The article first appeared in The Sunday Times on 5 April.

The miracle worker

This is the story of a scientist who has uncovered the deepest secrets of paralysis after injury, not through wishful thinking and guesswork, but through unflinching focus over 40 years on one of nature’s strangest quirks.

The mechanics of spinal-cord injury have been known for decades, and Raisman has been intimately involved in their discovery. While still in his twenties, he staked a niche in the history of neuroscience by showing that the brain and central nervous system have an astonishing capacity to reorganise themselves after loss or trauma. He called it “plasticity”.

Born and raised in a poverty-stricken district of Leeds, obdurate in his decision to marry the girl of his dreams at 18, thus risking his university education before it even got started, Raisman has always been, by his own admission, “bloody-minded”. As a young researcher he was dubbed a scientific heretic for insisting that a damaged brain and spinal cord can repair themselves; but he has proved his critics wrong. He has always followed his instincts, backed by long-term systematic experiment. He is now about to put to the test in human patients his theory that plasticity can be manipulated to cure some of nature’s cruellest afflictions.

Stem cells, primitive “mother cells”, which in theory can transform into many kinds of tissue or many blood types, are heralding a new era of medical science, with vaunted cures for everything from diabetes to Alzheimer’s. They are also the stuff of scientific flatulence and soiled nests: 2005 will go down in biotech history as the year when an eminent South Korean professor, Hwang Woo-suk (personal salary, $3m per annum), was found to have fabricated results in two papers published in America’s top research journal, Science. Hwang’s papers involved the cloning of embryonic stem cells for therapeutic purposes. His published pictures of cloned human stem cells were fakes. Worse: Nature magazine reports that many stem-cell lines in the laboratories of the world are duds because of a confusion between tagging a cell and correctly identifying its properties. The principle is simple: you can wear a tutu but it doesn’t make you a ballerina.

Yet if Raisman has anything to do with it, 2006 will be remembered as the year British biotechnology took the first step towards an authentic cure for spinal-cord injury in humans, with a promise of greater things to come. He aims to do this not with cells taken from embryos, but cells from high in the nose of a spinally injured patient. It’s a procedure, he claims, that can be applied to damaged optic nerves and deficits from stroke injury, such as loss of speech, hearing and movement. The plausibility of his proposal is in the fine detail: the relentless experiments, clinical trials and scientific papers that constitute his life project.

There have been other bids to use nasal cells for spinal-cord therapies, in Lisbon, Rio and Shanghai; the results have been ambiguous and short-lived. Raisman explains that, unlike most other attempts, his research programme has scientific depth and depends on monitored trials that eliminate chance dramatic remissions and slight improvements prompted by physiotherapy.

Raisman does not see himself in a race with these other attempts to exploit nasal cells, nor do any of his rivals. As he says, “Elsewhere, doctors are using nasal cells as a shot-in-the-dark treatment rather than as systematic, scientifically based trials.” His work has been acclaimed by top peer-group scientists.

Raisman’s proposal finds its origins in the vast, mysterious environment of the nerve cells, or neurons, of the brain and the central nervous system. We are born with over 100 billion neurons, the biological computing mechanisms that regulate thought, action and sensation. They send and receive messages that control the entire organism of the body. It has long been known that, apart from those extraordinary olfactory nerve cells in the nose, neurons do not replicate or regenerate when they die: you only ever lose them. But you have a lot to lose, and the loss of neurons is often compensated for by the flourishing growth of neighbouring neuronal branches known as dendrites, which take over the space vacated by a deficit.

Neurons send and receive their signals through myriad branch-like nerve fibres. They communicate with their neighbours by firing chemical substances across minuscule terminals known as synapses. There are more combinations of signals in the massed neuronal undergrowth than there are particles in the known universe. Neuronal signals are strengthened when we learn skills, such as a language or a new sport. Those neurons we fail to use atrophy and eventually die. Raisman tells me that when he gazed at neurons and their nerve fibres through an old-fashioned light microscope, they appeared motionless, “like a forest of trees, silent in a windless sky”. But when he first observed them through an electron microscope (with orders of magnification in the millions), “it was like snorkelling through a kelp forest… All was in a state of flowing motion… continual change”.

As he gazed into this jungle of the brain and central nervous system in the mid-1960s, he was inspired to propose his theory of “plasticity”: the first step in his bid to mend a broken spinal cord.
When a neuron dies, the synapses decay and break down irretrievably. But then the nerve fibres of neighbouring healthy neurons sense a vacuum and extend new branches to compensate. Raisman likes to compare this phenomenon to a Hindu god with many arms and hands. “Losing a neuron is like the god losing an arm and accompanying hand. But it’s as if a neighbouring arm sprouts new hands to make up for that loss.” He gives me another image: “Imagine a ring of dancers holding hands. One drops out and the ring is broken until the dancers on either side join hands around the empty space, completing the ring again.”

Raisman’s theory of neuronal plasticity was not well received in the 1960s, because it challenged a sacred cow of neurology. When neuronal connections in the spinal cord are lost, by falling off a horse, say, like the late Christopher Reeve, scar tissue forms at the site of the break and the affected neurons die. Neurologists were once convinced that the devastating effects of spinal-cord injury, which can involve all bodily functions, including breathing, were not just the result of the barrier caused by scar tissue, which quickly grows at the site of the damage, but were simply due to the fact that neurons lost in an accident are never replaced. Yet now there was Raisman’s plasticity bombshell: “The neurons don’t grow back,” he declares, brightly, “but the branches of the neighbouring healthy neurons move in to take their place.”

So why do these new connections fail to link up with their corresponding partners on the other side of a scar? Is it because of the density and hostile environment of scar tissue? Or are there other factors? Raisman’s answer – discovered in the nerve cells of the nose – lay more than 20 years ahead. Meanwhile, he sat on his controversial idea of plasticity: “It’s amazing how unwilling the world is to accept new ideas, even when they are positive ones.”

Raisman never forgets the day he first realised that his pathway hypothesis had worked. “It was in the depths of winter. I had gone to examine my rat model at 2am. My breath was like steam in the frozen night air.” The rat, with an artificially induced lesion preventing movement of its left paw, had been treated with a graft of nasal glial cells from its own nose.

“I offered it some food, and could hardly believe my eyes. It put its left paw forward. For a moment we looked at each other in shocked surprise. Then it took the food. It was a moment that occurs maybe just once in a scientist’s lifetime – if you’re very lucky.” Since then, Raisman and his team have treated similar injuries in rat models dozens of times, including mending the part of a rat’s spinal cord that controls breathing.

Now the time has come to work on human patients. In December 2005, Raisman moved his team to a facility in Queen Square, London, under the auspices of the Institute of Neurology and University College London.

Essential to his plans is the involvement of the neurosurgeon Professor Tom Carlstedt, renowned for his work on the human spinal cord. They have permission for the first preliminary safety study, which begins this autumn.

The team aims to mend a collection of injured nerve fibres at a point known as the dorsal root, where nerve fibres emerge high in the spinal cord and into the shoulder. The site – the brachial plexus – is often severed in traffic accidents, especially when bikers take a tumble, landing on their shoulders. The consequent injury, known as a “brachial plexus avulsion”, results in a paralysed arm and acute pain. “It’s as if the still-living fibres are putting out a mass of white noise,” Raisman says. “The pain is so great, the patient sometimes becomes suicidal.”

The surgeon will retrieve olfactory ensheathing cells from the patient’s nose. Being autologous – in other words, containing the patient’s own DNA – there is no likelihood of rejection. First the cells, numbering about a million, but collectively as small as a pinhead, will be cultured before being grafted into the site of the break by two surgeons and their teams. Within several weeks it is expected that these glial cells will have created the desired pathway for the severed nerve fibres to grow through, and that normal sensation and movement will be restored. “From here,” says Raisman, “the way is open to evolve techniques for repairing larger spinal-cord injuries of the type that Christopher Reeve suffered. In the more distant future, we’ll be able to repair damage to the optic nerve that causes blindness, and brain injuries of the type endured in strokes, causing deafness and loss of speech.” The treatment process will be the same.

Where the injury has been caused by a disruption of the nerve-fibre pathways – in the optic nerve, for example – the patient’s own olfactory glial cells will be surgically grafted into the site in the expectation that damage will be repaired. “We believe,” says Raisman, “that the nasal cells can act as bridges, allowing regeneration of severed nerve fibres in any part of the brain or the central nervous system.”

He admits there is a limiting factor, “where the grafts would not be long enough to create a bridge all the way between undamaged areas”.

Raisman is cautious about the details of such alternative prospects to spinal injury, but he insists that there is no difference in principle between providing new pathways for nerve fibres damaged by stroke (resulting in the inability to speak, or to hear) and mending the nerve fibres in the brachial plexus.
Getting to know Raisman and his work over a period of several weeks involved reading a quantity of the 300 technical papers he has written in the past 40 years. Most relate to his original discovery of that property he calls plasticity of the brain and central nervous system. As I talked with him in his lab high up in the concrete skyscraper that houses the Institute of Neurology in Holborn, or walking round Queen Square below, I was struck by his lifetime’s concentration on what seemed to me such a narrow focus of neurophysiology. “Don’t you ever get bored with the sheer confinement of your preoccupation?” I asked him.

Raisman was amazed at the narrowness of my perspective. “Observing the plasticity of the nervous system,” he said, “is a keyhole into a universe of extraordinary, never-ending wonder… You don’t stop at the cells and the molecules, you are gripped by the extraordinary complexity of nature’s imagination.” If Raisman fails, it is more likely to be because of his dogged refusal to become involved with attempts to patent his discoveries. A token of his maverick “bloody-mindedness” is his determination to give away freely the intellectual property rights of his procedures.
Unlike most other spinal-injury research, he has no links with the pharmaceutical industry or prospective income from private treatments. “We have no funding from any research council, from any university or from government,” he told me. “Everything comes from my efforts with charities and in finding benevolent donors… and we have just enough funds to sustain the team beyond three years.”