This post is not about a “breakthrough” in spinal cord regeneration. It is about a baby-step. But it is a notable baby-step. A colleague of mine who does spinal cord research noted years ago that over the next few decades, if we succeed in fixing spinal cord injury, it will not be through any big breakthrough. It will be through a hundred baby-steps. We should celebrate each one, but keep them in context. Mainstream media’s obsession with “breakthroughs” simultaneously oversells and diminishes the real value of these advances.

So here it is – published online in Nature Neuroscience is a study in mice in which researchers have documented meaningful regeneration of neurons distal to a spinal cord injury. They did this by deleting a gene that downregulates another genes that promotes neuronal regeneration. Here’s the background:

The broad concept here is that biological systems have evolved mechanisms to inhibit cell growth and proliferation. As cells mature and differentiate they generally lose their ability to proliferate (most tissues contain stem cells to produce new cells). This inhibition is critical – without it cancers would run rampant. But this inhibition also limits healing and regeneration (a necessary evolutionary trade-off).

One critical pathway of the inhibition of cell proliferation and regeneration is the mammalian target of rapamycin (mTOR) – mTOR regulates protein translation. Essentially, it stimulates cell growth. In fact mTOR is getting a lot of attention as a potential target for treating a wide range of cancers. Inhibiting mTOR may help reduce the growth of some cancers – especially if mTOR activity is abnormally increased in those cancers.

But mTOR is also inhibited in mature neurons, and this keeps them from regenerating after an injury. Products of the PTEN gene are known to inhibit mTOR, and therefore PTEN plays an important role in preventing cancer, but also prevents mature spinal cord neurons from regenerating.

It should be noted that peripheral nerves have the ability to completely regenerate after injury (assuming there is no ongoing injury, anatomical barrier, or disease that will keep them from regenerating). But nerves in the central nervous system do not regenerate. So it is thought (hoped) that the potential is there but just inhibited. Pten inhibition of mTOR is a good candidate for at least part of that inhibition (it is likely not the whole picture). It has also been discovered that Pten inhibition of mTOR is increased following injury.

What these researchers did is take mice that had the Pten gene deleted and then cut halfway through their thoracic spinal cord. They then did extensive studies to see what happens. They demonstrated that the neurons were able to sprout new axons and these axons extended beyond the site of injury, and even formed synapses (connections to other neurons). The control mice did not show any such regeneration. They conclude:

Together, our results indicate that Pten deletion enables injured adult corticospinal neurons to mount a robust regenerative response that, to the best of our knowledge, has not been observed previously in the mammalian spinal cord. Both compensatory sprouting of intact CST axons and regenerative growth of injured CST axons were markedly increased by Pten deletion, suggesting that these two forms of regrowth have similar underlying mechanisms.

Conclusion

This is an interesting and promising study, and further supports the importance of the Pten/mTOR system in regulating cell growth. It is interesting that we may find it a useful target of inhibition to treat cancers and stimulation to treat injury.

The story of repairing spinal cord injury is a complex one, and this is one tiny piece of it. There are other inhibitory pathways, such as NOGO which inhibits myelin regrowth (myelin is the insulation around nerve fibers). There are also growth factors, support cells, and anatomical considerations. Researchers have been looking into scaffolding, and transplanting a variety of stem cells. Successful treatment of spinal cord injury may likely involve a combination of many of these approaches simultaneously.

But while this is all very encouraging, we are still years away from translating this knowledge to humans. An actual treatment is far enough off that we cannot predict how long it will take. We just have to keep taking baby-steps and hope for the best.