The Inflamed Mind Read online

  Of course, the real importance of these linked new sciences of neuro-immunology and immuno-psychiatry is not that they give me a different way of explaining why I don’t like going to the dentist. What matters much more is that once we have begun to map a path to follow from the body, via the immune system, to the brain and the mind - once we have articulated a post-dualist concept of the inflamed mind - we should be able to find entirely new ways of dealing with mental health disorders.

  The revolution will not be televised

  Depression, schizophrenia, autism, addiction, Alzheimer’s disease . . . there is a long and mournful list of disorders that psychiatrists, clinical psychologists and neurologists ordinarily treat either as if they were “all in the mind” or as if they were “all in the brain”. Let’s say I had not bounced back to work the day after the dentist. Let’s imagine I had become progressively more withdrawn and melancholic until my wife had eventually persuaded me to see a doctor. What would have happened? My GP would probably have asked me a few questions about my state of mind and then offered a course of psychotherapy (to resolve my issues about mortality) or a prescription of anti-depressants (to correct some notional imbalance of serotonin or other neurotransmitters in my brain). It is unlikely my doctor would have attached much diagnostic significance to the root canal story. It is virtually certain that he would not have ordered a blood test to measure cytokine levels, or to see if I had genetic risk factors for a depressive response to inflammation. It is inconceivable that he would have recommended an anti-inflammatory drug (like aspirin) instead of an anti-depressant (like Prozac). In all probability, I would have been sensibly, competently, traditionally treated as if my mood had nothing to do with my immune system. Just like I had traditionally treated Mrs P.

  Scientifically there may still be questions to resolve about causality but the link between inflammation and depression is indisputable. So why am I so confident that the doctor I might have consulted about post-dental depression would pay no attention to my immune system? The answer is partly just that medicine is a conservative, highly regulated profession. It is not unusual for changes in practice to lag several decades behind conceptual advances in biological science. A good example of the sometimes slower-than-hoped-for pace of medical progress is the real-life impact of the double helix.

  Watson and Crick published the architectural principles of deoxyribonucleic acid (DNA) in 1953,11 opening up entirely new fields of genetic science and molecular biology. This was a critical turning point in the formation of what became the central orthodoxy of biology - the theory that genetic information is coded by the sequence of DNA molecules, and that different sequences of DNA specify how different proteins are assembled by precisely stringing together hundreds of thousands of amino acids. Since proteins are an enormously large and diverse group of molecules in the human body - including antibodies, cytokines, enzymes and many hormones - our deeper understanding of how protein synthesis is genetically controlled by DNA has been widely recognised as one of the most important advances in the history of biology.

  About 50 years later, when President Bill Clinton celebrated the sequencing of the human genome at a White House ceremony in January 2000, he spoke with unbounded millennial optimism about the genome: “without a doubt the most important, most wondrous map ever produced by humankind”.12 He saw this as a scientific advance with the potential to deliver medical breakthroughs on an extraordinary scale and at an extraordinary rate. “It is now conceivable that our children’s children will know the term cancer only as a constellation of stars.” Now, almost 20 years after he spoke those words, Bill Clinton is a grandfather but we are nowhere near consigning the word to common use only in horoscopes. In the British National Health Service (NHS) in 2018, genetics has made a life-or-death difference to some patients with leukaemia or breast cancer, who are lucky enough to have a genetic profile that makes them more likely to respond to new anti-cancer medicines. But it will take many more generations for the therapeutic potential of genetics to play out across the whole spectrum of health services.

  So it is reasonable to expect a fairly slow burn for immuno-psychiatry in practice. In the NHS in 2018, immunology has made no difference whatsoever to any patients with depression, psychosis or Alzheimer’s disease. There are no licensed medicines or other treatments for depression that act primarily on the immune system. There are fascinating new insights into how high levels of social stress can increase bodily inflammation. And there is growing evidence that people who have experienced adversity or abuse in childhood are more likely to be inflamed as children and adults.13-15 It is also increasingly clear that depressed patients who are also inflamed are less likely to respond well to treatment with conventional anti-depressant drugs.4 But there is as yet no well-known way by which doctors or other mental health practitioners can leverage this new knowledge to help people with depression. And until my GP is in a position to offer an immunological treatment for depression, I wouldn’t expect him to spend too much time entertaining a fancy new immunological way of thinking about where depressive symptoms come from.

  Personally, I expect this to change. I can imagine a future in which the old dividing lines between mental and physical illness are redrawn, the 400-year-old habit of dualist diagnosis is kicked, and the immune system becomes much more central to how we think about - and treat - psychological and behavioural symptoms like depression. I can easily imagine that there could be some decisive moves in this direction over the next five years or so. The lesson of history is that medical revolutions do not make good reality TV. But there is a current of scientific change running under the surface of day-to-day medical practice which could transform the way we deal with depression and other mental health disorders. And that is the idea behind this book. We can move on from the old polarised view of depression as all in the mind or all in the brain to see it as rooted also in the body; to see depression instead as a response of the whole organism or human self to the challenges of survival in a hostile world.

  Chapter 2

  THE WORKINGS OF THE IMMUNE SYSTEM

  To get to this new way of thinking about depression, we have to start in an unfamiliar place: the realm of the lymph node, the spleen and the white blood cell. This is the realm of immunology, the science of the immune system that explains the mechanisms and rationale for inflammation. Thanks to immunology, we know that inflammation is what happens when the immune system is aroused to defend us against our enemies.

  Dealing with inflammation has always been central to medicine and while I was training as a physician, before I started in psychiatry, I studied clinical immunology quite diligently until about 1990. Then I didn’t look at an immunology textbook or paper again until about 2012, when I was truly dazzled by what had happened since I last paid attention.

  Twenty-first-century immunology is built on some of the same foundations that I was taught in the 20th century - the bare bones of some of the textbook diagrams are the same - but in every respect the picture is now marvellously more detailed and complex. Several completely new things have been discovered. And several old certainties have been destroyed. This new and still growing immunology is scientifically and therapeutically powerful in many unprecedented ways.16 In particular, as far as we’re concerned, it empowers us to think differently about the links between the immune system, the brain, behaviours and states of mind. Your body’s state of inflammation, your immune system’s level of threat arousal, can have a direct effect on how you feel, and what you think about. To put it more scientifically, inflammation of the body can cause changes in how the brain works, which in turn cause the changes in mood, cognition and behaviour that we recognise as depression.

  Inflammation and infection

  To see how this works from the ground up, let’s start with the basic building blocks of the human body - its microscopic cells - which occur in millions of different varieties, each specialised for a different function. Nerve cells make up most of the nervo
us system, white blood cells make up most of the immune system and endothelial cells form the inner lining of the arteries and veins in the cardiovascular system. White blood cells can be further subdivided into more specialised immune cells, like macrophages, lymphocytes and microglial cells. These cells are the A-list actors in the immune system (Fig. 1).

  The raw material of all cells is protein and there are billions of different proteins in the human body, each built according to a DNA code that we inherited genetically from our parents. All antibodies and enzymes are proteins, as are cytokines and many hormones, like insulin. Many proteins act as biological signals, which communicate information within a cell or between cells, by recognising and binding to another protein, called a receptor. This biological hierarchy of systems, cells, proteins and, ultimately, DNA constitutes an organism, for example a human, like one of us. Inevitably, the human self will be attacked by non-human organisms, like bacteria, collectively called antigens or non-self. Inflammation is what the immune system does to defend the self from the non-self, to protect us against them.

  We have known something about inflammation since the ancients. The first recognisable account is attributed to Celsus, a Roman physician who was once so renowned in medical circles that even 1,500 years after his death the most original and boastful physician in medieval Europe could think of no more exalted trade name for himself than Paracelsus (beyond Celsus).

  It was Celsus who originally described inflammation as a syndrome, a cluster of diagnostic symptoms and signs: redness, heat, swelling and pain. He recognised that inflammation often followed injury. So, for example, if a man was stabbed in the hand, the wounded area would become hot, red, swollen and painful (Fig. 2). The hand became acutely inflamed - that much was clear by clinical examination, and the concept of acute inflammation has remained enduringly useful to medicine ever since. What was not so clearly resolved until more modern times were the key mechanistic questions: how and why does the body respond to injury in this particular way?

  Figure 1: Immune cells. These “immunojis” represent the key players in the immune system. Macrophages are big eating cells that eat bacteria and produce cytokines, or inflammatory hormones. They are ubiquitous in the body. Microglia or microglial cells are macrophages that are located uniquely in the brain. Lymphocytes produce antibodies to help macrophages fight infection. Endothelial cells form the inner lining of arteries and veins.

  Immunology has answered these questions with remarkable precision. We can now see how hundreds of proteins interact with each other in complex signalling pathways to translate the traumatic stimulus of the wound into an inflammatory response. We can spell out step by step a molecular chain of cause and effect that explains how the inflammatory response to injury dilates the local blood vessels, allowing more blood to flow into the wounded area, causing the ancient symptom of heat. We know exactly how inflammation makes blood vessel walls leakier, allowing more fluid to leave the circulation and accumulate in the muscles and other tissues of the hand, causing the classical symptom of swelling. We know these and many other biological details about how the immune system generates an inflammatory response. We now also know why.

  Inflammation and immunity are what keep us alive in a hostile world. We know that people who are unfortunate enough to be born without a fully functioning immune system, due to a rare genetic mutation, often do not survive very long after birth. Without an immune system, we are easy meat for our enemies. And we are surrounded by enemies that ancient physicians like Celsus simply couldn’t see: bugs, germs, pathogens, viruses, bacteria, worms, protozoa and fungi. There is a very long list of mostly microscopic organisms that have evolved to succeed by infecting us. And generally their success is our failure.

  Figure 2: Inflammation. (Clockwise from top) From the time of the earliest humans, fighting and conflict have been a common cause of physical injury and infection. In modern times, immunology has explained how the body makes an inflammatory response to the trauma and invasion by hostile bacteria caused by a knife wound. Macrophages eat the bacteria contaminating the knife blade and release cytokines into the bloodstream, which attract more macrophages to swarm into the wounded area to overwhelm the bacteria and successfully defend the self from the non-self. These microscopic workings of the immune system explain the classical symptoms and signs of acute inflammation — swelling, redness and tenderness of the wounded hand.

  If the knife that stabs the hand is dirty, or even if it is ordinarily clean rather than rigorously disinfected, the blade will be covered with bacteria. The stabbed hand will be infected by whatever bacteria are contaminating the knife and once the bacteria are comfortably at home in the hand they will start to proliferate, to reproduce at an astonishing rate. What will this do to us? It depends partly on what types or species of bacteria happened to be sitting on the knife in the first place. There are millions of different bacterial species in the world and they are not all equally dangerous to humans.

  But let’s suppose that one of the bacteria contaminating the knife was Clostridium tetani. That could turn a minor injury into a cause of death; because C tetani - as you might have guessed - causes tetanus. More mechanistically speaking, it produces a poison or toxin that gets into the nervous system and upsets the normal balance between excitation and inhibition of nerve cells. The poisoned nerve cells become uninhibitedly excited and send non-stop signals to the muscles, causing them to contract in prolonged and painful spasms. The first sign is typically lockjaw. The muscles that normally open and close the mouth become permanently contracted so that the mouth can no longer open: the patient can no longer speak, eat or drink. Likewise tetanic spasm of the facial muscles causes the corners of the mouth to be uplifted so that, even as the patient is suffering severely, becoming progressively, painfully paralysed to the point of immobility and death, he wears a fixed expression of mild amusement, a sardonic smile.

  So that’s what we’re up against and always have been up against. We are constantly under attack by hostile and dangerous enemies. It is our immune system that defends each of us - the self - from the biological warfare waged against us by alien organisms - the non-self. And there are key features of the immune system’s organisation that equip it superbly for this vital defensive role: its location, its methods of communication and its capacity for rapid rebuttal and learning.

  But, marvellous though it is, the immune system is not infallible. It can make mistakes. And when the immune system gets it wrong it can become a cause of diseases as serious as the diseases it defends us against so brilliantly when it gets it right. We’ll start with the upside.

  Location, location, location

  This doesn’t just mean that location is very important for the immune system; but also that the immune system is in many locations. Most of the nervous system is compactly located in the head. Most of the respiratory system is encaged in the chest. The immune system is not like that. You can’t point to one place in your body and say “that’s where my immune system is”. The immune system is nowhere because it is everywhere.

  It has to be everywhere because infectious attack can come from anywhere. Viruses and bacteria can infect the body through multiple different portals - some can penetrate the skin, others are infectious through the lungs or the gut. Any surface between the self and the non-self, between the body and the outside world, is open to attack; and all such surfaces are frontlines of biological warfare between hostile non-self agents - like C tetani - and the perimeter defences of the self.

  The immune cells that are most widely distributed throughout the body and that guard most of the perimeter are called macrophages. This is a 19th-century word made up of two ancient Greek roots: macro meaning big and phage meaning eat. You can think of a macrophage - usually pronounced to rhyme with page - as a big cell that eats a lot (Figs. 1 and 2). And what it eats are often bacteria. It destroys hostile germs by enveloping them in a membrane and enzymatically digesting them. It is an extremely effective ki
lling machine but its most powerful weapons against infection are also short-range weapons. To eat the germ, the macrophage obviously has to be in direct physical contact with it. So a single macrophage will only be able to deal immediately with a bacterial infection within a restricted radius - a few millimetres - of its location. To protect the entire perimeter many millions of macrophages have to be stationed like border guards or centurions, each guarding a local patch of tissue, strategically concentrated in positions that are most likely to be attacked.

  The gut is a major battleground against infection. The lining of the gut has to be relatively thin and receptive to the outside world, in order to absorb nutrients from food. It can’t be physically protected from infection like the skin, by a tough external layer of keratin, and yet it is continually exposed to the thick broth of bacteria and more-or-less digested food that passes through our bowels on a daily basis. The gut wall is constantly being penetrated by bacteria; and it is constantly being defended by a legion of macrophages that are permanently and densely stationed from mouth to anus.