Can someone explain why this isn’t crazy? ARPA-H is new and supposed to be ambitious, but I assume they are still tethered to reality, so I must be misinderstanding.
Physically transplanting the eye ball and having it survive and not be rejected by the body is a challenging feat, but it’s been done quite recently and is based on known principles and techniques. However, that is like 1% of the difficulty. The hard part is making the eye nerves, which are basically an extension of the brain, talk coherently to the rest of the brain. Seems like it’s only slightly less hard than trying to take a chunk of donor brain, implant it in someones skull, sew it to their brain, and hope that they can use it to think. (Yes you can wave your hands and say “brain plasticity”, but brains adapting to damage by routing around it is just a completely different thing than getting pieces that have been mechanically severed to heal and interact usefully.)
Is there any reason this wouldn’t start in animals decades before it could work in humans? To my knowledge, no one has ever shown an animal can get any useful vision info from a transplanted eye, and that seems confirmed by the article.
Like, I don’t think we can even get cats raised from birth in weird optical environments (lack of horizontal lines) to see fully normally. You need to like completely reset the biological development stage of the animal. If we thought we could do that using stem-cell-whatever magic, wouldn’t it be a lot easier to start by treating minor developmental eye disorders than do full-on eye transplants?
You are right and this is more than a moon shot or Mars shot. A Titan shot. Until eye transplants work in mice or rats it is nuts to try this.
Retinal ganglion cells will very reluctantly regrow toward the thalamus after a nerve crush, but reestablishing any functional contacts in the dorsal lateral geniculate or superior colliculus, let alone “vision”, has not succeeded. Not nearly suceeded. And not for lack of trying 100+ methods. Albert Aguayo was the first to make headway in mammals in the 1980s:
Eldon E. Geisert and colleagues at Emory have coaxed a small percentage of retinal ganglion cells to grow through and far beyond the crushed region of the optic nerve in some genotypes of mice (but not other genotypes of mice). His group studied a very wide variety of genotypes of mice—30 or more. Impressive effort and real progress rather than a shadow of a unicorn. But getting to the geniculate is still a huge unachieved reach even in mice. Regrowth distances in human are roughly 20x farther. And there is a huge difference between a crushed optic nerve and a whole eye transplant.
It isn't nuts to try it if there isn't much downside. The donors are dead already, the person receiving is blind already. What's to lose? Money and some time and inconvenience?
Yes but you can pick up an infection while immunocompromised that kills you even after you remove the graft and stop the immunosuppressant drugs, or before you have a chance to do so.
A team who works in the space thinks it's sufficiently likely they are going to spend time working on it. These aren't a pack of losers off the street - these people have real options in life to do all kinds of interesting work.
Yes, for many reasons. What else were you expecting? It tends to be more a cost-effective way of using the research money, it's considered more ethical, it has less legal risk, and so on.
If you're saying you want to perform a full-head transplant on humans without ever succeeding on apes, people would very rightly call you delusional.
There are compassionate treatment exemptions for research procedures, but they need to have a snowball's chance in hell of working. It's nice that the people behind this think that this meets that bar, but I'll believe it when independent experts in the field can vouch for the procedure having a reasonable chance of working.
If they do, great, go for it. If they don't, no amount of rabble-rousing of the uninformed (people like me) should permit them to operate on humans.
So the short TLDR answer is that they are only working on one part of this. There are 30+ teams who were awarded funding and are working on the THEA project across the US [1]. Those teams are each working on aspects of one of the three different technical areas. Those technical areas are:
TA1: Retrieval of donor eyes and tissue preservation
TA2: Optic nerve repair and regeneration
TA3: Surgical procedures, post-operative care, and functional assessment
So this is very much a divide and conquer problem and no one team is planning to just figure out the whole solution. They are all still very ambitious projects but they are targeting much more discrete problems and working with other relevant teams on the project to bridge the gaps between their specific projects. To get a better idea of how it all ties together you probably want to skim through their proposers day presentation [2].
The issues I am talking about are all TA2, so the breakdown doesn't help. It's just a completely different technology readiness level.
Edit: Just looked at the video. There is ONE THIRD OF A SLIDE described for less than 90 seconds (28:27) that addresses the issues I raise. They just list random things people might try like "stem cells". Just bizarre
I have downgraded my respect for ARPA-H. Hopefully this is just some fluke to have gotten approved.
I was linking the proposers day video not as a direct answer but rather to try and show how that specific aspect is connected to all the other research going on on this topic as well.
And they even mentioned in that video that TA2 is the particularly hard problem.
And to address your question I linked the teaming page which does go into what the teams are pursuing to solve that problem. One of the teams addressing the specific issue you brought up is the USC team. They are developing electric field stimulus systems to drive regeneration of optic nerves along with real time imaging/monitoring equipment so that they can control said stimulus to drive regeneration along the paths they want.
TA2 is very big/broad and a lot of different teams are taking quite different approaches at how to address aspects of TA2.
It is likely going to be possible to grow an eye in a vat.
I talked to a retinologist who was working on genetic diseases like retinitis pigmentosa and he mentioned that in the lab their stem cell developments were growing not only retinal cells but at least malformed somewhat recognisable eye structures.
I fully believe that at some point in the next 50 years full organ replacements from the patients own stem cells (perhaps with lightly edited genetics) will be commonplace.
They are probably counting on the brain's remarkable ability to make sense of input. Consider that a birth-blind person has no prior experience with sight, and so can possibly rely on the brain to make sense of the input, no matter how imperfect. For example, humans can adapt to inverted images within about 8 days (https://en.wikipedia.org/wiki/Upside_down_goggles)
Naive hope. The regrowing axons would have to decussate (cross over or not correctly) at the optic chiasm.
That is beyond highly unlikely in a transplanted eye.
And then the growing axons would also have to grow into the correct layers and roughly the correct retinotopic regions of the lateral geniculate or superior colliculus.
I would expect the brain’s vision system to have completely been repurposed for other things for a birth blind system and no longer functions in that way. This is very different from changing the signal for your vision system and having it apply a, while impressive, very basic correction.
I explicitly brought up brain plasticity as not a convincing argument.
People who are blind (even if just blindfolded) from birth and have their sight restored as adults are still functionally blind. They get a bit of light and color, but basically can't interpret objects.
Interesting. Do you have a reference for that claim? I am somewhat skeptical if only because of an analogy with cochlear implants - deaf people can start hearing once the signal starts!
As one might expect, when people have their vision restored while still young children, they do OK. The older they are, the worse they do. For adults, it's basically nothing except the crudest things like brightness and vague large objects.
> I am somewhat skeptical if only because of an analogy with cochlear implants - deaf people can start hearing once the signal starts!
I don't think this is right. Again, kids can do ok, and the younger they are, the better. But my impression is that adults who get cochlear implants having been deaf since birth are not able to interpret almost anything. Like, they can sense there are louder or quieter noises, but they can't understand speech, match up sounds to objects, get directionality, or anything like that.
I agree that it would be totally bonkers to go from 0 to humans, but I think a lot of the theory is that human brains are pretty malleable so if you manage to get an electrical signal from the eye to the brain, the brain will probably be able to do something with it (even if it's not what a "normally" connected eye would provide)
Do we have regeneration of spinal cord tracts after injury yet? Nope—not even in rodents.
Sorry, the mammalian brain is not really malleable at this level of organization. We might get there but not by winging it with transplants in humans. Get it to work in rats or pigs and I am happily on-board.
Neural malleability is its own separate problem from lacking neural regeneration technically.
We have digital brain-spine bridges already to translate thoughts into movement via the spine via electrodes and they have done artificial spinal tissue connects in mice already. We just might have the pieces to start 'soldering' it together. Still a low chance of success. Maybe they think it might help with learning things that the mouse models cannot teach?
So one of the things I didn’t expect when I had a detached retina…. no darkness in that eye. The big flashing and swirling blob of light was there whether my eye was open or closed, day or night. I could look at it and identify shapes like when you look at clouds.
Many, if not I think most actually blind people don’t see blackness. I’ve read many stories about varying levels of visual ‘hallucinations’. In the absence of input the brain will come up with stuff (https://en.m.wikipedia.org/wiki/Visual_release_hallucination...).
I lost vision in my right eye after failed retina detachment surgery damaged the optic nerve. I don’t see blobs of light like you describe, though I do see a dim pattern of swirling lines when I walk into a dark room. Also, weirdly, if there’s a sudden noise while I’m in the dark, I often see a flash of light go off, like an old flashbulb. I’m guessing that’s my visual system somehow rewiring itself to other sensory input.
The other thing I found insanely wild was that if I looked at a repeating pattern and held still (like say a tiled floor or carpet), the image from my good eye would slowly start expanding over and filling in the big blind spot in my bad eye.
Also if lighting conditions were just right (mostly dim but bright enough to make out shapes like in the middle of the night with only some light coming through windows), my brain would ‘forget’ the other eye couldn’t see and it would look like I could see out of both eyes again. It was trippy as hell.
I have the same phenomena - loud sharp noise is like a flashbulb goes off. Reading another commenter mention EHS and looking it up, I don’t think that’s it either. Have had multiple RD surgeries myself. Hope your vision is otherwise stable!
> Also, weirdly, if there’s a sudden noise while I’m in the dark, I often see a flash of light go off, like an old flashbulb.
I get that same effect, and weirdly was just thinking about it earlier today. I don't have vision loss, but I do also get visual noise in low light. I never did find any good information about it. The closest I could find was exploding head syndrome, which I can't entirely rule out but seems highly unlikely.
I thought blind people don’t “see” anything at all, not even blackness. Their perception of the world is no more than what you can see out behind the back of your head. Their existence is just a bundle of senses in a void, and the occasional mental imagery.
There are fascinating descriptions of patient hallucinations after loss of vision in the aptly named book "Hallucinations" by Oliver Sacks.
Tons of examples, but one that many musicians with partially lost vision experienced those missing parts of their vision randomly replaced by sheet music. Stare at sheet music your whole life, and your brain starts to predict sheet music anywhere. But when they tried to play the music, it didn't make sense.
For those with complete loss of vision, the hallucinations became immersive, featuring complete scenes with people and events.
I thought it was a spot near but definitely not at the very center of our field of vision, and an ad-hoc experiment to try to find my blind spot seems to confirm that? (It seems to rather be in the periphery.)
Or is there another, smaller blind spot dead in the center? That wouldn't fit the retinal nerves though, would it?
EDIT: This is the one I meant: "The blind spot in humans is located about 12–15° temporally and 1.5° below the horizontal and is roughly 7.5° high and 5.5° wide." https://en.m.wikipedia.org/wiki/Blind_spot_(vision)
> The centre is the bit we use for visual fidelity, or central focus.
When I got my retina imaged (routine, no problems found), I was amazed at how small that spot is when it was pointed out to me. Only a tiny part of the retina is actually seeing in high resolution. Which I guess at least partly explains why everything outside the very center of my vision seems so illegible and somewhat... "unstable" if I stare at one spot for longer.
Though the spinal chord is far thicker, the optic nerve is far denser in neurons. So the number of neurons in a cross section is roughly the same. If they can regenerate a section of optic nerve maybe they could reconnect spinal chords too. That may be the toughest part of a head transplant.
There are no neuronal cell bodies in the optic nerve or tract. Almost purely axons, glial cells and vasculature. The cell bodies that give rise to the axons/fibers in the optic nerve are in the retina.
That's a good point. Similarly, there is resistance against cochlear implants in the deaf community.
Side note: your writing is full of homophones (berth, grate, all though). While not a big deal, I would assume that modern NLP tools could fix that pretty reliably. Finally a solid use case for LLMs :)
As someone with optic nerve degeneration, if anyone who works here is looking for a CS person to help, let me know. I'll be watching this (pun intended) with great interest.
Dr. Cal Roberts, head of the program, has given an expected timeline of 3-6 years to see successful results. (Not sure if he meant proof of principle or clinical results, but probably the former, if there is an approval process required before wide-scale treatment of patients).
Patients with complete blindness will be given preferential priority over patients with partial blindness when this reaches the clinic.
These are all different projects awarded by ARPA-H as part of their THEA project [1]. They are all aimed at the same end goal but they have different approaches and specific focuses. Generally with ARPA and DARPA projects the best way to get a broad scope of what all is going on is via the proposers day videos [2]. And of course take a look at their teaming page to see what all 30-40 of the sub-projects/teams working on this overall project are doing [3].
I think this is great, but I doubt it will cure all blindness, but maybe most.
For example, blindness due to glaucoma. From what I understand that is caused by damage to the optic nerve. Maybe fixing the optic nerve is part of it(?).
Glaucoma is due to the gradual death of retinal ganglion cells. The cause of death is often metabolic stress caused by axonal damage near the lamina cribrosa (where fibers exit the eye).
High dose nicotinamide prevents some types if glaucoma in mice by improving the metabolic resilience of mitochondria and retinal ganglion cells.
So it's a bit of an open question exactly what causes glaucoma. Optic nerve degeneration is one of the potential causes but nerve damage within the eye due to decreased blood flow or due to increased intraocular pressure are both possible.
In the latter two cases, basically all of that damage is limited to within the nerves within the eye and the optic nerve head whereas more general degeneration of the optic nerve would likely occur across the entire optic nerve up to and potentially through and past the optic chiasma.
This project (THEA) is primarily about pursuing whole functional eye (i.e. the entire eye "ball") transplants and reconnecting/regenerating the optic nerve to a new eye. If this succeeds it would mean that any degeneration in the retina or optic nerve head would be curable. And potentially the techniques pioneered in regenerating the optic nerve would provide a starting point for addressing degeneration further up the optic nerve all the way through the optic chiasma and optic track up into the brain.
So TLDR: If this project is successful it should mean a functional cure for most degenerative eye diseases even including most forms of glaucoma. And potentially it could lead to inroads in curing dementia related vision loss and other cognitive decline related vision loss.
There is no doubt that retinal ganglion cell death causes glaucoma. But you are right that what causes ganglion cells to die is more complex. Mitochondrial stress and metabolic decompensation are certainly critical. Axonal injury is a key trigger in many cases. High intraocular pressure is the most common cause for metabolic cellular stress leading to gsngliin cell death.
Yep. I worded it a bit awkwardly but that was what I was getting at. And mostly I was trying to make the distinction between damage within the "eyeball" vs more comprehensive damage further up the optic nerve as that distinction would determine how viable a transplant would be at recovering lost vision.
If vision-restoring eye transplants are the novel domain of futuristic moonshot research, how did Jerry Orbach’s eye donation give the “gift of sight for two New Yorkers” twenty years ago?
EDIT: Ah I follow now: he donated his corneas, which is a more routine procedure than an aspirational, vision-restoring full eye transplant
Sorry, Bob, but your damaged Apple iEye was cryptographically tied to your iBrain account so a transplant of a generic SeeWorld eye is not possible. We still don’t have wetware right-to-repair laws on the books in 2124.
Physically transplanting the eye ball and having it survive and not be rejected by the body is a challenging feat, but it’s been done quite recently and is based on known principles and techniques. However, that is like 1% of the difficulty. The hard part is making the eye nerves, which are basically an extension of the brain, talk coherently to the rest of the brain. Seems like it’s only slightly less hard than trying to take a chunk of donor brain, implant it in someones skull, sew it to their brain, and hope that they can use it to think. (Yes you can wave your hands and say “brain plasticity”, but brains adapting to damage by routing around it is just a completely different thing than getting pieces that have been mechanically severed to heal and interact usefully.)
Is there any reason this wouldn’t start in animals decades before it could work in humans? To my knowledge, no one has ever shown an animal can get any useful vision info from a transplanted eye, and that seems confirmed by the article.
Like, I don’t think we can even get cats raised from birth in weird optical environments (lack of horizontal lines) to see fully normally. You need to like completely reset the biological development stage of the animal. If we thought we could do that using stem-cell-whatever magic, wouldn’t it be a lot easier to start by treating minor developmental eye disorders than do full-on eye transplants?