(Scanning at significantly smaller scales should always be assumed to be fine as long as end states are distinguishable up to thermal noise!)
So what I’m thinking about is something like this: imagine an enzyme,present at two sites on the membrane and regulated by an inhibitor. Now a toxin comes along and breaks the weak bonds to the inhibitor, stripping them off. Information about which site was inhibited is gone.
Okay, I agree that if this takes place at a temperature where molecules are still diffusing at a rapid pace and there’s no molecular sign of the broken bond at the bonding site, then it sounds like info could be permanently destroyed in this way. Now why would you think this was likely with vitrification solutions currently used? Is there an intuition here about ranges of chemical interaction so wide that many interactions are likely to occur which break such bonds and at least one such interaction is likely to destroy functionally critical non-duplicated info? If so, should we toss out vitrification and go back to dropping the head in liquid nitrogen because shear damage from ice freezing will produce fewer many-to-one mappings than introducing a foreign chemical into the brain? I express some surprise because if destructive chemical interactions were that common with each new chemical introduced then the problem of having a whole cell not self-destruct should be computationally unsolvable for natural selection, unless the chemicals used in vitrification are unusually bad somehow.
(Scanning at significantly smaller scales should always be assumed to be fine as long as end states are distinguishable up to thermal noise!)
This has some problems- fundamentally the length scale probed is inversely proportional to the energy required, which means increasing the resolution increases the damage done by scanning. You start getting into issues of ‘how much of this can I scan before I’ve totally destroyed this?’ which is a sort of percolation problem (how many amino acids can I randomly knock out of a protein before it collapses or rebonds into a different protein?), so scanning at resolutions with energy equivalent above peptide bonds is very problematic. Assuming peptide bond strength of a couple kj/mol, I get lower-limit length scales of a few microns (this is rough, and I’d appreciate if someone would double check).
Now why would you think this was likely with vitrification solutions currently used?
The vitrification solutions currently used are know to be toxic, and are used at very high concentrations, so some of this sort of damage will occur. I don’t know enough biochemistry to say anything else with any kind of definitety, but on the previous thread kalla724 seemed to have some domain specific knowledge and thought the problem would be severe.
If so, should we toss out vitrification and go back to dropping the head in liquid nitrogen because shear damage from ice freezing will produce fewer many-to-one mappings than introducing a foreign chemical into the brain?
No, not at all. The vitrification damage is orders of magnitude less. Destroying a few multi-unit proteins and removing some inhibitors seems much better than totally destroying the cell-membrane (which has many of the same “which sites were these guys attached to?” problems).
I express some surprise because if destructive chemical interactions were that common with each new chemical introduced then the problem of having a whole cell not self-destruct should be computationally unsolvable for natural selection
Its my (limited) understanding that the cell membrane exist to largely solve this problem. Also, introducing tiny bits of toxins here and there causes small amounts of damage but the cell could probably survive. Putting the cell in a toxic environment will inevitably kill it. The concentration matters. But here I’m stepping way outside anything I know about.
This has some problems- fundamentally the length scale probed is inversely proportional to the energy required, which means increasing the resolution increases the damage done by scanning.
We seem to have very different assumptions here. I am assuming you can get up to the molecule and gently wave a tiny molecular probe in its direction, if required. I am not assuming that you are trying to use high-energy photons to photograph it.
You also still seem to be use a lot of functional-damage words like “destroying” which is why I don’t trust your or kalla724′s intuitions relative to the intuitions of other scientists with domain knowledge of neuroscience who use the language of information theory when assessing cryonic feasibility. If somebody is thinking in terms of functional damage (it doesn’t restart when you reboot it, oh my gosh we changed the conformation look at that damage it can’t play its functional role in the cell anymore!) then their intuitions don’t bear very well on the real question of many-to-one mapping.
What does the vitrification solution actually do that’s supposed to irreversibly map things, does anyone actually know? The fact that a cell can survive with a membrane, at all, considering the many different molecules inside it, imply that most molecules don’t functionally damage most other molecules most of the time, never mind performing irreversible mappings on them. But then this is reasoning over molecules that may be of a different type then vitrificants. At the opposite extreme, I’d expect introducing hydrochloric acid into the brain to be quite destructive.
We seem to have very different assumptions here. I am assuming you can get up to the molecule and gently wave a tiny molecular probe in its direction, if required. I am not assuming that you are trying to use high-energy photons to photograph it.
How are you imaging this works? I’m aware of chemistry that would allow you to say there are X whatever proteins, and Y such-and-such enzymes,etc, but such chemical processes I don’t think are good enough for the sort of geometric reconstruction needed. Its not obvious to me that a molecular probe of the type you imagine can exist. What exactly is it measuring and how is it sensitive to it? Is it some sort of enzyme? Do we thaw the brain and then introduce these probes in solution? Do we somehow pulp the cell and run the constituents through a nanopore type thing and try to measure charge?
the intuitions of other scientists with domain knowledge of neuroscience who use the language of information theory when assessing cryonic feasibility.
I would love to be convinced I am overly pessimistic, and pointing me in the direction of biochemists/neuroscientists/biophysicists who disagree with me would be welcome. I only know a few biophysicists and they are generally more pessimistic than I am.
What does the vitrification solution actually do that’s supposed to irreversibly map things, does anyone actually know?
I know ethylene glycol is cytotoxic, and so interacts with membrane proteins, but I don’t know the mechanism.
I’ll quickly point you at Drexler’s Nanosystems and Freitas’s Nanomedicine though they’re rather long and technical reads. But we are visualizing molecularly specified machines, and ‘hell no’ to thawing first or pulping the cell. Seriously, this kind of background assumption is why I have to ask a lot of questions instead of just taking this sort of skeptical intuition at face value.
But rather than having to read through either of those sources, I would ask you to just take on assumption that two molecularly distinct (up to thermal noise) configurations will somehow be distinguishable by sufficiently advanced technology, and describe what your intuitions (and reasons) would be taking that premise at face value. It’s not your job to be a physicist or to try to describe the theoretical limits of future technology, except of course that two systems physically identical up to thermal noise can be assumed to be technologically indistinguishable, and since thermal noise is much larger than exact quark positions it will not be possible to read off any subtle neural info by looking at exact quark positions (now that might be permanently impossible), etc. Aside from that I would encourage you to think in terms of doing cryptography to a vitrified brain rather than medicine. Don’t ask whether ethylene glycol is toxic, ask whether it is a secure hard drive erasure mechanism that can obscure the contents of the brain from a powerful and intelligent adversary reading off the exact molecular positions in order to obtain tiny hints.
Checking over the open letter from scientists in support of cryonics to remember who has an explicitly neuroscience background, I am reminded that good old Anders Sandberg is wearing a doctorate in computational neuroscience from Stockholm, so I’ll go ahead and name him.
Do you have a page number in Nanosystems for a references to a sensing probe? Also, this is tangential to the main discussion, so I’ll take pointers to any reference you have and let this drop.
Don’t ask whether ethylene glycol is toxic, ask whether it is a secure hard drive erasure mechanism that can obscure the contents of the brain from a powerful and intelligent adversary reading off the exact molecular positions in order to obtain tiny hints.
I was using cytotoxic in the very specific sense of “interacts and destabilizes the cell membrane,” which is doing the sort of operations we agreed in principle can be irreversible. Estimates as to how important this sort of information actually is are impossible for me to make, as I lack the background. What I would love to see is someone with some domain specific knowledge explaining why this isn’t an issue.
I was using cytotoxic in the very specific sense of “interacts and destabilizes the cell membrane,” which is doing the sort of operations we agreed in principle can be irreversible.
Sorry, but can you again expand on this? What happens?
So I cracked open a biochem book to avoid wandering off a speculative pier,as we were moving beyond what I readily knew. A simple loss of information presented itself.
Some proteins can have two states, open and closed, which operate on a hydrophobic/hydrophilic balance. In dessicated cells or if the proteins denature for some other reason, the open/closed state will be lost.
Adding cryoprotectants will change osmotic pressure and the cell will dessicate, and the open/closed state will be lost.
Would strongly predict that such changes erase only information about short term activity, not long term memory. Protein conformation in response to electrochemical/osmotic gradients operates on the timescale of individual firings, it’s probably too flimsy to encode stable memories. These should be easy for Skynet to recover.
Higher level pattens of firings might conceivably store information, but experience with anaesthesia, hypothermia etc. says they do not. Or we’ve been killing people and replacing them all this time… a possibility which thanks to this site I’m prepared to consider..
Oh, and
Do you have a page number in Nanosystems for a references to a sensing probe?
Long-term memory, unlike short-term memory, is dependent upon the construction of new proteins.[30] This occurs within the cellular body, and concerns in particular transmitters, receptors, and new synapse pathways that reinforce the communicative strength between neurons. The production of new proteins devoted to synapse reinforcement is triggered after the release of certain signaling substances (such as calcium within hippocampal neurons) in the cell. In the case of hippocampal cells, this release is dependent upon the expulsion of magnesium (a binding molecule) that is expelled after significant and repetitive synaptic signaling. The temporary expulsion of magnesium frees NMDA receptors to release calcium in the cell, a signal that leads to gene transcription and the construction of reinforcing proteins.[31] For more information, see long-term potentiation (LTP).
One of the newly synthesized proteins in LTP is also critical for maintaining long-term memory. This protein is an autonomously active form of the enzyme protein kinase C (PKC), known as PKMζ. PKMζ maintains the activity-dependent enhancement of synaptic strength and inhibiting PKMζ erases established long-term memories, without affecting short-term memory or, once the inhibitor is eliminated, the ability to encode and store new long-term memories is restored.
Also, BDNF is important for the persistence of long-term memories.[32]
What I worry about being confused on when reading the literature is the distinction between forming memories in the first place, and actually encoding for memory.
Another critical distinction is that, proteins that are needed to prevent degradation of memories over time (which get lots of research and emphasis in the literature due to their role in preventing degenerative diseases) aren’t necessarily the ones directly encoding for the memories.
So in subjects I know a lot about, I have dealt with many people who pick up strange notions by filling in the gaps from google and wikipedia with a weak foundation. The work required to effectively figure out what specific damage to the specific proteins you mentioned could be done by desiccation of a cell is beyond my knowledge base, so I leave it to someone more knowledgeable than myself(perhaps you?) to step in.
What open/closed states does PKMζ have? What regulates those open/closed states? Are the open/closed states important to its roll (it looks like yes given the notion of the inhibitor?)?
Yes, it’s important to build a strong foundation before establishing firm opinions. Also, in this particular case note that science appears to have recently changed it’s mind based on further evidence, which goes to show that you have to be careful when reading wikipedia. Apparently the protein in question is not so likely to underlie LTM after all, as transgenic mice lacking it still have LTM (exhibiting maze memory, LTP, etc). The erasure of memory is linked to zeta inhibitory peptide (ZIP), which incidentally happens in the transgenic mice as well.
ETA: Apparently PKMzeta can be used to restore faded memories erased with ZIP.
Adding cryoprotectants will change osmotic pressure and the cell will dessicate, and the open/closedstate will be lost.
Now you know why I’m so keen on the idea of figuring out a way to get something like trehalose into the cell. Neurons tend to lose water rather than import cryoprotectants because of their myelination. Trehalose protects against dessication by cushioning proteins from hitting each other. Other kinds of solute that can get past the membrane could balance out the osmotic pressure (that’s kind of the point of penetrating cryoprotectants) just as well, but I like trehalose because of its low toxicity.
Nanotechnology, not chemical analysis. Drexler’s Engines of Creation contains a section on the feasibility of repairing molecular damage in this way. Since (if our current understanding holds) nanobots can be functional on a smaller scale than proteins (which are massive chunks held together Lego-style by van der Walls forces), they can be introduced within a cell membrane to probe, report on, and repair damaged proteins.
I have not read Engine’s of Creation, but I have read his thesis and I was under the impression most of the proposed systems would only work in vacuum chambers as the would oxidize extremely rapidly in an environment like the body. Has someone worked around this problem, even in theory?
Also, I’ve seen molecular assembler designs of various types in various speculative papers, but I’ve never seen a sensing apparatus. Any references?
Has someone worked around this problem, even in theory?
Later in the thread, Eliezer recommended Drexler’s followup Nanosystems and Freitas’ Nanomedicine, neither of which I’ve read, but I’d be surprised if the latter didn’t address this issue. Sorry that I in particular don’t think this is a worrisome objection, but it’s on the same level as saying that electronics could never be helpful in the real world because water makes them malfunction. You start by showing that something works under ideal conditions, and then you find a way to waterproof it.
Also, I’ve seen molecular assembler designs of various types in various speculative papers, but I’ve never seen a sensing apparatus. Any references?
(Scanning at significantly smaller scales should always be assumed to be fine as long as end states are distinguishable up to thermal noise!)
Okay, I agree that if this takes place at a temperature where molecules are still diffusing at a rapid pace and there’s no molecular sign of the broken bond at the bonding site, then it sounds like info could be permanently destroyed in this way. Now why would you think this was likely with vitrification solutions currently used? Is there an intuition here about ranges of chemical interaction so wide that many interactions are likely to occur which break such bonds and at least one such interaction is likely to destroy functionally critical non-duplicated info? If so, should we toss out vitrification and go back to dropping the head in liquid nitrogen because shear damage from ice freezing will produce fewer many-to-one mappings than introducing a foreign chemical into the brain? I express some surprise because if destructive chemical interactions were that common with each new chemical introduced then the problem of having a whole cell not self-destruct should be computationally unsolvable for natural selection, unless the chemicals used in vitrification are unusually bad somehow.
This has some problems- fundamentally the length scale probed is inversely proportional to the energy required, which means increasing the resolution increases the damage done by scanning. You start getting into issues of ‘how much of this can I scan before I’ve totally destroyed this?’ which is a sort of percolation problem (how many amino acids can I randomly knock out of a protein before it collapses or rebonds into a different protein?), so scanning at resolutions with energy equivalent above peptide bonds is very problematic. Assuming peptide bond strength of a couple kj/mol, I get lower-limit length scales of a few microns (this is rough, and I’d appreciate if someone would double check).
The vitrification solutions currently used are know to be toxic, and are used at very high concentrations, so some of this sort of damage will occur. I don’t know enough biochemistry to say anything else with any kind of definitety, but on the previous thread kalla724 seemed to have some domain specific knowledge and thought the problem would be severe.
No, not at all. The vitrification damage is orders of magnitude less. Destroying a few multi-unit proteins and removing some inhibitors seems much better than totally destroying the cell-membrane (which has many of the same “which sites were these guys attached to?” problems).
Its my (limited) understanding that the cell membrane exist to largely solve this problem. Also, introducing tiny bits of toxins here and there causes small amounts of damage but the cell could probably survive. Putting the cell in a toxic environment will inevitably kill it. The concentration matters. But here I’m stepping way outside anything I know about.
We seem to have very different assumptions here. I am assuming you can get up to the molecule and gently wave a tiny molecular probe in its direction, if required. I am not assuming that you are trying to use high-energy photons to photograph it.
You also still seem to be use a lot of functional-damage words like “destroying” which is why I don’t trust your or kalla724′s intuitions relative to the intuitions of other scientists with domain knowledge of neuroscience who use the language of information theory when assessing cryonic feasibility. If somebody is thinking in terms of functional damage (it doesn’t restart when you reboot it, oh my gosh we changed the conformation look at that damage it can’t play its functional role in the cell anymore!) then their intuitions don’t bear very well on the real question of many-to-one mapping.
What does the vitrification solution actually do that’s supposed to irreversibly map things, does anyone actually know? The fact that a cell can survive with a membrane, at all, considering the many different molecules inside it, imply that most molecules don’t functionally damage most other molecules most of the time, never mind performing irreversible mappings on them. But then this is reasoning over molecules that may be of a different type then vitrificants. At the opposite extreme, I’d expect introducing hydrochloric acid into the brain to be quite destructive.
How are you imaging this works? I’m aware of chemistry that would allow you to say there are X whatever proteins, and Y such-and-such enzymes,etc, but such chemical processes I don’t think are good enough for the sort of geometric reconstruction needed. Its not obvious to me that a molecular probe of the type you imagine can exist. What exactly is it measuring and how is it sensitive to it? Is it some sort of enzyme? Do we thaw the brain and then introduce these probes in solution? Do we somehow pulp the cell and run the constituents through a nanopore type thing and try to measure charge?
I would love to be convinced I am overly pessimistic, and pointing me in the direction of biochemists/neuroscientists/biophysicists who disagree with me would be welcome. I only know a few biophysicists and they are generally more pessimistic than I am.
I know ethylene glycol is cytotoxic, and so interacts with membrane proteins, but I don’t know the mechanism.
I’ll quickly point you at Drexler’s Nanosystems and Freitas’s Nanomedicine though they’re rather long and technical reads. But we are visualizing molecularly specified machines, and ‘hell no’ to thawing first or pulping the cell. Seriously, this kind of background assumption is why I have to ask a lot of questions instead of just taking this sort of skeptical intuition at face value.
But rather than having to read through either of those sources, I would ask you to just take on assumption that two molecularly distinct (up to thermal noise) configurations will somehow be distinguishable by sufficiently advanced technology, and describe what your intuitions (and reasons) would be taking that premise at face value. It’s not your job to be a physicist or to try to describe the theoretical limits of future technology, except of course that two systems physically identical up to thermal noise can be assumed to be technologically indistinguishable, and since thermal noise is much larger than exact quark positions it will not be possible to read off any subtle neural info by looking at exact quark positions (now that might be permanently impossible), etc. Aside from that I would encourage you to think in terms of doing cryptography to a vitrified brain rather than medicine. Don’t ask whether ethylene glycol is toxic, ask whether it is a secure hard drive erasure mechanism that can obscure the contents of the brain from a powerful and intelligent adversary reading off the exact molecular positions in order to obtain tiny hints.
Checking over the open letter from scientists in support of cryonics to remember who has an explicitly neuroscience background, I am reminded that good old Anders Sandberg is wearing a doctorate in computational neuroscience from Stockholm, so I’ll go ahead and name him.
Do you have a page number in Nanosystems for a references to a sensing probe? Also, this is tangential to the main discussion, so I’ll take pointers to any reference you have and let this drop.
I was using cytotoxic in the very specific sense of “interacts and destabilizes the cell membrane,” which is doing the sort of operations we agreed in principle can be irreversible. Estimates as to how important this sort of information actually is are impossible for me to make, as I lack the background. What I would love to see is someone with some domain specific knowledge explaining why this isn’t an issue.
Boom. http://www.nature.com/news/diamond-defects-shrink-mri-to-the-nanoscale-1.12343
Sorry, but can you again expand on this? What happens?
So I cracked open a biochem book to avoid wandering off a speculative pier,as we were moving beyond what I readily knew. A simple loss of information presented itself.
Some proteins can have two states, open and closed, which operate on a hydrophobic/hydrophilic balance. In dessicated cells or if the proteins denature for some other reason, the open/closed state will be lost.
Adding cryoprotectants will change osmotic pressure and the cell will dessicate, and the open/closed state will be lost.
Do we know about any such proteins related to LTM? Can we make predictions about what it takes to erase C. elegans maze memory this way?
Would strongly predict that such changes erase only information about short term activity, not long term memory. Protein conformation in response to electrochemical/osmotic gradients operates on the timescale of individual firings, it’s probably too flimsy to encode stable memories. These should be easy for Skynet to recover.
Higher level pattens of firings might conceivably store information, but experience with anaesthesia, hypothermia etc. says they do not. Or we’ve been killing people and replacing them all this time… a possibility which thanks to this site I’m prepared to consider..
Oh, and
Bam.
http://www.nature.com/news/diamond-defects-shrink-mri-to-the-nanoscale-1.12343
Here we have moved far past my ability to even speculate.
Presumably you can use google and wikipedia to fill in the gaps just like the rest of us.
Wikipedia: Long-term memory
What I worry about being confused on when reading the literature is the distinction between forming memories in the first place, and actually encoding for memory.
Another critical distinction is that, proteins that are needed to prevent degradation of memories over time (which get lots of research and emphasis in the literature due to their role in preventing degenerative diseases) aren’t necessarily the ones directly encoding for the memories.
So in subjects I know a lot about, I have dealt with many people who pick up strange notions by filling in the gaps from google and wikipedia with a weak foundation. The work required to effectively figure out what specific damage to the specific proteins you mentioned could be done by desiccation of a cell is beyond my knowledge base, so I leave it to someone more knowledgeable than myself(perhaps you?) to step in.
What open/closed states does PKMζ have? What regulates those open/closed states? Are the open/closed states important to its roll (it looks like yes given the notion of the inhibitor?)?
Yes, it’s important to build a strong foundation before establishing firm opinions. Also, in this particular case note that science appears to have recently changed it’s mind based on further evidence, which goes to show that you have to be careful when reading wikipedia. Apparently the protein in question is not so likely to underlie LTM after all, as transgenic mice lacking it still have LTM (exhibiting maze memory, LTP, etc). The erasure of memory is linked to zeta inhibitory peptide (ZIP), which incidentally happens in the transgenic mice as well.
ETA: Apparently PKMzeta can be used to restore faded memories erased with ZIP.
Now you know why I’m so keen on the idea of figuring out a way to get something like trehalose into the cell. Neurons tend to lose water rather than import cryoprotectants because of their myelination. Trehalose protects against dessication by cushioning proteins from hitting each other. Other kinds of solute that can get past the membrane could balance out the osmotic pressure (that’s kind of the point of penetrating cryoprotectants) just as well, but I like trehalose because of its low toxicity.
Nanotechnology, not chemical analysis. Drexler’s Engines of Creation contains a section on the feasibility of repairing molecular damage in this way. Since (if our current understanding holds) nanobots can be functional on a smaller scale than proteins (which are massive chunks held together Lego-style by van der Walls forces), they can be introduced within a cell membrane to probe, report on, and repair damaged proteins.
I have not read Engine’s of Creation, but I have read his thesis and I was under the impression most of the proposed systems would only work in vacuum chambers as the would oxidize extremely rapidly in an environment like the body. Has someone worked around this problem, even in theory?
Also, I’ve seen molecular assembler designs of various types in various speculative papers, but I’ve never seen a sensing apparatus. Any references?
Later in the thread, Eliezer recommended Drexler’s followup Nanosystems and Freitas’ Nanomedicine, neither of which I’ve read, but I’d be surprised if the latter didn’t address this issue. Sorry that I in particular don’t think this is a worrisome objection, but it’s on the same level as saying that electronics could never be helpful in the real world because water makes them malfunction. You start by showing that something works under ideal conditions, and then you find a way to waterproof it.
For the convenience of later readers: someone elsewhere in the thread linked an actual physical experimental example.
Not that I have seen, but I’m only partially through it.
And its an awesome example from just a few months ago! Pushing NMR from mm resolutions down to nm resolutions is a truly incredibly feat!