11 ms·

I sit next to Ritchie Chen, the first author on this paper. Let me know if any questions and I’ll try to get them answered :) Edit: for anyone that wants to re

by tbenst 6y ago

I sit next to Ritchie Chen, the first author on this paper. Let me know if any questions and I’ll try to get them answered :) Edit: for anyone that wants to read the paper, here’s a non-paywall link: https://web.stanford.edu/group/dlab/media/papers/chenNBT2020.pdf https://web.stanford.edu/group/dlab/media/papers/chenNBT2020...

whymauri 6y ago
Any thoughts on the immunogenicity of optogenetic approaches? Anecdotally, it was a major pain when working with optogenetic stimulation in the PNS.
- tbenst 6y ago
  Karl has said publicly a few times that he sees optogenetics as a tool for basic scientific discovery, that then inform treatment of human patients, ie where to use transcranial magnetic stimulation. Any method that requires genetic manipulation in humans will be tricky. PNS seems likely to be the first application in humans, although there are also clinical trials going in the retina, not sure how they’ve progressed though.
  - whymauri 6y ago
    That's unfortunate, because the resolution and fine control you get with optogenetics are really good in the periphery, offering high therapeutic potential for amputees and paraplegics. The main roadblock is the understudied immunogenicity problem, IMO.
echelon 6y ago
What is Ritchie's take on Neuralink? (Sorry to stray onto topics not related to optogenetics. I hope it doesn't irk him that Elon Musk has steered/captured public consciousness regarding neuroscience.) To stray into sci-fi territory a bit, if money gets poured into the field, is there a chance we might see the Matrix or brain uploads in our lifetimes? And if not in our lifetime, is it ever achievable? I'm extremely skeptical, but human BCI could be the best/most important development in our history. Any problem gradient with a chance of unlocking immortality should be leaned into. It's way more important than Angry Birds or iOS N+1. With regard to studying already-alive organisms (we can't splice in the genes required for optogenetics), are there non-invasive techniques that can produce signal from humans? Deuterium NMR cerebral imaging seems low resolution and awkward to deploy. Could ML / signal processing increase the resolution of EEGs? Could we ever extract video signal from an EEG? Can an EEG induce perception into a brain? With regard to optogenetics, what are the things currently being studied with the technique? What pressing questions can it be used to answer? Are there any improvements to the technique that could push it further? Sorry for so many off-topic questions, but I'd love to know what an expert in the field thinks. I'd especially like to get a grasp of the future of the field.
- BigBubbleButt 6y ago
  > Any problem gradient with a chance of unlocking immortality should be leaned into. Why? Death is an important, and probably the least appreciated, aspect of evolution. Humanity can't change if the powers-that-be literally never go away. And that's ignoring finite resources on the planet. Would you rather live forever or have children?
  - DivisionSol 6y ago
    Live forever.
  - Kinrany 6y ago
    Trying to help evolution is as stupid as throwing things down to help gravity.
  - causality0 6y ago
    I already don't want children. Immortality for me, thanks.
    - apocalypstyx 6y ago
      How do you have immortality in a universe with a finite lifespan? (so far as we understand). Any such thing would require a shift on par with the discovery of the existence of God (an equivalent). So really is it that the singularity isn't just a secularization of Christian apocalypticism at all, but a re-framing of the reality of reality?
      - causality0 6y ago
        Dude I just want to be as happy as possible for as long as possible.
      - NineStarPoint 6y ago
        I know that when I personally say immortality, what I mean is the ability to live for as long as I want. I highly doubt I would want to live as long as it would take to get to the heat death of the universe. I expect somewhere between a 10’000 and a few million years would feel about right, but for all I know it could only be a few hundred, or maybe billions. But yes, all signs point to the idea that death is inevitable. I would just personally like to be able to increase my time in this universe by a few orders of magnitude.
fudged71 6y ago
How much of the brain is accessible at 7mm depth? What applications would and would not be possible with this technique?
- tbenst 6y ago
  For the mouse or rat brain, most everything :). For primates/humans, the skull is a lot thicker, but perhaps cortex is still reachable / longer wavelengths of light might be able to penetrate deeper (multiphoton techniques)
sebastianhof 6y ago
Do you think this could solve Tinnitus and other ear related diseases? How long do you think it will take to heal several brain-/nerve-related diseases?
- tbenst 6y ago
  Unfortunately, tinnitus is usually caused by hearing loss which comes from the death of neurons in the ear, and we are a long way off from finding a solution. But to the extent that the percept of ringing comes from recurrently firing ensembles in the brain, than neuromodulation techniques may bring relief from the perceptual aspects. TMS seems modestly promising for tinnitus, but experiments thus far have been poorly controlled so hard to tell: https://www.nature.com/articles/s41598-019-48750-9 https://www.nature.com/articles/s41598-019-48750-9 Our lab has done work with using optogenetics for inhibiting neural activity, and I wonder if the inhibition approach might be better than disruption. It’s a bit hard to figure how TMS does inhibition vs excitation, even with electrical stimulation it’s complicated and varies by celltype!
- bboygravity 6y ago
  Check out FX-322. This med may be a way to simply cure tinnitus (and more).
deepnotderp 6y ago
Since infrared neuromodulation has been shown to be able to directly modulate neurons without genetic modifications, what is the advantage of optogenetics? The question sounds adversarial, but it's really just due to my lack of knowledge in this area haha
- tbenst 6y ago
  I’m not too familiar with infrared neuromodulation, but it isn’t a widely used technique in systems neuroscience. My guess is it would be hard to target individual neurons, let alone target a genetically defined population of cells. Heating is usually what causes damage from light stimulation, so we try to minimize heating as much as possible—the brain very tightly controls temperature
  - deepnotderp 6y ago
    Interesting! Thanks for the reply! Is the laser intensity much lower with optogenetics compared to infrared neuromodulation?

by tbenst 6y ago

whymauri 6y ago

Any thoughts on the immunogenicity of optogenetic approaches? Anecdotally, it was a major pain when working with optogenetic stimulation in the PNS.

tbenst 6y ago
Karl has said publicly a few times that he sees optogenetics as a tool for basic scientific discovery, that then inform treatment of human patients, ie where to use transcranial magnetic stimulation. Any method that requires genetic manipulation in humans will be tricky. PNS seems likely to be the first application in humans, although there are also clinical trials going in the retina, not sure how they’ve progressed though.
- whymauri 6y ago
  That's unfortunate, because the resolution and fine control you get with optogenetics are really good in the periphery, offering high therapeutic potential for amputees and paraplegics. The main roadblock is the understudied immunogenicity problem, IMO.

echelon 6y ago

What is Ritchie's take on Neuralink? (Sorry to stray onto topics not related to optogenetics. I hope it doesn't irk him that Elon Musk has steered/captured public consciousness regarding neuroscience.) To stray into sci-fi territory a bit, if money gets poured into the field, is there a chance we might see the Matrix or brain uploads in our lifetimes? And if not in our lifetime, is it ever achievable? I'm extremely skeptical, but human BCI could be the best/most important development in our history. Any problem gradient with a chance of unlocking immortality should be leaned into. It's way more important than Angry Birds or iOS N+1. With regard to studying already-alive organisms (we can't splice in the genes required for optogenetics), are there non-invasive techniques that can produce signal from humans? Deuterium NMR cerebral imaging seems low resolution and awkward to deploy. Could ML / signal processing increase the resolution of EEGs? Could we ever extract video signal from an EEG? Can an EEG induce perception into a brain? With regard to optogenetics, what are the things currently being studied with the technique? What pressing questions can it be used to answer? Are there any improvements to the technique that could push it further? Sorry for so many off-topic questions, but I'd love to know what an expert in the field thinks. I'd especially like to get a grasp of the future of the field.

BigBubbleButt 6y ago
> Any problem gradient with a chance of unlocking immortality should be leaned into. Why? Death is an important, and probably the least appreciated, aspect of evolution. Humanity can't change if the powers-that-be literally never go away. And that's ignoring finite resources on the planet. Would you rather live forever or have children?
- DivisionSol 6y ago
  Live forever.
- Kinrany 6y ago
  Trying to help evolution is as stupid as throwing things down to help gravity.
- causality0 6y ago
  I already don't want children. Immortality for me, thanks.
  - apocalypstyx 6y ago
    How do you have immortality in a universe with a finite lifespan? (so far as we understand). Any such thing would require a shift on par with the discovery of the existence of God (an equivalent). So really is it that the singularity isn't just a secularization of Christian apocalypticism at all, but a re-framing of the reality of reality?
    - causality0 6y ago
      Dude I just want to be as happy as possible for as long as possible.
    - NineStarPoint 6y ago
      I know that when I personally say immortality, what I mean is the ability to live for as long as I want. I highly doubt I would want to live as long as it would take to get to the heat death of the universe. I expect somewhere between a 10’000 and a few million years would feel about right, but for all I know it could only be a few hundred, or maybe billions. But yes, all signs point to the idea that death is inevitable. I would just personally like to be able to increase my time in this universe by a few orders of magnitude.

fudged71 6y ago

How much of the brain is accessible at 7mm depth? What applications would and would not be possible with this technique?

tbenst 6y ago
For the mouse or rat brain, most everything :). For primates/humans, the skull is a lot thicker, but perhaps cortex is still reachable / longer wavelengths of light might be able to penetrate deeper (multiphoton techniques)

sebastianhof 6y ago

Do you think this could solve Tinnitus and other ear related diseases? How long do you think it will take to heal several brain-/nerve-related diseases?

tbenst 6y ago
Unfortunately, tinnitus is usually caused by hearing loss which comes from the death of neurons in the ear, and we are a long way off from finding a solution. But to the extent that the percept of ringing comes from recurrently firing ensembles in the brain, than neuromodulation techniques may bring relief from the perceptual aspects. TMS seems modestly promising for tinnitus, but experiments thus far have been poorly controlled so hard to tell: https://www.nature.com/articles/s41598-019-48750-9 https://www.nature.com/articles/s41598-019-48750-9 Our lab has done work with using optogenetics for inhibiting neural activity, and I wonder if the inhibition approach might be better than disruption. It’s a bit hard to figure how TMS does inhibition vs excitation, even with electrical stimulation it’s complicated and varies by celltype!
bboygravity 6y ago
Check out FX-322. This med may be a way to simply cure tinnitus (and more).

deepnotderp 6y ago

Since infrared neuromodulation has been shown to be able to directly modulate neurons without genetic modifications, what is the advantage of optogenetics? The question sounds adversarial, but it's really just due to my lack of knowledge in this area haha

tbenst 6y ago
I’m not too familiar with infrared neuromodulation, but it isn’t a widely used technique in systems neuroscience. My guess is it would be hard to target individual neurons, let alone target a genetically defined population of cells. Heating is usually what causes damage from light stimulation, so we try to minimize heating as much as possible—the brain very tightly controls temperature
- deepnotderp 6y ago
  Interesting! Thanks for the reply! Is the laser intensity much lower with optogenetics compared to infrared neuromodulation?