For my entire career as a neurologist the ability to repair an injured spinal cord has been one of the holy grails. There has always been promising new research that definitely increases our knowledge but doesn’t lead to an effective treatment. This is not for lack of trying – I also remember the period when Christopher Reeve was a tireless promoter of spinal cord research, following his injury in 1995 (until his death in 2004).
I remain hopeful and find encouragement in new significant breakthroughs, but tempered by the realism that spinal cord repair is an extremely difficult challenge. With that in mind, researchers have recently reported some intriguing results using stem-cell infused nanobots to repair injured spinal cords in zebra fish and mice.
Since the early 2000s it seems stem cells have been the most promising mechanism to repair spinal cord injuries. During the peak of the stem cell hype this seemed highly plausible, leading to many fraudulent clinics claiming they could use stem cells to treat such injuries and many other conditions. But it turns out you can’t just inject stem cells into the site of an injury and have them make meaningful connections, survive, and function. If only it were that easy. Here we are a quarter of a century later and perhaps we are getting closer to the promises of that early hype.
Since 2006 we have been able to create induced pluripotent stem cells. This was an incredible boon to stem cell research, because we could create stem cells on demand, even from the skin cells of the person who would be the ultimate recipient of them (so no problem with rejection). They are not quite as good as embryonic stem cells, but pretty close.
But this only solved one of the technical challenges with stem cell therapies. We also need to get the cells to go where we need them to be, to turn into the types of cells we need, to survive and to function. Neurological applications also require that they make the proper connections. Further, we need the stem cells to not become cancerous. It has taken a couple of decades to work out these issues, to be able to produce large amounts of clinical-grade stem cells, and to demonstrate their safety.
It does seem like we are perhaps finally transitioning to a new phase of stem cell research. While it is still true that the only proven stem cell therapy remains blood-based stem cells, there are many potential treatments currently in late-stage clinical trials. There are also many companies developing stem cell therapies – so they have moved out of the lab into product development (which brings its own corporate hype, but at least around legitimate science rather than fraud). Other technologies, like advanced genetic modification with CRISPR, are also helping.
These stem cell treatments, however, still represent some of the low-hanging fruit, especially for neurological applications. For example, one trial is in Parkinson’s disease. Using stem cells for PD goes back to the 1980s, because it is theoretically simple in that all you need is for the cells to survive and make dopamine. They don’t have to network necessarily with other neurons.
Repairing spinal cord injury is perhaps at the other end of the difficulty spectrum – we need the stem cells to effectively bridge across the site of injury and make robust working connections. Even if we do this it is almost guaranteed there will be some of what we call “abnormal reinervation syndrome” in which the connections don’t go to exactly where they should. The brain has sufficient plasticity, however, that the person can retrain to use their new connections, a process likely to take many months. But this is a minor issue if you can actually repair a damaged spinal cord.
What does the new study accomplish? Researchers have found that using electrical stimulation is an effective way to get stem cells to migrate where we want them to be (at the site of injury) and to differentiate into neural cells and to function. However, this requires the implantation of small wires, an invasive procedure that is disruptive to the healing process. The new approach aims to solve this issue.
Rather than implanted wires, they use magnetic nanobots which are hybridized with the stem cells (called NPCbots for neural progenitor cell bots). They then can use magnetic fields to guide the nanobots and stem cells to the desired location, and to stimulate them electrically to help them differentiate. Once their use is done, the nanobots should eventually just dissolve.
They found that the nanobot-stem cell treatment was fairly effective with zebra fish. Fish that were paralyzed with a spinal cord injury were able to swim and explore. They write: “In a zebrafish spinal cord injury model, alternating magnetic field stimulation of NPCbots induced rapid in vivo neuronal and astrocytic differentiation, enhanced graft integration at the lesion site, and near-complete recovery of swimming and exploratory behaviours within 3 days.”
It needs to be noted that, unlike humans, zebrafish have the ability to spontaneously regenerate their spinal cords. So this study was a proof of concept that their technology works, but cannot be extrapolated to non-regenerating species. They therefore did a follow up with a non-regenerating species – a mouse. Here the stem cells were well tolerated and survived for at least 28 days, were able to move to the site of injury and make connections. The mice had improved movement in walking, coordination, and stride length. There was also no evidence of immune rejection or other issues.
Sounds fairly promising, but of course more research is needed, eventually in human spinal cord injury. We cannot always translate treatments from mice to humans because mice are very small and humans are large. The distance between the two ends of the injured spinal cord may be significant here, so we can’t get too excited until we have some positive human clinical research.
It took over two decades, but we may be finally approaching the time when stem cell therapy reality is catching up to the hype. The technology has proven far more difficult than we had hoped, but relentless progress has gotten us ever closer to actual applications. Still, we must be cautious. We may still need a decade or two before we really start to see the promise of stem cell therapies take off.
(Image copyright ETH Zurich)
