize been awarded so rapidly.40
We now know that among the hormones produced by our adrenal glands in response to stress, one that is especially significant to the immune system is cortisol.41 Cortisol works to prepare the human body for stressful situations by helping establish, for example, the body’s fight-or-flight response: increasing our blood sugar levels and dilating blood vessels for muscles to prepare the body for immediate action. Importantly, cortisol also quietens the immune system, perhaps to prevent an inflammatory reaction switching on or overshooting when the body is under stress, and perhaps also because an immune reaction isn’t of immediate importance in a fight-or-flight situation and energy is best used elsewhere. Overall, cortisol has an incredible impact on the human body, affecting the activity of around one in five of all 23,000 human genes.42
Substance X, compound E, substance Fa, compound H or, more precisely, the compound Merck managed to synthesise, was named cortisone (it is very closely related to cortisol; enzymes in the body can change one into the other).43 And it quickly became the most sought-after drug in history. For three years, there was a cortisone famine while companies worked out a way to mass-produce it.44 Even so, there was no detailed understanding of how it worked as a medicine. This was an era when randomised clinical trials had only just begun to be used,45 and very little was known about the components of the immune system, so demand for the hormone and how to use it – including the dose and type of patient to treat – all came from ad hoc observations, rumours and anecdotes. It’s probably lucky that it happened that way. If someone suggested today that a compound which impacts the activity of one in five of all human genes might make a useful drug, nobody would take them seriously. It would sound far too messy and complex to be likely to work.46
Hench knew that cortisone wasn’t a miracle cure for rheumatoid arthritis, even though some of the press reported that it was. It only gave relief of symptoms for a relatively brief time. ‘Cortisone is the fireman who puts out the fire, it is not the carpenter who rebuilds the damaged house,’ he said.47 More importantly, it soon became clear that there were significant side effects when cortisone was taken repeatedly at a dose high enough to help rheumatoid arthritis patients.48 These included muscle weakness, fatigue and weight gain. But it was then, just as the side effects of using cortisone for rheumatoid arthritis patients became clear, that its true lasting medical importance emerged. It was found that cortisone could treat asthma (as well as some other diseases) at far lower doses than were required for the treatment of rheumatoid arthritis. Since then, cortisone and its derivatives – often just called steroids, the name for this class of compounds with similar chemical structure – have, year after year, been among the world’s most widely prescribed medicines.
Cortisol itself is also used as a medicine – in which case it is often referred to as hydrocortisone – for example, in a cream that can be applied to skin to reduce swelling or treat minor irritations. A synthetic chemical very similar to cortisol – dexamethasone – is about forty times more powerful in suppression of immune responses and is used in an enormous number of ways, to treat rheumatic inflammation, skin diseases, severe allergies and more. Other medicines similar to cortisol are used in preventer inhalers for asthma.
It’s common for science books which feature medical advances to include anecdotes of patients’ stories as an emotive hook to the narrative. Encouraged by my publisher to do this, I asked my son, aged twelve at the time, what he thought of his asthma inhaler. He looked at me as if I had just asked ‘Shall we to go to Mars today?’ and walked out of the room. He makes a point. Many people with mild asthma no longer need think of themselves as a patient. Inhalers are a part of everyday life: an outcome from one of science’s greatest ever detective stories.
Surprisingly perhaps, Hench’s and Kendall’s scientific careers didn’t end in the glory one might expect. Although Hench wasn’t formally diagnosed, many, including his son John, thought that he became depressed, or at least that his demeanour changed, after winning the Nobel Prize. When scientists and clinicians criticised cortisone on account of its side effects, Hench took it personally. His son recalls that ‘along with other people…who don’t draw boundaries between their work and the rest of their lives, Dad found it very difficult to take criticism of his work and accomplishments as anything but disloyalty’.49
Hench had planned to write a book about the history of yellow fever. The topic is not as arcane as it might sound: US army doctors proved a Cuban scientist’s idea that the disease was carried by mosquitoes, which led to new paradigms in humanitarian medicine and ethics. To dig up the story, Hench applied the same depth of rigour that made him a great biologist. He spent twenty years collecting thousands of documents, photographs and artefacts, and interviewed many of the physicians and scientists involved. The items he collected filled 153 boxes.50 But he died, aged sixty-nine, the book unwritten.
For Kendall too, his past success proved to be no guarantee of future triumph. It is perhaps telling that his memoir, published in 1971, ends with his winning of the Nobel Prize in 1950.51 Soon after winning the prize, he was forced to leave the Mayo Clinic because of their strict policy that staff should retire at age sixty-five. He moved to Princeton, New Jersey, where he focused on searching for another adrenal hormone, one postulated to be like vitamin C. He spent twenty years searching for it, but it didn’t exist. Success – even at the highest level, discovering one of the world’s most important medicines and then winning a Nobel Prize – is essentially fleeting.
As well as being one of the world’s most important medicines, the discovery of cortisol opened up the molecular basis for how our mind and body are connected. 350 years after Descartes theorised the separation of mind and body, cortisol brought them together, showing how a mental experience – stress – results in physiological effects. Understanding the full implications of this connection between our mental state and our immune system is an especially fascinating but controversial subject of ongoing enquiry.
Our modern understanding of stress began in 1936 when Hans Selye, born in 1907 in Vienna and then working at McGill University in Montreal, discovered that rats exposed to different types of harmful situations – surgery, drugs or cold temperature – showed a similar physiological response, independent of the precise nature of the situation.52 At first his work received little attention but he soon gained fame and was nominated for a Nobel Prize several times.53 By the time he died in 1982, aged seventy-five, he had published 1,600 articles and thirty-three books about stress.54 Selye took stress to be ‘the nonspecific response of the body to any demand’.55 Or, as he wrote in one of his bestselling books: ‘The soldier who sustains wounds in battle, the mother who worries about her soldier son, the gambler who watches the races – whether he wins or loses – the horse and the jockey he bet on: they are all under stress.’56 When Selye was asked if he thought modern life had become too stressful, he replied: ‘People often ask me that question, sometimes comparing our lives with that of the caveman…They forget that the caveman worried about being eaten by a bear while he was asleep, or about dying of hunger, things that few people worry about much today…It’s not that people suffer more stress today. It’s just that they think they do.’57 And Selye often emphasised that stress is not all bad; that it is also, he said, the spice of life.58
As we have seen, stress – whether it is taking exams, relationship problems or strenuous exercise – causes the adrenal glands, situated on top of our kidneys, to pump out hormones including cortisol.59 Cortisol’s function is to prepare the body for a change in activity, and levels of cortisol in a person’s blood don’t only change with stress; they vary according to the time of day as well. Cortisol levels are highest in the morning, peaking around 7 to 8 a.m., and lowest at night. It’s thought that the morning increase helps the body prepare for the change in activity of waking up.60 Still, cortisol levels change much more dramatically with stress, and in so doing they dampen our immune system. Cortisol does this by reducing the efficiency with which immune cells engulf germs, produce cytokines or kill diseased cells. This is fine for a brief time, but if stress persists, our immune system may stay weakened.
There is evidence that people who are stressed for prolonged periods of time suffer worse from viral infections, take longer to heal wounds, and respond less well to vaccination.61 All kinds of stresses have been linked with diminished immune responses, from burnout at work to unemployment. Even natural disasters like a hurricane can alter the state of people’s immune system.62 Well over a hundred clinical studies have reported that stress can contribute to poor health, which leads many to suppose that a super-charged lifestyle perhaps increases our risk of all kinds of illnesses, from autoimmune disease to cancer.63 The topic remains controversial, however, because so many factors affect our ability to fight disease that it is difficult to assess the effect of any one.
To explore the relationship between stress and health, without the added complication of stressed individuals being more likely to exercise less, sleep poorly, drink alcohol or smoke, for example, some researchers turn to studying mice where the variables are more easily controlled.64 Mice can be stressed by placing them in a tunnel in which they can freely run up and down, but are not able to turn around. This type of restraint, applied overnight when mice are most active, causes dramatic changes to the immune system. When given a dose of flu, there’s a delay in the immune response of stressed mice. Lower numbers of immune cells move into the infected lungs, and cytokine levels are lower.65 If the stressed mice have been given a drug which blocks the effect of cortisol beforehand, their immune system responds normally. This is strong evidence that stress and immunity are directly linked through cortisol levels. Similarly, rats stressed by predator odour or swimming in cold water are weakened in their ability to control a candida fungal infection.66
In humans, elderly people stressed by caring for a spouse with dementia have a reduced response to a shot of flu vaccine.67 There is also evidence that stress can affect our response to HIV. Our immune system can keep the virus in check before eventually AIDS develops, but the length of time it can do so varies between people. Over a five-and-a-half-year period of study, it was found that the probability of men infected with HIV developing AIDS increased two to three times if they had higher than average stress, or less social support.68 A separate study of homosexual men came to the conclusion that AIDS advanced more rapidly in men who conceal their sexuality, although the reasons for this were not established.69 Many other studies have found that stressed individuals are more prone to reactivation of herpes.70 Overall, the bad effect of stress on health is probably the best-established link between lifestyle and the immune system.
As well as stress, other states of mind likely also affect our immune system, although the evidence is less robust.71 Rugby players, for example, increase the level of cytokines in their blood when feeling angry or aggressive just before a match.72 This fits with the idea that, since aggression often precedes violence, a heightened immune system would be beneficial to deal with germs that enter wounds. Laughter may also help boost the immune system. People with diabetes who watched comedy films with hospital staff experienced increased activity of their immune system genes.73 This might be due to laughter itself, or perhaps the social camaraderie of laughter.74 The effects of laughter on the body are, in general, very little understood.
While many emotions may impact the immune system, only the influence of stress is widely accepted, which then raises the question of whether or not practices that might reduce stress – from adult colouring books to psychoanalysis – could directly boost our immune defences. There are any number of ways to relax, but two examples that have been studied for their effect on the immune system are t’ai chi and mindfulness.
Practitioners of t’ai chi, developed as a martial art in China, or related exercises such as qigong, perform a slow meditative choreography of movements. There is good evidence that t’ai chi can help improve pain and physical mobility for elderly arthritis patients.75 Whether or not t’ai chi impacts the immune system, however, is controversial. In one study, a t’ai chi class taken for an hour three times a week led to elderly adults responding better to a flu virus vaccine.76 This is an interesting result but this type of research is often less definitive than it might seem at first. One problem is that studies such as this often involve only small numbers of people. In this particular study, only fifty people were tested – twenty-seven people who took t’ai chi classes were compared to twenty-three who didn’t. Other studies testing for a link between practising t’ai chi and health test similarly small numbers of people.77 This is something like the number of people who would be enrolled in the first phase of a clinical trial for a new pharmaceutical drug, merely to test the safety of the drug, not whether it works. For a drug to be approved as a new medicine, it is usually tested in thousands of people, and compared to other interventions.
A second problem is bias. In around half the trials testing the effects of t’ai chi on immune defence, it’s not clear whether those who took the t’ai chi classes, as opposed to those who did not, were selected randomly.78 If those who took the classes had already been doing so before the study began, and were merely picked out as a group of people practising t’ai chi, then there is no way of knowing if the effects observed are owing to the classes themselves or to some other shared characteristic that also happens to result in people taking up t’ai chi. More subtly, the control group – those subjects who don’t take the class – should be given another activity to perform to replicate the possible benefits of a t’ai chi class that are not actually to do with t’ai chi itself, such as the contact time with a social group.79
A third problem – probably the most difficult to address – is how one measures the results. In the study mentioned, testing the effects of t’ai chi on the elderly, what was actually measured was the amount of antibody present in a person’s blood after they had been given a flu vaccine. While this might point towards t’ai chi having had an effect on the immune system, we don’t know, for example, whether a particular level of antibody increase is sufficient to appreciably impact a person’s well-being when infected with flu. The reason that this is such a difficult problem to address is that it’s not so easy to design an ethically sound trial to test for our reaction to an actual illness, because the illness would then need to be given deliberately.
Overall, a review of sixteen clinical trials concluded that: ‘Because of methodological flaws in existing studies, further vigorously designed large-scale placebo-controlled, randomized trials are needed.’80 Another analysis of thirty-four trials looking at the effects of t’ai chi, qigong, meditation and yoga came to a similar conclusion: that these practices can have a positive effect on some markers of the immune system, but there is not enough information to determine whether or not immunity is improved against a real infection.81 Both the National Institutes of Health in the USA and the National Health Service in the UK advise that t’ai chi may have various health benefits.82
That it may help is all we really know about a lot of things. When our children wanted my wife and me to buy them a home trampoline, they found plenty of evidence to demonstrate that bouncing on a trampoline has great health benefits – and claimed that this had been proven by NASA. Impressed by NASA’s involvement, I looked into it. As it turned out, the study in question was not as rigorous a programme of effort as that undertaken to land a man on the moon, involving as it did only eight students as subjects.83 Not only were there so few subjects, none of whom were women, but all eight students were given the same Nike shoes to wear. Would the results have been different if they had worn different shoes, or no shoes? No single study is definitive; it’s essential that studies are repeated by other scientists and the results successfully replicated if we are to trust them in order to rule out the possibility that the particulars of one experiment affected the results. We pointed out to our children that there are also safety risks with home trampolines to be balanced against any benefits.84
In the end, it’s your call (or your parents’) as to whether or not you buy a trampoline. And in the case of some things that are supposed to offer health benefits – such as a trampoline – it seems right that it’s left to you to decide. But we don’t want to have to decide for ourselves about pharmaceutical drugs; we want rigorous clinical trials to inform us if and when they work. Practices like t’ai chi fall somewhere in between.
What sets t’ai chi apart from bouncing on a trampoline is that it provides not just a method of exercise but a narrative for health. There is a story to the movements of t’ai chi; practitioners talk about moving energy around the body to balance one’s chi. The power of story is often part of a cure. It’s why naming a condition is important, and why a physician’s bedside manner, their description of an illness and how they intend to deal with it, can have such a major impact on how patients respond. This power of t’ai chi – the power of its narrative – is hard to quantify.
To take another example, there has recently been great interest in using mindfulness, a non-religious form of meditation, to improve health. Developed in 1979 by Jon Kabat-Zinn – the son of an immunologist85 – at the University of Massachusetts Medical School, mindfulness uses attention-focusing techniques to instil a moment-to-moment awareness. As Ruby Wax, comedian, writer and mindfulness practitioner, puts it: ‘Mindfulness is a way of exercising your ability to pay attention: when you can bring focus to something, the critical thoughts quieten down.’86
A review of forty-seven trials testing a total of 3,515 participants concluded that mindfulness can indeed ward off the negative effects of stress, anxiety, depression and pain. The effect is small but similar to what is often achieved with an antidepressant drug.87 In one clinical trial directly comparing mindfulness with antidepressants, both improved the well-being of patients with recurrent depression to a similar extent.88
As well as helping people cope with depression or anxiety, mindfulness is practised more widely as a way of dealing with everyday stress. To enthusiasts, mindfulness is the ideal antidote to the pre-eminent problem of our age: distraction.89 It might be assumed that, like t’ai chi, reducing stress by practising mindfulness could lower a person’s cortisol levels and, in turn, boost the immune system. And in 2016, an analysis of twenty trials with a total of 1,602 participants tested this exact idea.90
It was found that mindfulness could indeed lower some markers of inflammation and increase numbers of particular T cells in HIV-diagnosed individuals, but other measures – levels of cytokines or antibodies in blood, for example – were affected in some trials and unaffected in others. The authors concluded: ‘we caution against exaggerating the positive effects of mindfulness meditation on immune system dynamics until these effects are further replicated and additional studies are performed’.91 In fact, it’s not actually clear whether mindfulness impacts cortisol levels at all; different trials come to different conclusions.92 Unsatisfactory as it is, all we know is that mindfulness may help.
One of the reasons we don’t know for sure if t’ai chi or mindfulness can boost the immune system is that the cost of finding out is prohibitively high. In general, a clinical trial big enough that it would lead to FDA approval if the results were positive costs around $40 million. Eyeing up the possible profits, pharmaceutical companies are willing to pay such sums to test their novel compounds. But who would, should, or could pay to test an unpatented practice like t’ai chi?
While the medical importance of cortisol, and its derivatives, is clear, there remains much more to be understood in how our body, brain and behaviour each affect one another. Evidently, our immune system is a realm of interaction not just between the body and other organisms but also between the body and the mind, and between our physical and mental well-being. And as we shall see next, it also connects us to the solar system itself.