Two new light switches
Even adult visual and cranial nerves can reform and repair themselves. Researchers may soon be able to help them in a targeted manner: by providing the right enzymatic stimuli or simply by creating a successful environment.
Seeing the blind again and making the lame walk again was once nothing short of a miracle. It has stayed that way, despite all the progress made to date. It has long been clear why this is so - because injuries to nerve tissue do not simply close like normal wounds.
A neuron, i.e. the specialist cell of the body's own intelligence service, seemed irreplaceable from a certain degree of maturity - and is therefore something completely different from a typical field, forest and meadow cell. In the adult central nervous system, neurons can always reconnect, but never reinvent themselves, arise freshly and grow out. In case of need, nerves must therefore probably be dispensed with, and a severed spinal cord, a severed optic nerve can never become the same again. As I said, that much was clear. But it isn't anymore. More and more studies had accumulated in which severely damaged or destroyed nerve bundles were able to regenerate organisms that had outgrown the embryonic stage. Two teams of researchers are now providing supplies and raising hopes that one day they might be able to restore sight to the blind – whether they were blinded by an injury or were blind from childhood.
However, the rat still has to serve as a guinea pig - both for Tommaso Pizzorusso from the Italian Institute for Neurosciences in Pisa and his team and for a research group led by Larry Benowitz from the Children's Hospital in Boston. Both de alt with animals that had gone blind - but for different reasons.
The rodents in Pizzorusso's laboratory – animal models for amblyopia, a specific type of weak-sightedness also found in humans – could hardly see in one of their eyes as adults because it had been experimentally connected to them in early childhood. In such cases, the withdrawal of all light stimulus information in the brain is not without consequences: In the growing but chronically underemployed visual cortex, certain neuron networks that are crucial for processing are not even connected.
Even if the visual impairment is then removed in older animals, they cannot compensate for the early failure: Rat Hans no longer learns what the nerve in the little rat hadn't practiced - a clear case of a lack of plasticity in a mature neuron bundle. The rats remain weak-sighted, even when the actual visual apparatus is working and suddenly delivers information to the brain.
Pizzorussos and colleagues set out to find the reasons for the lack of plasticity in the rodent cortex. Her thesis: The cellular environment of the emerging neurons – more precisely, the extracellular matrix – is one of the decisive factors for the outgrowth of nerves. This long-unnoticed conglomerate of proteins and exotic sugar threads in front of the cell gates provides crucial impetus for growth - but on the other hand it can also prevent new nerve bridge building, for example through certain molecules such as chondroitin sulfate proteoglycans.
Pizzorusso's team then dismantled these proteoglycans in the extracellular matrix of their blind rats with the help of injections of a specific degradation enzyme into the damaged visual cortices - and waited anxiously to see whether this would help the rats to repair their neural network, which was not formed in youth still functional afterwards.
The experiment was successful: When the proteoglycans that slowed them down were broken down, the rats were able to see more clearly again on the previously weak-sighted side after a week. The visual information processed there was also fed back into downstream brain regions to a much greater extent than before and was therefore rated higher there. According to Pizzorusso [1].
The rats in the laboratory of Benowitz and his colleagues were far worse off than their Italian rodent colleagues at Pizzorusso – their main optic nerve was surgically severed for experimental reasons [2]. Such injuries are currently the most common when examining the ability of adult nerve bundles to regenerate. In the case of Benowitz' rats, however, the effort seems to have paid off for once.
The researchers wanted to get to the bottom of the strange observation that inflammatory reactions at the wound incision apparently promote the regeneration of the severed nerve bundles. Macrophages seem to be decisive here, the body's own immune cells, which are attracted to the inflamed area and in turn spit out nerve repair-promoting substances - but what?
The researchers tested all kinds of potential substances in the macrophage arsenal in Petri dishes containing cut up neurons. One substance turned out to be particularly potent: oncomodulin, a calcium-binding growth factor protein. In the experiment, it bound to the destroyed nerve cells and made their growth visibly stronger than any other tested molecule.
The only thing left was to test the substance on living blind rodents. Released from small molecule transporters, oncomodulin actually increased nerve regeneration five to sevenfold. The growth factor switched on a potpourri of different genes. The researchers did not observe any inflammatory processes in the damaged region - a substance tested completely "out of the blue" proved to be more effective than "all other substances for nerve regeneration tested so far", says Benowitz, amazed and enthusiastic.
The researchers hope that the substance could one day also be used to treat various types of nerve damage in humans. However, there are still obstacles: Substances that have not yet been identified often block the regeneration of mature brain nerves, despite all stimulation by growth factors. Pizzorusso's Italian team may have found one of these stumbling blocks in the extracellular matrix of the visual cortex - perhaps the two research groups should exchange rodents, ideas and results in order to make good progress together.
