Another Huge Step: Axons Can Regenerate

By |2019-01-02T14:00:45+00:00January 2nd, 2019|
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Kate WilletteIn the October 2018 issue of NEW MOBILITY, I told you about a breakthrough experiment in which Dr. Xiaoguang Li and his team of scientists in Beijing had managed to get surviving corticospinal axons to grow down across an injury site with the help of a scaffold (“bridge”) treated with a nerve growth factor. Axons, remember, are the gossamer threads that project out from neuron cell bodies in the brain; they carry your thoughts (brain signals) through the cord to other neurons and eventually on to your muscles. Broken axons are why people stay paralyzed. The conventional wisdom is that once damaged, they can’t regenerate.

The Beijing story is exciting all by itself, but — amazingly — it’s not the only time this year that a scientist has broken that old conventional wisdom into tiny little pieces. Last February, a team at the University of California in Davis did the same thing, but with a completely different method. In their test with animals’ damaged cords, the Beijing team had inserted a tiny, growth-factor-infused plug made of a naturally dissolving material into the gap. Using the same species of monkey, the UC Davis team, led by Dr. Mark Tuszynski, grafted a matrix of living cells into a similar gap.

The Beijing idea was to simply make it possible for surviving axons to get through the famously axon-unfriendly lesion. Tuszynski’s plan was to use cell grafts to create a living relay system right in the injury site. One treatment is about a physical bridge that lures surviving axons through and then gently disappears when no longer needed. The other is about a transplant of friendly cells that grow out in both directions, forming a sort of living relay circuit that’s meant to survive indefinitely and become part of the host’s body.

About those friendly cells. Not a single day has passed in two decades when a researcher somewhere wasn’t attempting to figure out how to use some kind of cells to replace the damaged ones. That’s a lot of cell types and a whole lot of rats.

In his rhesus monkey research, Tuszynski used what are called neural progenitor cells. These are not embryonic stem cells. They’re also not mature neurons. They’re progenitors — a little like special grandfather seeds that are able to generate only three specific kinds of grandchildren. NPCs can become neurons, oligodendrocytes, or astrocytes. That’s it.

The reason the offspring of NPCs are so limited is that during pregnancy, fetal cells develop in a way that’s a lot like a tree branching. The trunk is embryonic stem cells; they’re all exactly the same. Over time, though, the cells differentiate, which you can picture as four big branches coming off that trunk. One of those big branches is made up of neural stem cells.

If you go along that big branch further and further until you’re right at the point where the branch splits into three smaller ones, you’ll arrive where the NPCs live. The next thing that will happen is that the NPCs have to make a choice about which smaller branch they’ll take — neuron, oligodendrocyte, or astrocyte? It has to be one of those. Tuszysnski’s team used human NPCs from a lab in Baltimore donated by a company called NeuralStem, a for-profit organization that has been investing in neural cell research for a long time. When the Tuszynski team was ready to do its cell transplants, the folks at NeuralStem overnighted their cells to California.

Encouraging Results in the Complicated Quest for ‘Cure’

Going in, the UC Davis scientists had five explicit goals for their cell grafts:

  • A critical mass of them had to survive and develop into neurons.
  • They had to successfully lure injured host axons down and into the graft.
  • They had to form synapses with those host axons.
  • They had to extend their own axons down and out of the injury site.
  • Those new axons had to form synapses with host neurons below the injury site.

Synapses, recall, are the infinitesimal points of contact between one neuron and the next — they’re the locked-in spaces where cell-to-cell communication happens. If synapses don’t form, it doesn’t matter how many axons grow, the message won’t get through.

Those five goals were all met, but it wasn’t a straightforward process. The first attempts failed because cerebrospinal fluid filled the injury site so quickly that the new cells just washed away. That problem was solved by tilting the operating table 30 degrees, allowing the fluid to drain off and making time to place the cell graft. The scientists also adjusted the ingredients of the matrix so that it would “gel” into place in a few seconds.

So far, so good. The graft filled the injury cavity and the cells survived — but only for a couple of months. If this treatment is ever going to become a therapy for humans, we’re going to need that transplant to be permanent. Fortunately, a stronger dose of immunotherapy drugs was all that was needed. From the paper:

Grafts occupied the majority of the lesion cavity in all subjects and integrated well with the host spinal cord … human axons emerged [in both directions] from grafts in extraordinary numbers and over long distances … corticospinal axons readily crossed the host-graft interface to penetrate distances up to 500 micrometers into the graft [about half a millimeter].

At this point, it would be great to say that these animals then recovered significant function as a result of the transplants. I’m not going to say that, though. The monkeys did recover measurable movement in their front paws, and the evidence shows that this happened as a result of the new cells forming working connections with host cells from both above and below the injury site. But recovery of function wasn’t the point of this particular effort.

Remember the five goals? The researchers wanted to show that NPCs could live, could differentiate into all three kinds of spinal cord cells and could form synapses with host cells. If this had been a human trial, it would have been called “Phase I,” meaning it was not supposed to improve function. But that does not diminish the importance of what the researchers found, and how it is encouraging news for the SCI community.

Getting At the Source of the Real Problem

A few weeks ago I was in Vancouver, British Columbia, at the 2018 Working2Walk annual conference, where wheelchair users, caregivers, PTs, researchers, industry representatives, charitable foundations and government regulators had gathered to talk about the gnarly issues that are keeping progress toward cures so slow. The list of issues is very long. But this year’s W2W was heavily concentrated on efforts to improve bowel, bladder and sexual function. These are the daily issues that make life with SCI such a challenge.

A lot of the progress we want to see is currently being addressed through epidural and transcutaneous stimulation, but no one is pretending that this technology is going to be the ultimate answer. Why? It doesn’t get at the source of the problem, at least not in the sense that it restores the full range of motor and sensory function we all want.

For that, we need scientists like Tuszynski and Li patiently moving forward with their axon regeneration work — that is where the ultimate solution lies. The fact that both of them have had success with non-human primates is a giant step forward. Giant.

For a series of reports on W2W, check my blog at w2w2018.wordpress.com.

Resources
• “Bridging the SCI Site,” New Mobility, October 2018, newmobility.com/2018/10/bridging-the-sci-injury-site
• “Stem Cell Reality Check,” New Mobility, January 2018, newmobility.com/2018/01/research-matters-stem-cell-reality-check
• NeuralStem, neuralstem.com
• Working2Walk, u2fp.org/working-2-walk/speakers.html