October 25, 2021

I, Science

The science magazine of Imperial College

Does the solution to paralysis emulate an infant’s developing nervous system? Can we regrow spines?

Medicine has come a long way in the past century, and like most technology, progress has been exponential with the addition of automated machinery and global research collaboration. However, there remain conditions stubbornly resistent to the physician’s intent to cure. Many of these recalcitrant conditions involve the central nervous system. It makes us a higher organism but it leaves us vulnerable.

A striking example is spinal cord paralysis. Not only is this imminently life threatening, but the long-term disability is extensive. Not only does it involve the striking loss of motor function, but there can be incredible pain, numbness, impotence, inability to regulate blood pressure, incontinence, and gut motility problems. Like a modem and a computer, distal and proximal parts are functional, but without a connection the net outcome is useless. Unfortunately the nervous system can’t be programmed to respond to wireless … yet.

Several thousand years ago, the bible tells us, Jesus of Nazareth made a lame man walk.

Afterward Jesus returned to Jerusalem for one of the Jewish holy days. Inside the city, near the Sheep Gate, was the pool of Bethesda, with five covered porches. Crowds of sick people—blind, lame, or paralyzed—lay on the porches. One of the men lying there had been sick for thirty-eight years. When Jesus saw him and knew he had been ill for a long time, he asked him, “Would you like to get well?”

“I can’t, sir,” the sick man said, “for I have no one to put me into the pool when the water bubbles up. Someone else always gets there ahead of me.”

Jesus told him, “Stand up, pick up your mat, and walk!”

Instantly, the man was healed!

(John, Chapter 5)

Whilst physiotherapists can command their charges to perform various exercises with balls, weights and rubber bands, walking is rarely the final outcome, nor is it instantaneous!

Modern medicine is yet to come up with a suitable alternative to Jesus.

There has been a lot of recent hype about a study where paralysed rats were made to walk again. Beyond walking they could sprint and climb stairs. This is the first study where any serious resumption of motor function has been regained.

The rats’ spinal cords were cut in two places. The cords were then injected with various chemicals and stimulated electrically whilst the rats were encouraged to perform movement, moving towards a treat. A prosthetic harness that supported their lower back and hindlegs was used to guide movement on a treadmill during periods of electrical stimulation. At first only tiny movements were managed, up until complete recovery was made over a period of weeks. The theory is that this technique strengthens intact minicircuits that survived the spinal injury, rather than re-piecing together the original pathway. Eventually electrical stimulation and prostethic support isn’t needed, because the cortex once again has enough strings to pull in order to get the limb muscles to respond.

An equivalent way of thinking about it is a mutual friend playing cupid between a guy and a girl. Cupid arranges the date, tells each what time to meet and where, tells the guy how to get in with the girl, and vice versa. Eventually, once this tentative connection has been superceded by the boy and the girl talking to each other and communicating themselves, cupid (i.e. the prosthesis/electrical stimulation) can step away and watch it all happen.

In many ways this emulates the normal way we learn to perform movement. Intricate neuronal networks are formed when we learn movements – which neurons are activated depends on their activity state (characterised by certain gene expression/chemical surroundings) and stimulation from neighbouring neurons. Thus in the state of a damaged cord, usually the surroundings are full of inflammatory, hostile chemicals and electrical stimulation from severed neurons is not sufficient to trigger movement. The legs do not move, the brain cannot make them move, and eventually all communication is lost. Thus physiotherapy is vital in improving the outcome after any nerve injury.

These two conditions – chemicals and timely electrical activity – sum up how nearly all circuits are put together in the nervous system.

So why has it taken this long to fix a spinal injury and why isn’t it working in humans?

The first problem lies in the intrinsic nature of the central nervous system itself. Invertebrates are very good at rehealing their nervous systems, they can regrow perfectly functional entire limbs. However, vertebrates simply don’t regrow damaged neurons. The reasons are manifold and include inhibitory proteins that coat the axons of neurons, chemicals that actively prohibit growth and protein sysnthesis in local neurons, and the fact damaged neurons tend to commit suicide.

Often these reasons are broken down into intrinsic and extrinsic factors and both must be managed if we want to restore growth. The neuronal environment in infants is actually very welcoming and contains vast amounts of growth factors, however these also disappear in the adult nervous system. Since the ability to regrow one’s spinal cord would be of supreme benefit in survival of the fittest, we must assume there is an even better reason we don’t do so.

The arguments for this tend to include the fact that we are geared up for stability (our circuits have to last us eighty years plus), that walking on two legs is very complicated, as is remembering everybody’s names, as is being able to recall lifelong memories, as are all the cognitive programmes we constantly enlist when dealing with day-to-day life. The lifetime benefit of this far outweighs the small chance of us sustaining a spinal injury. Unlike frogs who just have to swim around and mate, and are better at doing this when they can recover from devastating injuries they are more likely to experience.

Hence studies have taken considerable time finding the right mix of chemicals that involve both growth factors and blocking inhibitory factors. Then you have to block the signalling cascade that triggers suicide in damaged neurons – to do this you need to be quick. You also need to limit inflammation because this creates a milieu of fire and brimstone that is quite toxic to neurons – but blocking inflammation completely is also a bad thing, since a local invasion of white cells appears to promote neuronal healing, as they clear up debris and secrete friendly chemicals.

Once this has been done neurons can actually be encouraged to grow! But rarely more than 2mm. And this may well work for little rodents, but 2mm in the context of human neurons which can be nearly 6 feet long is less impressive. Particularly when spinal injuries are often crush injuries that take out sections of spine more than 2mm long.

Scientists have tried to bypass the havoc by grafting nerves from one place across the gap. Even when the ends can be persuaded to physically join up, the electrical signals are still in complete disarray. Neurons in different areas of spine have different patterns of gene expression and different receptors. Matching these up whilst applying myriad chemicals to promote healing can be like searching for a needle in a haystack, in the dark, with boxing gloves on.

However, external electrical stimulation in a timely manner that occurs in sync with correct movements might well overcome this melee of confusion by simply strengthening detour circuits and appears to have worked in the rats.

The next step is to see if we can achieve similar results in damaged human tissue.

Even if the same techniques work, remodelling has to be proportionally greater in humans, and usually the injuries people sustain are not the discrete, precise transections used in laboratory animals. Furthermore, it was the corticospinal tract that was cut in these rats (the fibres responsible for movement), whilst real-life injuries often involve the spinothalamic tract and dorsal columns, responsible for pain, temperature and joint sense. Re-aligning all these circuits would be a logistical nightmare.

However, a form of physiotherapy for this sort of sensation would probably be effective in the same way as motor therapy – certainly joint sense would improve along with motor function. However the loss of autonomic function (control of organs and continence) will probably remain a medical issue.

This recent study is very exciting, taking us away from the notion that we have to regrow neurons to fix an injury, and showing instead that we can adapt what it is left. And in adaptation, if nothing else, humans excel.

Restoring Voluntary Control of Locomotion after Paralyzing Spinal Cord Injury
Science, 1 June 2012
DOI: 10.1126/science.1217416