Thanks so much! LMK if you have any questions or thoughts about the post. Or if you want to offer an argument for standards below “traceable connectome”. I know we’ve had a longstanding difference of opinion on that and I’d be delighted to chat about it here if you want!
Sure! First, to be clear, I fully agree with you that legal death via MAID followed by perfusion fixation offers (clearly) the best preservation quality available today.
I think of the BPF traceability criteria by contemporary volume EM as more of a rule-in than rule-out standard for preservation quality. Just because it’s not possible to trace all of the processes today doesn’t mean that a sufficient amount of information isn’t still present in the preserved brain that would allow connectivity to still be traced by future inference techniques. Briefly, this is because I think that it is very likely that in the future we will be able to use combinations of biomolecules that are (combinatorially) unique to each cell/cell process to solve ambiguities caused by discontinuities in cell process tracing. See: https://brainpreservation.github.io/Inference
I suspect that we probably agree on most things, so let’s try to find something we disagree about!
I think we probably agree about the following (let me know if I’m wrong about any of these):
Damage that seems like it should destroy information often doesn’t. Our intuitions are often wrong on what can be inferred, and the bias is normally in the direction of more information being lost than is actually lost. We tend to think something’s “a mess” when it can actually be fully reconstructed.
Even with a frozen brain, you can’t prove that any information relevant to restoring a person is truly lost. Straight freezing crushes and disrupts brain tissue, but maybe there’s enough biomolecular information to reconstruct everything. I personally wouldn’t be that surprised if this was the case.
There’s some physical change in the vasculature of brains that happens post-mortem and causes difficulty in re-perfusion, and that change happens at approximately the 7-15 minute mark depending on how you measure it. Brains that sit with blood inside them, but no blood flow, for longer than this window, will not re-perfuse uniformly with blood, washout solution, or fixative, but instead there will be sections of brain that fail to perfuse.
Brains can become severely damaged and even outright necrotic in some areas pre-mortem, before the person’s heart stops and legal death could be declared. The amount of brain damage present at death depends on how the person dies, but it’s relatively common for people to experience terminal comas lasting hours to days before death.
We (humanity) know enough neuroscience today to say that some aspects of a person don’t need to be preserved. Dynamic electrical activity is one such thing that can say with confidence doesn’t need to be preserved, because otherwise it would contradict our clinical experience with DHCA.
As we learn more neuroscience, we would be able to definitively say that more things don’t need to be preserved. For example, we might be able to show that certain brain regions share so much mutual information with other regions that only one needs to be preserved, with “doesn’t need to be preserved” meaning that a person could be preserved, the thing discarded, and the person restored with no or minimal clinically relevant problems. We might learn enough neuroscience to say that inhibitory synapses don’t need to be preserved, because ultimately they are implementing non-memory-relevant network regulatory tasks. We might be able to say that the spinal cord or brainstem or hippocampus doesn’t need to be preserved, because they’re all inferable from cortex.
Now here’s where I think we differ, and it’s on what the standards for our standards should be!
What should the bar for “acceptable preservation” be today, given our current neuroscience knowledge?
I think we know enough neuroscience today to say that preservation does work as long as almost all biomolecules are preserved and the brain remains traceable after preservation, and “works according to current neuroscience” should be our minimal bar for “acceptable preservation”.
This standard demands a lot from today’s preservationists, but it’s demonstratively achievable given the work I’ve done in pigs / human cadavers over the last several years. And so we as preservationists should hold ourselves to this standard, out of humility and a desire to offer the future something they can use. If we want to lower that standard we can, but a lower standard needs to come with additional neuroscience knowledge so that we can confidently say that a lowered standard does work according to current neuroscience in spite of not preserving as much.
I think that if we always hold our “acceptable preservation standard” to be demonstrably preserving enough information that neuroscience says it works, then that both gives us the best chance to deliver to the future something they can actually use, and gives us the best shot at becoming a standard, evidence-based part of end of life care.
The “standard for our standards” should be “works according to current neuroscience knowledge.”
I want preservationists of this era to be able to be sued for malpractice because their technique was sloppy and they didn’t deliver preservative chemicals to a dime-sized brain region within 15 minutes post-mortem.
I want straight freezing, traditional cryonics, or any other method to be accepted as good techniques, if and only if they come with enough new neuroscience knowledge so that we know they’re preserving enough information that they work.
Now, I suspect you would want to argue for a different “preservation standard standard” that’s not “works according to current neuroscience”, I’d love to hear your thoughts!
Thank you so much for explaining where you think we agree and disagree. I totally agree that finding disagreements is more interesting, even though we overall seem to agree on this topic more than the vast majority of people in the world.
I agree with all of your bullet points with the partial except of the 7-15 minute perfusion one. I don’t think there’s necessarily a physical change that occurs in the vasculature within that time window that absolutely prevents subsequent perfusion. To me it seems more complicated on both the higher and lower ends of the range. For example, my understanding is that animals have been revived after global cerebral ischemia for up to 30 minutes. I think it depends on the perfusion system used and there also seems to be a significant amount of currently unexplained biological variability. But this is a topic I’d like to learn more about and I don’t pretend to totally understand it, so I’m curious to hear more of your reasoning.
Regarding standards for brain preservation, I find the discussion very important but not yet settled. To use an analogy from clinical medicine, we are discussing the use of surrogate endpoints to predict whether or not someone can be revived in the future when technology has improved. Unfortunately, we don’t have any well validated endpoints for this outcome. Ken has proposed the criteria of connectome tracing by contemporary volume EM. However, this completely ignores the possibility of future molecular mapping to infer the original states in the case of morphological alterations. If this is possible, which I think it is, it changes everything. So I think we first have to determine more rigorously what the surrogate endpoints are that indicate information theoretic death. Basically, while I agree with you that one or multiple surrogate endpoints are urgently needed in the field, I just don’t agree with the current ones that have been proposed so far. So I think there is more basic science research needed to determine that, specifically regarding (a) how different types of structural information such as molecules and morphology correlate with one another in the preserved brain and (b) what types of structural information can be used to infer cognitive information (such as research related to the Aspirational Neuroscience Prize). More on this here: https://brainpreservation.github.io/Assessment#volume-electron-microscopy
I like that Nectome uses this approach and those standards; I think it’s a very valuable organization to have as part of the brain preservation ecosystem.
I think exploring some form of standards, or at least some options for third party quality reviews would be very valuable.
I want preservationists of this era to be able to be sued for malpractice because their technique was sloppy and they didn’t deliver preservative chemicals to a dime-sized brain region within 15 minutes post-mortem.
I imagine you’re not making the following strong claims, but I can’t tell for sure, so would like to check.
You’re not saying “It should be illegal for someone to get their brain preserved if it takes more than 15 minutes to start the procedure because the medical intervention wouldn’t be good enough so they should be forced to completely die instead and not attempt to preserve them.”, right? I would strongly disagree if that’s what you were saying.
You’re not saying “It should be illegal for someone to prioritize other preservation metrics over methods that allow for easier microscopy verification of structural preservation even if that’s what they prefer”, right? I would also disagree with that, both because I want people to be able to do whatever they want, and also because there’s still enough uncertainty that I don’t think we can be sufficiently confident about some alternative approaches not being actually meaningfully superior in some ways. (I do assign more probability mass to prioritizing structural preservation, and that influences my decision making for myself, but also I’m not aware of research proving that cryonics without fixative does not preserved important structure, and forcing people to not use that seems at the very least premature.)
Absolutely not saying either of those things. If nothing else, I don’t think the government has any business telling people what they can do with their own brains, or what kind of medical procedures they can hire someone to perform on them.
We’ll get into more detail in future posts about what kind of mechanisms for accountability we are excited about. Broadly speaking, though, we’re interested in labeling and certification, not in any kind of prohibition on alternative services. The hope is fundamentally that ordinary laypeople will be able to easily understand the stance of the scientific community at large and what procedures meet a reasonable standard of care.
Congrats on the launch and on getting your pig results published!
Thanks so much! LMK if you have any questions or thoughts about the post. Or if you want to offer an argument for standards below “traceable connectome”. I know we’ve had a longstanding difference of opinion on that and I’d be delighted to chat about it here if you want!
Sure! First, to be clear, I fully agree with you that legal death via MAID followed by perfusion fixation offers (clearly) the best preservation quality available today.
I think of the BPF traceability criteria by contemporary volume EM as more of a rule-in than rule-out standard for preservation quality. Just because it’s not possible to trace all of the processes today doesn’t mean that a sufficient amount of information isn’t still present in the preserved brain that would allow connectivity to still be traced by future inference techniques. Briefly, this is because I think that it is very likely that in the future we will be able to use combinations of biomolecules that are (combinatorially) unique to each cell/cell process to solve ambiguities caused by discontinuities in cell process tracing. See: https://brainpreservation.github.io/Inference
I suspect that we probably agree on most things, so let’s try to find something we disagree about!
I think we probably agree about the following (let me know if I’m wrong about any of these):
Damage that seems like it should destroy information often doesn’t. Our intuitions are often wrong on what can be inferred, and the bias is normally in the direction of more information being lost than is actually lost. We tend to think something’s “a mess” when it can actually be fully reconstructed.
Even with a frozen brain, you can’t prove that any information relevant to restoring a person is truly lost. Straight freezing crushes and disrupts brain tissue, but maybe there’s enough biomolecular information to reconstruct everything. I personally wouldn’t be that surprised if this was the case.
There’s some physical change in the vasculature of brains that happens post-mortem and causes difficulty in re-perfusion, and that change happens at approximately the 7-15 minute mark depending on how you measure it. Brains that sit with blood inside them, but no blood flow, for longer than this window, will not re-perfuse uniformly with blood, washout solution, or fixative, but instead there will be sections of brain that fail to perfuse.
Brains can become severely damaged and even outright necrotic in some areas pre-mortem, before the person’s heart stops and legal death could be declared. The amount of brain damage present at death depends on how the person dies, but it’s relatively common for people to experience terminal comas lasting hours to days before death.
We (humanity) know enough neuroscience today to say that some aspects of a person don’t need to be preserved. Dynamic electrical activity is one such thing that can say with confidence doesn’t need to be preserved, because otherwise it would contradict our clinical experience with DHCA.
As we learn more neuroscience, we would be able to definitively say that more things don’t need to be preserved. For example, we might be able to show that certain brain regions share so much mutual information with other regions that only one needs to be preserved, with “doesn’t need to be preserved” meaning that a person could be preserved, the thing discarded, and the person restored with no or minimal clinically relevant problems. We might learn enough neuroscience to say that inhibitory synapses don’t need to be preserved, because ultimately they are implementing non-memory-relevant network regulatory tasks. We might be able to say that the spinal cord or brainstem or hippocampus doesn’t need to be preserved, because they’re all inferable from cortex.
Now here’s where I think we differ, and it’s on what the standards for our standards should be!
What should the bar for “acceptable preservation” be today, given our current neuroscience knowledge?
I think we know enough neuroscience today to say that preservation does work as long as almost all biomolecules are preserved and the brain remains traceable after preservation, and “works according to current neuroscience” should be our minimal bar for “acceptable preservation”.
This standard demands a lot from today’s preservationists, but it’s demonstratively achievable given the work I’ve done in pigs / human cadavers over the last several years. And so we as preservationists should hold ourselves to this standard, out of humility and a desire to offer the future something they can use. If we want to lower that standard we can, but a lower standard needs to come with additional neuroscience knowledge so that we can confidently say that a lowered standard does work according to current neuroscience in spite of not preserving as much.
I think that if we always hold our “acceptable preservation standard” to be demonstrably preserving enough information that neuroscience says it works, then that both gives us the best chance to deliver to the future something they can actually use, and gives us the best shot at becoming a standard, evidence-based part of end of life care.
The “standard for our standards” should be “works according to current neuroscience knowledge.”
I want preservationists of this era to be able to be sued for malpractice because their technique was sloppy and they didn’t deliver preservative chemicals to a dime-sized brain region within 15 minutes post-mortem.
I want straight freezing, traditional cryonics, or any other method to be accepted as good techniques, if and only if they come with enough new neuroscience knowledge so that we know they’re preserving enough information that they work.
Now, I suspect you would want to argue for a different “preservation standard standard” that’s not “works according to current neuroscience”, I’d love to hear your thoughts!
Thank you so much for explaining where you think we agree and disagree. I totally agree that finding disagreements is more interesting, even though we overall seem to agree on this topic more than the vast majority of people in the world.
I agree with all of your bullet points with the partial except of the 7-15 minute perfusion one. I don’t think there’s necessarily a physical change that occurs in the vasculature within that time window that absolutely prevents subsequent perfusion. To me it seems more complicated on both the higher and lower ends of the range. For example, my understanding is that animals have been revived after global cerebral ischemia for up to 30 minutes. I think it depends on the perfusion system used and there also seems to be a significant amount of currently unexplained biological variability. But this is a topic I’d like to learn more about and I don’t pretend to totally understand it, so I’m curious to hear more of your reasoning.
Regarding standards for brain preservation, I find the discussion very important but not yet settled. To use an analogy from clinical medicine, we are discussing the use of surrogate endpoints to predict whether or not someone can be revived in the future when technology has improved. Unfortunately, we don’t have any well validated endpoints for this outcome. Ken has proposed the criteria of connectome tracing by contemporary volume EM. However, this completely ignores the possibility of future molecular mapping to infer the original states in the case of morphological alterations. If this is possible, which I think it is, it changes everything. So I think we first have to determine more rigorously what the surrogate endpoints are that indicate information theoretic death. Basically, while I agree with you that one or multiple surrogate endpoints are urgently needed in the field, I just don’t agree with the current ones that have been proposed so far. So I think there is more basic science research needed to determine that, specifically regarding (a) how different types of structural information such as molecules and morphology correlate with one another in the preserved brain and (b) what types of structural information can be used to infer cognitive information (such as research related to the Aspirational Neuroscience Prize). More on this here: https://brainpreservation.github.io/Assessment#volume-electron-microscopy
I like that Nectome uses this approach and those standards; I think it’s a very valuable organization to have as part of the brain preservation ecosystem.
I think exploring some form of standards, or at least some options for third party quality reviews would be very valuable.
I imagine you’re not making the following strong claims, but I can’t tell for sure, so would like to check.
You’re not saying “It should be illegal for someone to get their brain preserved if it takes more than 15 minutes to start the procedure because the medical intervention wouldn’t be good enough so they should be forced to completely die instead and not attempt to preserve them.”, right? I would strongly disagree if that’s what you were saying.
You’re not saying “It should be illegal for someone to prioritize other preservation metrics over methods that allow for easier microscopy verification of structural preservation even if that’s what they prefer”, right? I would also disagree with that, both because I want people to be able to do whatever they want, and also because there’s still enough uncertainty that I don’t think we can be sufficiently confident about some alternative approaches not being actually meaningfully superior in some ways. (I do assign more probability mass to prioritizing structural preservation, and that influences my decision making for myself, but also I’m not aware of research proving that cryonics without fixative does not preserved important structure, and forcing people to not use that seems at the very least premature.)
Absolutely not saying either of those things. If nothing else, I don’t think the government has any business telling people what they can do with their own brains, or what kind of medical procedures they can hire someone to perform on them.
We’ll get into more detail in future posts about what kind of mechanisms for accountability we are excited about. Broadly speaking, though, we’re interested in labeling and certification, not in any kind of prohibition on alternative services. The hope is fundamentally that ordinary laypeople will be able to easily understand the stance of the scientific community at large and what procedures meet a reasonable standard of care.
wonderful!