James Fawcett runs one of the six labs that form the Reeve Foundation International Research Consortium on Spinal Cord Injury. His lab is located at Addenbrooke’s Hospital at the University of Cambridge, in England, and is part of the Center for Brain Repair, an institute formed in 1995 and funded by the British Medical Research Council.
Dr. Fawcett started his career as a doctor, working in the autoimmune disease area, including very tough conditions such as systemic lupus. "One of the things about being a doctor, you eventually become competent at what you are doing. For some people, that's great. Others might feel, 'what's new? I don’t want to do this for 40 years.' I decided I wanted to start doing research." One of Fawcett's options was to stay in the area of autoimmune diseases. "It's is an interesting field and would have been an easy move but at the time, the basic immunology science was not in place to ask sensible questions about how to address autoimmune problems. Indeed, nothing much happened in that field until the immunology caught up with it just five or six years ago."
Fawcett had an undergraduate interest in nervous system development and followed that toward a Ph.D.; he then had the choice: clinic or lab. "I enjoyed the science so much I decided to do that. But having been a doctor, one is always thinking about treating patients in the end. I felt that if we can understand how the body first makes a brain and nervous system, maybe we can understand how to fix it. It was a no-brainer to go into neuroregeneration."
More Progress in Research
Dr. Fawcett went to work on one of the central issues in spinal cord science: the environment of the spinal cord is inhibitory to axon regeneration. "So the first experiment I did was to look at the different sorts of glia [support cells in the nervous system] to see which ones were inhibitory. My first paper was on oligodendrocytes, the next one was on astrocytes. I discovered that Martin Schwab [an original member of the Reeve Consortium whose lab is in Zurich] was well away with the oligodendrocyte story [having discovered the inhibitory substance Nogo] so I decided to stick with astrocytes and the glial scar."
In about 1990 Dr. Fawcett set out to show that astrocytes in the glial scar could block regeneration. “That wasn’t straight forward so we had to develop a sort of three-dimensional tissue culture model. The next step was to demonstrate that inhibitory molecules were found in the extracellular matrix [the molecules that surround living cells, offering support and cohesion]. We were able to identify these as chondroitin sulfate proteoglycans. These are the inhibitory molecules I’ve been working on pretty much since then."
Dr. Fawcett's lab then showed that these proteoglycans could be digested with the enzyme chondroitinase. "By doing this we could remove the inhibition and thereby allow axons to regenerate in the spinal cord." At the time the field was aware of chondroitinase, which helps break down sugar in proteoglycans, but, says Dr. Fawcett, "It had not been appreciated for its role in removing inhibition."
There was more to the enzyme than inhibition. 'To our surprise the axons recovered much faster and much better than they should have given the amount of regeneration we observed. At that point we realized that chondroitinase could also stimulate plasticity; indeed, we felt plasticity must be its main mode of action rather than regeneration."
The Fawcett lab took out a patent on using chrondroitinase for axon plasticity. The U.S. biotech company Acorda Therapeutics licensed the molecule for potential clinical use. Regulatory and safety tests are moving forward for a clinical trial in the not-too-distant future.
Says Dr. Fawcett, "We have a huge amount of animal data but still have to do a lot of safety work to determine the final formulation. And we have to figure out how to best administer the enzyme. Typically, in animals, we inject it either directly to the spinal cord or in larger quantity around the cord. In humans, though, the cord is much larger; the enzyme cannot diffuse very far, so you cannot put it in the fluid surrounding the cord and expect it to get into the middle. That means we probably have to inject it; one is cautious about putting needles into the injured spinal cord."
An enzyme that helps dissolve scar and boosts plasticity at the site of injury, does this look like a potential therapy for chronic SCI? That’s not clear, says Dr. Fawcett. "We know we can give chondroitinase to rats one month after injury and it works pretty much the same as in an acute animal. Whether that means it will work in a very chronic animal we don't know. For people, our view is that chondroitinase needs to be given at the same time as rehabilitation is going on. The two have a positive interaction. Rehab usually begins at three weeks or so after injury, and that would be a good time to do the chondroitinase treatment."
The way chondroitinase enables recovery, Dr. Fawcett suggests, is by forming "bypass circuits." The spinal cord is very rarely severed, he said, which means there are almost always a few fibers that survive the injury. "Plasticity in this case means that fibers above the lesion area make connections to interneurons which project through the region. Or, undamaged axons below the lesion make new connections - in the nervous system there appear to be a lot of synapses that are non-functional. It could be that they are activated by sprouting, which is activated by the chondroitinase. By opening up the silent synapses, a bypass is formed." One certainty in any clinical trial for chondroitinase is that it will be accompanied by rehab. "In our various experiments to show that chondroitinase stimulated plasticity, we found that using it in combination with rehab improved efficacy."
Recently, the Fawcett lab found other beneficial effects for chondroitinase. "A cartilage type structure called the perineuronal net forms around some neurons and seems to turn off their plasticity," said Dr. Fawcett. This is not related to trauma but to age. "This net forms after about the age of five - we're very plastic as young children; we can recover from many types of trauma." Chondroitinase removes these nets.
Also, chondroitinase makes it easier for implanted cells to migrate and integrate within the spinal cord. Chondroitinase is being used in experiments in other labs using various combinations with implanted Schwann cells or stem cells. For example, Dr. Charles Tator's lab in Toronto, funded by the Reeve Foundation, is using chondroitinase along with neural stem cells and a scaffold structure (see p. 10 ). Combinations are an active area of research, says Dr. Fawcett. He is currently conducting a large collaboration with the Consortium's Schwab lab to test chondroitinase along side the anti-Nogo antibody [which removes the Nogo inhibitor]. "It is too early to be sure but initial results look like there is an additive effect."
About one-third of the Fawcett lab is working on plasticity. Another third is on a different angle: understanding why nerve fibers themselves lack the ability to grow. Dr. Fawcett is ready to move on: "My view of the inhibition molecules, the scar, chondroitinase, Nogo, the rest of it, is that we've kind of done that. We’ve found the inhibitory molecules and know what to do about them. The problem we have to solve now is that nerve fibers are not very good at regeneration; they are intrinsically poor at it. We are looking at ways to fix that."
In work that has not yet been published, the Fawcett lab found a very specialized filter at the initial segment of the axon. "A lot of the molecules you need to make an axon grow are getting blocked at this point. Once a neuron matures, this filter kicks in - molecules that used to get in to the axon to make it grow in the embryo are suddenly no longer there. The axon is simply not equipped with the right molecules."
Others in the Fawcett lab are going in another direction, working on a neuro-electrical interface to facilitate bypassing spinal cord injury by taking signals from the brain or spinal cord above the lesion to control muscle or a prosthetic below. Said Dr. Fawcett, "All of this works quite well except at the interface with the nervous system. Interfacing electronics and the nervous system, that's the unsolved problem. The prosthetics are coming along well, and the software is getting pretty sophisticated. It is our view that it is no good having a prosthesis if the brain can't control it."
Dr. Fawcett envisions the eventual answer to treatment of SCI as a combination biological repair plus prosthetics. "Biologic repair is never going to be complete; it will mostly be focused on the area of the spinal cord fairly close to the injury. That means the prospects for people to get back arm control are pretty good. But I don't think the prospects are as good for walking, regaining bladder or sexual function. Those connections are an awful lot further down the spinal cord."
The Fawcett lab was invited to join the Reeve Foundation Consortium "out of blue," said Dr. Fawcett. Setting up a collaboration enriches and expands the field but it doesn't necessarily happen on its own. Said Dr. Fawcett, "It's not so much an issue of trust, rather it’s an issue of getting to know what the possibilities are in each lab. You can't interact with someone unless you have a clear idea of what the other lab is doing. These are big labs but as we meet and share data, we eventually learn what's going on. Then you listen. You hear something, aha, that relates to a problem I'm trying to solve, you pick up on it, and you have a collaboration." Fawcett recently completed a collaboration with the Consortium’s Mendell lab, in Stony Brook, NY. "This was a combination experiment with growth factor in their lab and chondroitinase from our group. We wanted to see if there was a combined effect. There was. We also found something unexpected: in the undamaged area around the spinal cord all the nerve fibers stopped conducting action potentials. This conduction block had not been seen before. We were even more surprised to see that chondroitinase could relieve the conduction block and allow axons to carry on. This finding helps explain why a number of nerve fibers near the injured area don't seem to be working, even though their anatomy looks okay.
Dr. Fawcett is a busy investigator with many non-science obligations. "It's a sort of Catch 22," he said. "You are hired because you can do experiments but you do fewer of them as you become more senior and successful. It is a bit frustrating. I love doing experiments. I don't get to have as much fun."
-- Sam Maddox