ROCHESTER, N.Y. (WROC) — The 2019 attack on Rochester Police Officer Denny Wright robbed him of his eyesight.
Blind in both eyes ever since, Wright’s doctors tell him the problem lies in the optic nerves of both eyes.
Over in Boston, Dr. Larry Benowitz with Boston Children’s Hospital has dedicated his professional life to figuring out how to regenerate connections in the optic nerve. He talked with Adam Chodak about his own research and its progress along with other avenues being explored in order to restore eyesight.
Adam Chodak: Dr. Benowitz, why don’t we start with your motivation. What attracted you to this field?
Dr. Larry Benowitz: I was very fortunate to do my Ph.D. research in the lab of Roger Sperry at Caltech, who subsequently won a Nobel Prize, but some of his work involved regeneration of the optic nerve. That was my first introduction into the idea that at least in lower vertebrates – his work was in amphibians – and people in his group worked on fish as well, where we saw that the simple vertebrates are able to regenerate the optic nerve, but of course mammals cannot. But the fact that any species can lends encouragement to the idea that regeneration in principle might be possible.
So later I became interested in the question of how connections become modified in the brain, and it occurred to me that by studying the proteins that are involved in the production of new connections where nerve fibers are regenerating, perhaps that can give some insight into plasticity that occurs in the adult brain.
AC: While there has been a lot of promise, it’s hard to find a field where’s there also been as much disappointment and struggle. Have you found that to be the case as well?
LB: The optic nerve turns out to be a great example of a central nervous system pathway which normally does not show any capacity to regenerate, but there have been breakthroughs in my lab and others in getting it to regenerate, and part of the motivation for studying the regeneration of the optic nerve is the hope that things that are learned in that system can be carried over to the spinal chord and other parts of the central nervous system and, in fact, that has proven to be the case. So while none of these findings are yet in clinical practice there have been discoveries that have carried over to enable, at least in animal models, some degree of regeneration. Some of the basic principles that we are learning in the optic nerve turn out to be applicable to the spinal cord as well.
AC: When it comes to your most recent research, I sat there a bit slack-jawed as it appears that you and your team have discovered the regulator —the switch if you will— in the retinal ganglion cell that can spark regeneration. If you could talk a little more about that, it just seems like that is a pretty big deal.
LB: This is part of a long-term collaboration with colleagues at UCLA and elsewhere. We are all part of a research collaboration that was established by the Adelson Foundation while Mr. Adelson was alive in 2005, and this has proven to be an enormously successful consortium of investigators who have pooled their knowledge and skills together to try to advance knowledge beyond what any of us can do in isolation and it’s been very successful that way. So what we did in the study you’re referring to is to look at the genes that gets switched on —in other words, the portions of the genetic code when the retinal ganglion cells, that is the neurons in the eye that send their axons through the optic nerve so it’s the retinal ganglion cell— what we investigated was what are the genes that get switched on when we’re able to promote regeneration using a cocktail of treatments that we developed in our lab and others.
And so with this cocktail, we were able to get a substantial amount of regeneration. Then using methods of analyzing the messenger RNAs that are present in the cell, in other words a reflection of which parts of the DNA are become transcribed we, again with the colleagues at UCLA, we were able to determine the genes that get turned on during regeneration. Then using computational methods, that team was able to look at the upstream regions of those genes that get switched on. Those are the region of the gene where what are called transcription factors. Those are proteins that bind to the DNA and determine whether a gene will be read out or not. And so with bioinfomatics that are now available in data banks we were able to predict what are the transcriptions that are responsible for the “switching on” regeneration program and from that we kind of found the number one candidate.
There are candidates both for switching on genes and there are candidates that repress a regenerative program under normal circumstances, and so by removing the repressor of gene expression we were able to get substantial levels of regeneration.
I should mention that another interesting aspect of that study is that we also worked in collaboration with Dr. Jeff Goldberg, who’s the chair of ophthalmology at Stanford. Jeff’s lab contributed a complementary piece of data which is to look at what happens when retinal ganglion cells are normally developing. So as the nervous system is developing, the cells in the retina extend axons back into the brain and they do this very successfully and very vigorously so that the complementary question to what we did, to what we studied in regeneration, is the question of what transcription factors enable nerve cells to rapidly grow their connections during development, and the remarkable finding is that the comparison between developing retinal ganglion cells and regenerating retinal ganglion cells turned up the very same transcription factors, so we were very excited about that and this one transcription factor that was featured in that paper in both cases turned out to be a major repressor of the regenerative program, so during development that repressor comes into play and shuts off the growth program whereas in regeneration that repressor is inactivated and enables the cells to grow axons.
The first stage is obtaining the gene expression profile from the cells both from the development and during regeneration and compared to the state where they’re not growing, but looking at the genes that I differentially expressed, then predicting what the master regulators are that control turning on or turning off that regenerative program, and then the proof of the pudding is testing these transcription factors and seeing that lo and behold it actually works. Just by manipulating this one transcription factor we get a substantial amount of regeneration. It’s not the whole thing. It’s not the whole program, but it’s a very substantial part of it, and carrying this work further one would hope that we could continue the analysis of what the regulators are in that just a small number of these regulatory molecules might account for a full-blown program that it still has to switch into in order to re-grow its connections.
AC: Do you foresee treatment coming from something like this?
LB: That’s the hope of course. I should say that work from our lab and others have pointed to a number of ways to get retinal ganglion cells to regenerate axons for considerable distances, now all the way down the full length of the optic nerve and into the relays areas of the brain that then relay these signals up to the cortex and to other centers for higher level processing or for visual aid guided behaviors. So that’s a little bit and it’s glimmer of hope, but we’re still pretty far from having sufficient regeneration to support what any of us would recognize as substantial levels of vision.
So, some of the barriers are when the visual system is forming there are very precise signals that enable to nerve cells in the retina to connect to the very appropriate centers in the brain. These are called guidance molecules and then in order for the visual world to be mapped onto the brain in an orderly fashion the near-neighbor relationships in the retina —this cell right next to this cell, right next to this cell— those cells’ connections have to then go and project in an orderly fashion onto the brain so that is the mapping issue. And some really exciting research going back 20 to 25 years identified some of the principal molecules that enable these maps of the visual world and other properties to form in the brain, throughout the nervous system. So we don’t know if that can be recapitulated yet during development. Whether targeting the right projection areas, that we think can happen but the formation of an accurate map of the visual world is kind of the next frontier.
AC: I’m going to ask you take your crystal ball out there and when you say it’ll take some time, what is the time frame, your best guess?
LB: I would say maybe 10 years we’ll have satisfactory levels of regeneration if we don’t discover other insuperable barriers. I should also mention, though, your listeners may be interested in hearing other approaches that are looking very promising.
So my work has been focused pretty exclusively on the issue of regenerating the pathway, the connections from the retina back to the brain, but other methods of restoring vision to the blind include the use of assistive devices that capture the image of the outside world, transform this into a series of electronic signals that either get projected back into the brain, that is a very active field, the level of precision of the visual image is still very low, but at least there’s an indication that it might be feasible to restore at least some level of vision.
Another advance along those lines came from José-Alain Sahel and his group in Paris, also in Pittsburgh and collaborators including Botond Roska in Switzerland, so a very exciting paper from that group I think it’s now two years old showed that in the case where the photo-receptors, not the retinal ganglion cells, but in the cases where the photo-receptors degenerate —which is a fairly common occurrence, fairly common source of visual loss— what happens there is that the photo-receptors send signals back up through the other cells of the retina through a very complex network of cells up to the retinal ganglion cells, the cells we study which are the final integrators of visual information in the retina, those are the cells that then send signals back to the brain. And what this very exciting paper out of the group showed is that even though the photo-receptors are gone, you can put genes into the retinal ganglion cells using gene transfer to make the retinal ganglion cells sensitive to light signals, then through the use of an electronic device and goggles feed an image of the visual world directly onto the retina to activate that protein in the retinal ganglion cells. That activation of that protein by light then activates the retinal ganglion cells and that allows a signal to be sent back to the brain. So studies that were published from that group in Paris showed that people who had been blind for years can start to identify objects or at least reach for objects in front them.
One other area, the use of stem cells in order to replace the lost retinal ganglion cells. There are several groups in the forefront of that. Dr. Goldberg is one, Dr. Zack at Hopkins is another, Tom Reh in Seattle is another. I’m probably leaving out a lot of important research and they’re working to get stem cells adopt the identity retinal ganglion cells, put those into the retina and see if they will acquire the properties of retinal ganglion cells and form appropriate connections back to the brain. So these other areas are still very works in progress, but I’d say putting all these methods together things are looking far more hopeful than they did 10 years ago.
AC: We’re talking about life-changing treatment here. We had Officer Wright here who in the course of his job lost complete eyesight and the fact that within his lifetime he may be able to see something again, to me, is just extraordinary.
LB: Vision is the sense that we most use to interact with the outside world so if this were to succeed, you’re right, it could be life changing.