Fascinating. I’ve been waiting for a while for a well-educated neuroscientist to come here, as I think there are a lot of interesting questions that hinge on issues in neuroscience that are at least hard for me to answer (my only exposure to it is a semester-long class in undergrad). In particular, I’d be interested to know what level of resolution you think would be necessary to simulate a brain to actually get reasonable whole-brain emulations (for instance, is neuronal population level enough? Or do we need to look at individual neurons? Or even further, to look at local ion channel density on the membrane?)
Local ion channel density (i.e. active zones), plus the modification status of all those ion channels, plus the signalling status of all the presynaptic and postsynaptic modifiers (including NO and endocannabinoids).
You see, knowing the strength of all synapses for a particular neuron won’t tell you how that neuron will react to inputs. You also need temporal resolution: when a signal hits the synapse #3489, what will be the exact state of that synapse? The state determines how and when the signal will be passed on. And when the potential from that input goes down the dendritic tree and passes by the synapse #9871, which is receiving an input at that precise moment—well, how is it going to affect synapse #9871, and what is the state of synaps #9871 at that precise moment?
Depending on the answer to this question, stimulation of #3498 followed very soon after with stimulation of #9871 might produce an action potential—or it might not. And this is still oversimplifying things, but I hope you get the general idea.
You also need temporal resolution: when a signal hits the synapse #3489, what will be the exact state of that synapse? The state determines how and when the signal will be passed on. And when the potential from that input goes down the dendritic tree and passes by the synapse #9871, which is receiving an input at that precise moment—well, how is it going to affect synapse #9871, and what is the state of synaps #9871 at that precise moment?
How much of this do we actually need in practice? Humans can be put in states where there’s almost no brain activity, such as an induced coma, and brought out of it with no damage. That suggests that things like the precise state of #9871 at that moment shouldn’t matter that much.
All of it! Coma is not a state where temporal resolution is lost!
You can silence or deactivate neurons in thousands of ways, by altering one or more signaling pathways within the cells, or by blocking a certain channel. The signaling slows down, but it doesn’t stop. Stop it, and you kill the cell within a few minutes; and even if you restart things, signaling no longer works the way it did before.
So even in something like the Milwaukee protocol there’s still ongoing activity in every neuron? So what is different between human neurons and say those of C. elegans? They can survive substantial reductions in temperature with neuronal activity intact. Even bringing them down to liquid nitrogen temperatures leaves a large fraction surviving and that’s true if they are cooled slowly or quickly. What am I missing here?
In Milwaukee protocol, you are giving people ketamine and some benzo to silence brain activity. Ketamine inhibits NMDA channels—which means that presynaptic neurons can still fire, but the signal won’t be fully received. Benzos make GABA receptors more sensitive to GABA—so they don’t do anything unless GABAergic neurons are still firing normally.
In essence, this tunes down excitatory signals, while tuning up the inhibitory signals. It doesn’t actually stop either, and it certainly doesn’t interfere with the signalling processes within the cell.
You are mixing three different processes here. First is cooling down. Cooling down is not the same as freezing. There are examples of people who went into deep hypothermia, and were revived even after not breathing for tens of minutes, with little to no brain damage. If the plan was to cool down human brains and then bring them back within a few hours (or maybe even days), I would put that into “possible” category.
Second is freezing. Some human neurons could survive freezing, if properly cultured. Many C. elegans neurons do not survive very deep freezing. It depends on the type of neuron and its processes. Many of your ganglionic neurons might survive freezing. Large spiny neurons, or spindle cells? Completely different story.
The third is freezing plus cryoprotectants. You need cryoprotectants, otherwise you destroy most cells, and especially most fine structures. But then you get membrane distortions and solvent replacement, and everything I’ve been talking about in other posts.
Thanks for the response. Do you think it is important to explicitly consider the tertiary structure of proteins along the membrane, or can we keep track of coarser things such as for instance whether or not a given NMDA channel is magnesium-blocked or not?
EDIT: Also, you mentioned optogenetics at some point. Do you work with Ed Boyden by any chance?
We are deep into guessing territory here, but I would think that coarser option (magnesium, phosphorylation states, other modifications, and presence and binding status of other cofactors, especially GTPases) would be sufficient. Certainly for a simulated upload.
No, I don’t work with Ed. I don’t use optogenetics in my work, although I plan to in not too distant future.
Fascinating. I’ve been waiting for a while for a well-educated neuroscientist to come here, as I think there are a lot of interesting questions that hinge on issues in neuroscience that are at least hard for me to answer (my only exposure to it is a semester-long class in undergrad). In particular, I’d be interested to know what level of resolution you think would be necessary to simulate a brain to actually get reasonable whole-brain emulations (for instance, is neuronal population level enough? Or do we need to look at individual neurons? Or even further, to look at local ion channel density on the membrane?)
Local ion channel density (i.e. active zones), plus the modification status of all those ion channels, plus the signalling status of all the presynaptic and postsynaptic modifiers (including NO and endocannabinoids).
You see, knowing the strength of all synapses for a particular neuron won’t tell you how that neuron will react to inputs. You also need temporal resolution: when a signal hits the synapse #3489, what will be the exact state of that synapse? The state determines how and when the signal will be passed on. And when the potential from that input goes down the dendritic tree and passes by the synapse #9871, which is receiving an input at that precise moment—well, how is it going to affect synapse #9871, and what is the state of synaps #9871 at that precise moment?
Depending on the answer to this question, stimulation of #3498 followed very soon after with stimulation of #9871 might produce an action potential—or it might not. And this is still oversimplifying things, but I hope you get the general idea.
How much of this do we actually need in practice? Humans can be put in states where there’s almost no brain activity, such as an induced coma, and brought out of it with no damage. That suggests that things like the precise state of #9871 at that moment shouldn’t matter that much.
All of it! Coma is not a state where temporal resolution is lost!
You can silence or deactivate neurons in thousands of ways, by altering one or more signaling pathways within the cells, or by blocking a certain channel. The signaling slows down, but it doesn’t stop. Stop it, and you kill the cell within a few minutes; and even if you restart things, signaling no longer works the way it did before.
So even in something like the Milwaukee protocol there’s still ongoing activity in every neuron? So what is different between human neurons and say those of C. elegans? They can survive substantial reductions in temperature with neuronal activity intact. Even bringing them down to liquid nitrogen temperatures leaves a large fraction surviving and that’s true if they are cooled slowly or quickly. What am I missing here?
In order, and briefly:
In Milwaukee protocol, you are giving people ketamine and some benzo to silence brain activity. Ketamine inhibits NMDA channels—which means that presynaptic neurons can still fire, but the signal won’t be fully received. Benzos make GABA receptors more sensitive to GABA—so they don’t do anything unless GABAergic neurons are still firing normally.
In essence, this tunes down excitatory signals, while tuning up the inhibitory signals. It doesn’t actually stop either, and it certainly doesn’t interfere with the signalling processes within the cell.
You are mixing three different processes here. First is cooling down. Cooling down is not the same as freezing. There are examples of people who went into deep hypothermia, and were revived even after not breathing for tens of minutes, with little to no brain damage. If the plan was to cool down human brains and then bring them back within a few hours (or maybe even days), I would put that into “possible” category.
Second is freezing. Some human neurons could survive freezing, if properly cultured. Many C. elegans neurons do not survive very deep freezing. It depends on the type of neuron and its processes. Many of your ganglionic neurons might survive freezing. Large spiny neurons, or spindle cells? Completely different story.
The third is freezing plus cryoprotectants. You need cryoprotectants, otherwise you destroy most cells, and especially most fine structures. But then you get membrane distortions and solvent replacement, and everything I’ve been talking about in other posts.
Thanks. This comment and your other comments have made me substantially reduce my confidence in some form of cryonics working.
Thanks for the response. Do you think it is important to explicitly consider the tertiary structure of proteins along the membrane, or can we keep track of coarser things such as for instance whether or not a given NMDA channel is magnesium-blocked or not?
EDIT: Also, you mentioned optogenetics at some point. Do you work with Ed Boyden by any chance?
We are deep into guessing territory here, but I would think that coarser option (magnesium, phosphorylation states, other modifications, and presence and binding status of other cofactors, especially GTPases) would be sufficient. Certainly for a simulated upload.
No, I don’t work with Ed. I don’t use optogenetics in my work, although I plan to in not too distant future.