4 ms·

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 misinderstan

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?

adgjlsfhk1 2y ago
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)
- tantalor 2y ago
  Imagine all you got was noise. Woof. Torture.
  - deleted 2y ago
    [deleted]
  - deadbabe 2y ago
    Most of our vision is already noise, we just make sense of it.
    - simpaticoder 2y ago
      Even more than noise, the very center of our field of vision is blank, accounting for the retinal nerve, which the brain masks.
      - kelseyfrog 2y ago
        The fovea and the optic disk?
      - anyfoo 2y ago
        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) https://en.m.wikipedia.org/wiki/Blind_spot_(vision)
      - _carbyau_ 2y ago
        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) https://en.wikipedia.org/wiki/Blind_spot_(vision)
        2y ago
- robwwilliams 2y ago
  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.
  - Nasrudith 2y ago
    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?
CuriousCosmic 2y ago
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/teaming https://arpa-h.gov/research-and-funding/programs/thea/teamin... 2. https://www.youtube.com/watch?v=fRNpeU8_RLo https://www.youtube.com/watch?v=fRNpeU8_RLo
- colechristensen 2y ago
  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.
- jessriedel 2y ago
  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.
  - CuriousCosmic 2y ago
simpaticoder 2y ago
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 https://en.wikipedia.org/wiki/Upside_down_goggles)
- robwwilliams 2y ago
  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.
  - Dylan16807 2y ago
    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.
    - deleted 2y ago
      [deleted]
- vlovich123 2y ago
  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.
- jessriedel 2y ago
  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.
robwwilliams 2y ago
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 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/ https://pubmed.ncbi.nlm.nih.gov/39416210/
- danielmarkbruce 2y ago
  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?
  - robwwilliams 2y ago
    Huge lost opportunity cost! I am all for innovative science but this is beyond silly until it works in rats.
    - danielmarkbruce 2y ago
      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.
WalterBright 2y ago
If the eye nerves can be hooked up, a severed spine should be possible to repair.
rob74 2y ago
Yeah - my first thought was if it wasn't a more approachable goal to first try to heal spinal cord injuries.

adgjlsfhk1 2y ago

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)

tantalor 2y ago
Imagine all you got was noise. Woof. Torture.
- deleted 2y ago
  [deleted]
- deadbabe 2y ago
  Most of our vision is already noise, we just make sense of it.
  - simpaticoder 2y ago
    Even more than noise, the very center of our field of vision is blank, accounting for the retinal nerve, which the brain masks.
    - kelseyfrog 2y ago
      The fovea and the optic disk?
    - anyfoo 2y ago
      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) https://en.m.wikipedia.org/wiki/Blind_spot_(vision)
    - _carbyau_ 2y ago
      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) https://en.wikipedia.org/wiki/Blind_spot_(vision)
      - 2y ago
robwwilliams 2y ago
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.
- Nasrudith 2y ago
  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?

CuriousCosmic 2y ago

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/teaming https://arpa-h.gov/research-and-funding/programs/thea/teamin... 2. https://www.youtube.com/watch?v=fRNpeU8_RLo https://www.youtube.com/watch?v=fRNpeU8_RLo

colechristensen 2y ago
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.
jessriedel 2y ago
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.
- CuriousCosmic 2y ago

simpaticoder 2y ago

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 https://en.wikipedia.org/wiki/Upside_down_goggles)

robwwilliams 2y ago
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.
- Dylan16807 2y ago
  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.
  - deleted 2y ago
    [deleted]
vlovich123 2y ago
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.
jessriedel 2y ago
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.

robwwilliams 2y ago

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

danielmarkbruce 2y ago
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?
- robwwilliams 2y ago
  Huge lost opportunity cost! I am all for innovative science but this is beyond silly until it works in rats.
  - danielmarkbruce 2y ago
    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.

WalterBright 2y ago

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

rob74 2y ago

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