Scientists Make Blind Mice See Again
In the future, blindness may no longer be considered a permanent condition.
Something pretty incredible has happened inside a Stanford medical laboratory. Mice, made blind through damage to their optic nerve, have been trained to see again through a combination of gene and visual stimulation therapies. This is the first time ever that broken connections between the eye and the brain have been re-established successfully in a mammal, and could offer hope for humans with a wide variety of eye injuries and disease, including glaucoma.
“I’m very optimistic that within the next five years, we’re going to have some treatment that might not be complete restoration of vision, but some treatment for blindness in a number of important conditions,” Andrew Huberman, senior author of the research, tells Inverse. The results of the study in mice were published Monday in Nature Neuroscience.
Here’s what Huberman’s team did. The experiment involved close to 100 mice in total; scientists “induced blindness” in one eye by making a surgical incision and pinching the optic nerve with forceps. Unlike cells elsewhere in the body, nerve cells of the central nervous system do not naturally regenerate. It’s similar to the way spinal cord injuries and strokes lead to permanent physical impairment; the neurons that connect the eye to the brain function the same way.
After making the mice functionally blind, researchers started playing around with ways to stimulate regrowth of neurons. Some mice received a viral gene therapy — their eyes were injected with a virus, but instead of being harmful, this virus delivered a section of DNA designed to stimulate growth in the target cells. This method worked … sort of. The neural axons showed some growth back towards the brain, but not enough to reestablish connection. The mice were as blind as they were without treatment.
Another group of mice received a non-invasive visual stimulation treatment. They were placed in “a kind of IMAX theatre for mice,” says Huberman, where for a few hours a day moving stripes of black and white were shown to them. The idea here is that neurons won’t regrow unless there are electrical pulses running through them. This intense stimulation should, in theory, encourage axons to push beyond the site of injury and into the brain. Results? Meh — the therapy kinda sorta worked, but not really. The mice who received this treatment showed about as much neural regrowth as those who received gene therapy.
The magic happened when the researchers combined the two therapies. “We saw enormous synergistic effect,” says Huberman. “There was a 500-fold increase in the distance and speed that the retinal ganglion cell axons grew. And in the same period of time that normally they wouldn’t grow at all, they managed to grow all the way back into the brain. So that was really incredible, and when we first saw that, we didn’t even really believe it. But we repeated it a number of times, in at least 20 mice, and we also confirmed it with a variety of control experiments, and we trust that result now.”
And here’s the amazing part: Those mice could see again. Their vision was not fully restored, but it was good enough that they could make out a growing shadow, mimicking an approaching predator, and respond appropriately by running for cover. This would be the functional equivalent in humans of going from completely blind to being able to make out large objects and their position in a room, says Huberman.
Another important research question was whether, if neuron regrowth could be stimulated, those neurons would grow in the correct direction and connect with the right spot in the brain. “Could it be that the reason that neurons don’t regenerate is because it’s better to have no connections than the wrong connections?” asks Huberman. There are different kinds of retinal ganglial cells, and you wouldn’t want, for example, the cells that respond to motion connecting with the part of your brain that regulates mood. “That would be bad, because then, you could imagine, every time something moves through your visual field, then you would reset your mood, or have some mood adjustment.”
But, for whatever reason, the severed axons retained their ability to find the correct pathway and connect with the correct region of the brain. The researchers were able to demonstrate this by genetically modifying some of the mice so that only certain types of cells in their optic nerve express green fluorescent protein (GFP). Then, after the pathways had regrown, the scientists could see where they had gone and confirm that they reconnected to the same place where they had been before injury. “What we discovered is that when these cells regenerate, they find their way home. They follow these long, tortuous paths, but they find their way,” says Huberman.
That’s great news — especially since Huberman doesn’t want to waste any time on experimenting with human subjects. “We’re going straight to human,” he says. “I have been working on retina and visual system development for close to two decades now, and I’ve gotten to the point where I feel like the field has the tools and is ready to start doing gene therapy trials in humans.” Some researchers are already using similar viral gene therapy in human trials, he says.
Huberman also is working with researchers in virtual reality, gaming, and phone software to develop programs that will work like an IMAX for mice as a way to stimulate connections through the optic nerve. Glaucoma is the second leading cause of blindness in humans, and it works very much like the pinching of the optic nerve in the mice, resulting from an increasing pressure on the optic nerve that progressively degenerates the neural connections. (The leading cause of blindness in humans is cataracts, which are curable through surgical removal.)
But the implications for this research go beyond returning sight to the blind, Huberman stresses. Similar interventions could be developed to deal with degeneration of the central nervous system in a variety of conditions — spinal cord regrowth after injury, reconnecting pathways for motor neurons after a stroke, perhaps even maintaining neurons involved with learning and memory in the face of Alzheimer’s.
Huberman says he’s pretty confident that this area of research will continue to make great strides. The National Eye Institute has started its Audacious Goals Initiative, which specifically commits to developing treatments for blindness where the cause of blindness is in the connection between the eye and the brain. Imagine: There could be a future where degeneration is replaced with regeneration.