Researchers launch "moonshot" to cure blindness through eye transplants | Hacker News Reader

Researchers launch "moonshot" to cure blindness through eye transplants

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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:

https://scholar.google.com/citations?user=ruTKhvUAAAAJ

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.

Here is a recent bioRxiv paper:

https://pubmed.ncbi.nlm.nih.gov/39416210/

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?

Huge lost opportunity cost! I am all for innovative science but this is beyond silly until it works in rats.

What other thing could these specific people be working on that would have as much upside as making blind people see?

Your misunderstanding of risk/reward is astounding.

They could likely fail & learn with rats 10,000 times for the same cost.

...and much faster, leading to more blind people having their sight restored sooner.

Needing to take immunosuppressants for the rest of your life is exceptionally dangerous and you best have a proper justification for it.

Removing the eyeball is an option though if it doesn't work.

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.

They’re wiring new inputs to their brains. This could affect things like sleep and wakefulness in ways that are unpredictable and not well studied.

Surgery is risky and resource-intensive.

Surgery is inherently dangerous.

The person is blind. The upside is dramatic.

People have surgery all the time for significantly less upside.

Can you call it an upside if it has ~no chance of working?

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.

There is no chance it has no chance.

But they've never demonstrated the operation working on an animal...

so what? "that's the way it's usually done" ?

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.

How about think instead. The amount of precaution required is a function of the risk and reward.

That's a stupid analogy. The downside would be death.

The upside in this case is zero.

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].

1. https://arpa-h.gov/research-and-funding/programs/thea/teamin...

2. https://www.youtube.com/watch?v=fRNpeU8_RLo

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.

You could say the same sort of thing about Europe's Human Brain Project.

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.

The work here is an obvious preliminary.

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.

If you actually get into the right area of the brain, messed up or missing crossover sounds like a pretty minor issue to work out.

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!

> Do you have a reference for that claim?

https://en.wikipedia.org/wiki/Recovery_from_blindness

https://www.newyorker.com/tech/annals-of-technology/people-c...

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.

Let me know if you have cites to the contrary.

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?

Imagine all you got was noise. Woof. Torture.

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.

Most blind people have some vision. From light, shapes, or colors. Macular degeneration limits the field of view.

Yeah should have been more specific there — ‘people that have lost their sight’.

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.

> Stare at sheet music your whole life, and your brain starts to predict sheet music anywhere.

Sounds like the Tetris effect.

https://en.m.wikipedia.org/wiki/Tetris_effect

Most of our vision is already noise, we just make sense of it.

Even more than noise, the very center of our field of vision is blank, accounting for the retinal nerve, which the brain masks.

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)

My understanding is the Blind spot is nowhere near the "centre" of our vision. The centre is the bit we use for visual fidelity, or central focus.

[0]"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."

It is however quite freaky how well the brain smoothes it over so convincingly!

[0] https://en.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.

The optic disk is not all that close to the fovea. The brain does not need to mask the blind spot when both eyes are open.

The fovea and the optic disk?

Yes, tinnitus is an auditory version of what could happen. Probably not though.

If the eye nerves can be hooked up, a severed spine should be possible to repair.

Yeah - my first thought was if it wasn't a more approachable goal to first try to heal spinal cord injuries.

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.

Wouldn't the be a "body 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.

Blind from berth here. Would not want!

I am blind and blind is me. All though I am now 42 years old so learning to use a new set of eyes would be hard if not impossible.

Having to take a bunch of pills for the rest of your life to stop your body from casting your eyes out of your face is not for me!

This could be a grate thing for young kids that have had eye trauma or cancer.

Your brain does not learn to use your eyes until the age of about 7 anyway so that could help in the brain learning to use the new eyes.

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.

Here is the ARPA-H THEA program website, for anyone interested: https://arpa-h.gov/research-and-funding/programs/thea

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.

I saw this is a K-drama once. A girl went blind so her boyfriend donated his eyes to her. This tech must already exist in Korea.

It might not be a whole-eye transplant but a section of it? The first whole eye transplant operation was only done last year.

In K-dramas, all things are possible!

Seems to be related (although competing?) New funding could make whole-eye transplants a reality (11 points, 3 days ago, no comments) https://news.ycombinator.com/item?id=42301313

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].

1. https://arpa-h.gov/research-and-funding/programs/thea

2. https://www.youtube.com/watch?v=fRNpeU8_RLo

3. https://arpa-h.gov/research-and-funding/programs/thea/teamin...

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.

https://arpa-h.gov/research-and-funding/programs/thea

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.

I mean, even curing 1% of blindness would be a huge leap.

Putting a person on the moon was a lot less risky than this. It was merely an engineering problem.

I'm immediately reminded of John Mulaney's "Jerry Orbach's eyes" bit.

Wait I remember those ads and I’m now confused.

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

https://youtu.be/_Im4-7LQQRk

I volunteer to donate my brain to an otherwise young and healthy person who is lacking one!

worked for tom cruise in minority report so sounds good to me

Reminds me of the eye designer in the original Bladerunner

“Chu, If only you could see what I’ve seen with your eyes”

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.

This is insane advancement, tech in bio

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