Signal then storm

Listen to this essay 28 minute listen One night in 2000, Allan Basbaum was at the Pierre Hotel on Central Park, wearing a tuxedo after presenting a neuroscience award to one of his colleagues before a roomful of scientists, Nobel laureates among them. His wife, Carol, a cancer biologist, had accompanied him from San Francisco, where they both ran laboratories at the University of California. Late that night, he was struck by agonising stomach pain. Alarmed, they went to the emergency room at Lenox Hill Hospital, where the waiting area was jammed and hours passed before anyone could see him. ‘So I’m out in the waiting room; I’m periodically screaming,’ Basbaum says. After two hours, Carol went to the bathroom, leaving him alone. Finally, a man came over and began speaking to him, gently prodding him. ‘He checks my pulse, he asks: “Does this hurt?”’ Basbaum says. As the man attended to him, ‘the pain really started to get much better,’ and Basbaum relaxed. When Carol returned, he told her about the long-awaited treatment. ‘She says: “Allan, he’s one of the patients. He’s been doing that to everybody here.” But finally, someone was taking care of me.’ And that brought relief. By then, Basbaum had spent three decades studying the physiology of pain, mapping the neural circuits that carry signals from the body toward the brain. He wanted to understand how those signals become pain. His experience brought to life the questions he’d been marvelling at for years: how do fear, context and expectation shape the body’s most urgent alarm? How do placebos work? And how could someone relieve his pain, just by paying attention? Basbaum understood the Gordian knot at the heart of pain: the brain could influence pain before a person consciously felt it. His work over the past 50 years has been to untangle that loop, following signals through the spinal cord to the brain and back again. Basbaum likens pain to the experience of beauty. Take Piet Mondrian. One person sees a painting of coloured bars and squares, and thinks: I could do that. Another, steeped in the history and meaning of the work, is moved to tears. The image on the retina may be much the same; the experience is not. Pain, Basbaum argues, works in a similar way. There is no such thing as an inherently painful stimulus, only stimuli that, in most people, under most conditions, will produce pain. A truly subjective experience, pain can seem ephemeral. Yet, like all bodily sensations, it arises from the interactions of molecules and cells. At age 78, still at the University of California, San Francisco (UCSF) leading one of the nation’s most prolific pain research groups, Basbaum’s aim remains unchanged: unravel the signal to find ways of treating pain. The brain is not where Basbaum wants treatment to begin. ‘My bias is to understand how the information gets to the brain and look for places along the way, preferably way out in the periphery, that I think are important drivers to initiate the whole process,’ he says. ‘By interfering with those drivers, we can disrupt chronic pain altogether.’ Nerve-cutting procedures didn’t produce lasting relief, and patients reported that pain could return worse than before The history of pain research goes back centuries. René Descartes, who declared a split between body and mind, placed pain in the physical realm. His Treatise of Man (1662) included a famous illustration: a fire burns a boy’s foot, its heat activating a withdrawal reflex through a tube-like structure to the brain. However crude, that model helped lay the foundation for modern sensory physiology. Two centuries later, Johannes Müller refined that model. Sensory information reached the brain through nerves, he argued, with each sense travelling along its own neural system. Pain was grouped with touch, heat, cold, itching and pleasure in the body’s broad field of feeling. By 1894, Max von Frey had divvied bodily feeling into four parts: mechanical touch, warmth, cold and pain, each carried by distinct nerve types. Pain, he added, was contained within its own system, its signals travelling to discrete pain centres in the brain. Around this time, researchers drew a distinction between the complex experience of pain and ‘nociception’, the sensory response to a noxious or harmful stimulus. That distinction, coined by Sir Charles Sherrington, remains a core principle of pain research today. Nociception occurs in the body, in the nerves and the spinal cord. Pain requires the brain. These complexities undermined the old notion of a single pain pathway. Historically, the idea was simple: injury sent pain input like a telephone wire to the brain. ‘You want to get rid of it? Poof – you just cut it,’ Basbaum says. But nerve-cutting procedures didn’t produce lasting relief, and patients reported that pain could return worse than before. Nor did injury and pain always correspond. Field surgeons in the United States Civil War reported that amputees felt excruciating phantom pain in limbs no longer there; soldiers with severe wounds sometimes felt little pain at all. These phenomena pointed to a system much more complex than a telephone wire from body to brain. Even so, sensory communication did travel electrically. By the mid-20th century, Alan Hodgkin and Andrew Huxley had worked out the action potential, the bioelectrical pulse by which neurons communicate, and researchers had begun tracing the anatomy of sensation from body to brain. Sensory neurons live in clusters called dorsal root ganglia just outside the spinal cord. Each has an unusual architecture: one long, thin axon – a nerve fibre that carries electrical signals – extends out to the body, while a shorter branch reaches into the spinal cord. Large cells with insulated axons carry fast-moving touch signals; smaller, slower-conducting cells with bare axons relay temperature and pain. But details beyond that were sketchy. By that time, pain was a matter of fierce dispute. That’s when the Canadian psychologist Ronald Melzack and the British neuroscientist Patrick Wall – the two men who would become Basbaum’s mentors – teamed up to tackle the problem. In a 1962 publication, Melzack and Wall boiled down the controversy to two prevailing theories. The first, ‘specificity theory’, held that pain occupied its own system: pain sensors in the skin relayed information through pain nerves to pain centres in the brain. But that model was too rigid. It could not explain why pain varied so much with context, expectation or injury. The newer alternative was ‘pattern theory’, which held that pain did not travel along its own dedicated pathway. Instead, sensations depended on how many nerves fired, how fast they fired and in what combination. A light touch might register one way; a stronger, more sustained barrage of activity might be read as pain. But pattern theory was too vague. It did not explain what produced those firing patterns, or how the nervous system knew when to read them as touch, heat or pain. Both theories were wrong, said Melzack and Wall, but both had elements of truth. In response, they developed what they called ‘gate control theory’. The theory challenged an old assumption: that pain travelled like a message along a fixed pathway from injured tissue to the brain. ‘Gate control theory was really about trying to get away from the view of a pathway, a telephone wire system,’ Basbaum says. Rather than a simple relay from body to brain, the theory proposed that sensory signals are mixed and processed in the spinal cord on their way to the brain. The spinal cord was not just a cable. It could act as a gate, allowing some signals through while dampening others. The brain was not merely receiving the body’s message. It was assessing the situation and regulating the signal Basbaum describes the theory in action. ‘You burn your hand, and what do you do? You shake it or rub it – you stimulate it more. Why? That seems crazy.’ But rubbing the burn activates larger nerve fibres, the ones that carry touch and vibration rather than pain. In the spinal cord, those signals can inhibit the pain-carrying input. That is the closing of the metaphorical gate. But gate control theory went further. It also allowed for signals travelling from the brain back down to the spinal cord. ‘It was called the central control trigger,’ says Basbaum. ‘And that said the brain can also regulate the gate.’ That idea reflected the unusual partnership behind the theory. Wall worked out the spinal circuitry; Melzack, the psychologist, cared about phantom limb pain, placebo and the way context changes pain. ‘Melzack was the brain guy,’ Basbaum says. Together, they argued that the brain plays an active role even in the earliest stages of pain. It was not merely receiving the body’s message. It was assessing the situation and regulating the signal. Melzack and Wall published their idea in a paper titled ‘Pain Mechanisms: A New Theory’ (1965). It was a seismic shift in physiology, and the paper remains one of the most influential studies in the history of pain research. Just two years later, in 1967, Basbaum joined Melzack’s laboratory, accidentally beginning his career in pain research. Basbaum had no particular interest in studying pain after his junior year at McGill University in Canada. Like everyone he knew, he had applied for a summer host position at Expo ’67, the world’s fair in Montreal, in the Australian Pavilion. ‘The whole world was coming,’ he says. ‘I really wanted that job.’ But after weeks of waiting and in need of a summer job, he gave up on the dream and applied to work as a lab technician for Melzack. Basbaum had taken a course called ‘Motivation’ with the psychology professor. He got the position and accepted. ‘But soon after, I was offered the Expo job. And my father said: “You can’t take it. That’s too bad.” So now I was working in a pain research lab.’ He spent the summer training rats, rather than chatting up international tourists. Meanwhile, Ed Perl, a neuroscientist at the University of North Carolina, had been studying how painful signals originate in the body. Recording from individual sensory neurons rather than whole nerve bundles, Perl identified cells that responded only to noxious, or potentially harmful, stimuli. He called them nociceptors, echoing Sherrington’s distinction between noxious sensory detection and pain. Perl later showed that neurons in the spinal cord receiving input from nociceptors were also specialised for pain processing. Specificity theory, it turned out, was not entirely wrong. Around then, Basbaum was continuing his studies in one of the first graduate programmes in the US in neuroscience, at the University of Pennsylvania. His PhD thesis took up what was still called the pain pathway. According to the prevailing view, pain travelled to the brain along a single nerve tract, the spinothalamic pathway. But that simple route did not fit the evidence, or Melzack and Wall’s new theory. People whose spinal cords had been cut to interrupt the pathway could still feel pain; in some cases, pain abated but then returned. ‘Wait a second,’ Basbaum remembers thinking. ‘How did that happen?’ The idea of a single tract carrying pain to the brain was beginning to fall apart. To test the idea, Basbaum designed an experiment in rats. The challenge was exceptionally precise: he had to make tiny, controlled lesions in the spinal cord, damaging the presumed pain pathway while leaving the animals able to move and respond. First, he trained the rats to turn their heads in response to a painful stimulus. Then he made the delicate cuts. The prevailing theory held that pain travelled upward along two long spinothalamic tracts, one on each side of the cord. So Basbaum cut one tract on one side, then cut the corresponding tract on the other side at a different level. If those long tracts were the only route to the brain, the signal should have been blocked, and the animal never would have experienced pain. But Basbaum suspected the system had other routes. When the animals awoke from surgery, they still turned their heads in response to the painful stimulus. Pain had found another path. ‘That told me that the way pain is generated is more complicated than a single line,’ he says. By 1972, Basbaum had left for University College London, UK, to work with the other half of the famed duo: Pat Wall. He’d already shown that pain did not travel along a single upward path, and in Wall’s lab, he began to ask the inverse question: could the brain send signals back down the spinal cord to control pain before it fully took hold? The question had urgent implications for treatment. Opioid drugs had been used for millennia for their powerful pain-relieving effects, but in the early 1970s no one knew how they worked. Researchers today know that the brain produces its own endogenous opioids – molecules that act on opioid receptors throughout the nervous system. Back then, Basbaum says, ‘we just knew that morphine relieved pain, but no one knew how.’ Then, in 1971, researchers at the University of California, Los Angeles (UCLA), led by John Liebeskind, offered a clue. His team had been testing whether electrical stimulation of specific brain regions could alter pain in rodents. When they stimulated an area of the midbrain, the effect was dramatic: awake animals showed profound pain relief, on par with a hefty dose of morphine. Liebeskind proposed that cells in the midbrain were sending some kind of pain-blunting signal down to the spinal cord. For opioid receptors to evolve in nature, the brain must be making its own opioid-like molecules Basbaum went looking for the route by which the brain’s pain-relief signal travelled down the spinal cord. First, he stimulated the midbrain, producing pain relief. Then he made tiny lesions in the spinal cords of rats, cutting candidate pathways one by one, and stimulated the midbrain again. If the pain relief disappeared after a particular pathway was cut, that pathway was likely carrying the message. One pathway stood out: the dorsolateral funiculus, or DLF, a bundle of nerve fibres running along the outer edge of the spinal cord. Basbaum made a precise lesion in the DLF partway down the spinal cord. The cut was placed so that a descending signal from the brain could still reach the forepaws, but could not continue past the lesion to reach the hind paws. After the lesion, the animals still felt pain. That was not the test. The test was whether stimulation of the midbrain could still turn down that pain. When Basbaum stimulated the midbrain, the animals showed pain relief in their forepaws, above the cut, but not in their hind paws, below it. The result showed that the pain-relief message from the brain travelled down the spinal cord through the DLF. Basbaum had identified the route. Around the same time, other researchers were revealing the chemistry that could switch on that route. In 1973, Candace Pert and Solomon Snyder found opioid receptors in the brain. The discovery raised an obvious issue: those receptors could not have evolved in us for morphine, a drug from outside the body. For those receptors to evolve in nature, the brain must be making its own opioid-like molecules. Soon after, John Hughes and Hans Kosterlitz identified enkephalins, molecules produced in the brain that activate those receptors. Then Liebeskind’s group showed that naloxone, a drug that blocks opioid action, also blocked the pain relief produced by midbrain stimulation. The pieces now fit together. The brain produced its own opioids. Those molecules acted in the midbrain. And signals from the midbrain travelled down the spinal cord through the DLF, dampening incoming pain before it reached the brain. From London, Basbaum went on to a postdoctoral fellowship with Howard Fields, another major figure in pain research, at UCSF. Basbaum’s wife Carol had found work in London, but they had made a deal: after the UK, she would choose their next destination. She had a fantastic opportunity at UCSF, so that’s where they went. Basbaum knew little about California. ‘I thought the Golden Gate Bridge connected San Francisco and Los Angeles,’ he joked. But Wall recommended Basbaum, assuring Fields: ‘I think he’ll work out.’ Basbaum shows me an old snapshot of his younger self being held in a jokey headlock by a fit, theatrical man. The man mugs for the camera – wearing stylish Italian glasses and a thick, gold wedding band, a gold watch and chain, and gold buttons on his jacket, he plants a kiss on Allan’s forehead. The man is John Bonica, an army doctor in Washington State who immigrated to the US from Sicily as a child and made his way through medical school as a professional wrestler using the monikers ‘The Masked Marvel’ and ‘Johnny Bull Walker’. Today, Bonica is recognised as the father of chronic pain care. Bonica understood chronic pain not only as a neural problem, but as a treatment crisis. He had treated Second World War veterans whose pain lasted long after their injuries had healed, and he suffered chronic pain himself from wrestling injuries. At the University of Washington, he pioneered the idea that chronic pain requires treatment by a team of providers. Together with a nurse and a neurosurgeon, Bonica established the world’s first multidisciplinary pain clinic. Patients would check in and stay for three weeks or more, receiving care from doctors, nurses, therapists and psychologists. Importantly, members of the care team – including research scientists – met regularly to discuss cases. Bonica’s treatment model was effective but expensive, and it required intensive care. ‘The insurance companies would never go for it,’ Basbaum says. Although Bonica’s pain treatment clinics proliferated around the world for a time, the lack of insurance coverage eventually shuttered them in the US. Decades later, the most successful pain clinics in operation today are multidisciplinary, bearing Bonica’s imprint. Basbaum was presenting – then a senior researcher stood up in the audience and challenged him Bonica and his colleagues also helped create the institutions that made pain a field: the first medical training programme in pain, and eventually the International Association for the Study of Pain. At the association’s 1975 meeting in Florence in Italy, Basbaum presented the work he had recently completed with Wall in London: the delicate spinal-lesion experiments showing that the DLF carried descending pain control. By then, he had moved to San Francisco for a second postdoctoral fellowship with Fields, but he was still a junior scientist. The talk was nerve-wracking, but he got through it. What Basbaum was presenting – evidence that the brain could dampen incoming pain – rested entirely on the precision of those spinal lesions. Then a senior researcher named Arthur Taub stood up in the audience and challenged him. ‘I don’t believe you,’ he said, according to Basbaum. ‘Nobody could make those lesions without screwing up the animal.’ Taub was arguing that no one could make those cuts cleanly enough for Basbaum’s conclusion to hold. Basbaum was devastated. ‘I’m a postdoc, and this big shot, Arthur Taub, he’s basically telling me I’m full of shit.’ Shaken, Basbaum prepared to return to Fields’s lab in California. Before he left, Ron Dubner, an influential pain researcher at the National Institutes of Health (NIH), approached him. Dubner had heard the exchange. ‘You know Allan, on your way home to San Francisco, why don’t you come to the NIH and give us a talk about this?’ he said. The invitation helped restore Basbaum’s confidence. But after Basbaum gave the talk at NIH, Dubner made another request. Some rats, he said, were about to undergo surgery. Could Basbaum show them how to make those spinal-cord lesions? Basbaum agreed. He made the lesions as he had done so many times before. When the rats woke up, they walked around normally. Only then did Dubner reveal the point of the exercise. ‘Holy shit, you really can do it!’ he said. ‘It was a test,’ Basbaum says. ‘He didn’t know whether to believe Taub or me.’ What Dubner had really tested was whether Basbaum could be trusted to read his own results. That trust would be earned again in Fields’s lab at UCSF, where a technical error became a discovery. Fields was trying to map the upward routes for pain: the pathways by which signals leaving the spinal cord travelled into the brain. To follow those routes, he and Basbaum used radioactive tracers – dyes that nerve cells carry along their fibres. Inject the dye in one place, and it can reveal where the connected fibres lead. The plan was to inject the tracer into a region of the brainstem and follow the pathways upward toward the thalamus, a deep brain structure that acts as a relay station for sensory information. But Basbaum made a small technical error. The bevel of the needle faced the wrong direction, so the dye spread into a neighbouring midline region instead. Cells in the brainstem appeared to send signals directly to the spinal cord regions involved in pain That mistake lit up a pathway they had not meant to study. Instead of showing only routes upward toward the thalamus, the tracer revealed fibres descending back down toward the spinal cord. When Basbaum and Fields followed those fibres, they found that they ended in the outer layers of the dorsal horn, the part of the spinal cord where incoming pain signals from the body are first processed. The implication was striking: cells in the brainstem appeared to send signals directly to the spinal cord regions involved in pain. That gave anatomical support to the descending pain-control system Basbaum had been tracing since London. At first, some researchers dismissed the finding as an artefact. Over time, the evidence held. Shortly thereafter, Liebeskind of UCLA asked Basbaum to take his place speaking at the Winter Conference on Brain Research in Keystone, Colorado. He did, and the morning after giving his talk, Basbaum stood in line at the ski lift, as one does at Winter Brain, as it’s known. A gentleman unknown to Basbaum struck up a conversation; he turned out to be Fred Plum, a famous neurologist and editor of the prestigious Annals of Neurology journal. Plum invited Basbaum and Fields to review what was known so far about the spinal pathways relevant to pain, both ascending and descending. They published the succinct review article ‘Endogenous Pain Control Mechanisms: Review and Hypothesis’ (1978) that became a hallmark of Basbaum’s career. In it, they described the neural circuits of descending pain modulation – what was originally conceived as Melzack’s central control trigger in gate control theory. In the decades since then, Basbaum has continued his quest to come up with better treatments for people living with chronic pain conditions. Despite tremendous gains in pain physiology, neuroscience has not yet delivered on the promise of better therapeutics. The gap is not for lack of data. It is, Basbaum might say, the difference between the canvas and the painting – knowing every molecule in the pigment does not tell you what the viewer feels, but it just might tell you why. ‘There are two major limitations,’ says Basbaum. ‘One is side-effects of a drug, that creates real problems.’ Opioids, for example, are very effective painkillers, but their side-effects limit their safe use. Opioid receptors, it turns out, are found throughout the body and brain, not just in pain-control regions. That makes opioids powerful but blunt: a drug meant to quiet pain can also affect breathing, digestion, alertness and reward. ‘The other problem is the placebo effect, which is somewhat unique to pain,’ Basbaum says. The placebo effect occurs when someone experiences a therapeutic effect – in this case, pain relief – from an inert substance. ‘Pain is a product of the brain, influenced by psychology, so it’s very placebo sensitive,’ more so than illnesses like cancer. ‘That’s why the science hasn’t translated more rapidly and more efficiently’ into treatments. Pain may be what the brain makes of a signal, but somewhere, Basbaum insists, there is a signal The placebo effect, like pain itself, rests on the activity of neurons, receptors and circuits in the brain. ‘Placebos don’t act out in the ether. There’s a psychological intervention that releases endorphins, and that turns on a control system.’ Howard Fields ultimately showed that the placebo effect results from endogenous opioids, delivered to the spinal cord by the descending modulation system that he and Basbaum described. Basbaum experienced relief from a form of the placebo effect firsthand, back in that Manhattan emergency room, in a way he could never have comprehended intellectually at the time. ‘Pain is a percept of the brain: it has a sensory-discriminatory component, it has an emotional component, and it has a cognitive component.’ Basbaum knew that pain is shaped by context, and that psychological interventions can alleviate pain. But that night, his embodied experience of relief from an acute pain crisis brought it all home. ‘It was clear that there was a psychological impact. And I had never personally experienced how profound that could be.’ And yet Basbaum remains convinced that his greatest contribution to the field – if it ever comes – will be in the form of a medication that acts in the periphery, before sensory information becomes ‘pain’ at all. In 1997, Basbaum gave a talk at a meeting in Israel. Melzack, Basbaum’s very first mentor, attended. ‘I presented some work on the spinal cord and ways to treat pain,’ says Basbaum. ‘And he got up and said: “Allan, you’re only working on nociception. You’re wasting your time. You can’t treat pain like this.”’ Melzack meant that nociception – the nervous system’s detection of harmful stimuli – was not the same as pain. Pain, to him, was the whole experience: sensation, emotion, memory, attention and meaning. To search for treatment only in the periphery, or in the spinal signals coming from the body, was, in Melzack’s view, to mistake the raw input for the experience itself. Melzack never came around, and neither has Basbaum. Their disagreement, which stretched across half a century and outlasted Melzack’s death in 2019, was never only about evidence. It was about where you believe experience lives. Melzack, the psychologist, placed it in the whole: sensation, memory, emotion, attention – the viewer standing before the Mondrian, moved to tears by what she brings to it. Basbaum keeps looking earlier – for the brush, the paint. Pain may be what the brain makes of a signal, but somewhere, he insists, there is a signal. ‘I still believe that the percept of pain is driven by peripheral injury of some sort,’ he tells me. Even though pain is in the brain, he believes it must originate in sensory neurons. In some cases, Basbaum says, ‘we haven’t yet figured out where the peripheral injury is. Just because you don’t know where it is, doesn’t mean it doesn’t exist. And more and more,’ he says, researchers are finding the hidden, subtle sites of injury that may drive chronic pain. ‘Do I believe that the brain can make things worse? Absolutely. It can also make things better. But I believe there’s a peripheral driver that should be shut off.’ Find the physical driver and you find the place to intervene. Basbaum is banking on that.