[extropy-chat] Reply to Anders re Cryonics is the only option?

[Brett Paatsch]

From: "Anders Sandberg" <asa at nada.kth.se>

Brett Paatsch wrote:

>> .. Would you classify yourself as a believer in cryonics?
>
> I think that cryonic suspension does preserve synaptic structure
> (when done right and fast enough) and that the frozen brain contains
> enough information that it could in principle be reconstructed. Given
> that the information loss is not total, that subcellular scanning appears
> physically feasible and a result of many development paths and that 
> there is a finite chance that a stored brain could end up in a future
> where such scanning methods are present, I think that there is a 
> chance that at least some of current cryonics patients will end up
> uploaded.
> 
> Does that make me a cryonics believer in your eyes?


In my eyes, very probably.  

In your first sentence above you didn't use the word believe or belief,
you used "think" implying actual reckoning. And I think your are sort
of reckoning, (but largely intuiting), however I am almost certain that
you haven't seen for a fact that "cryonic suspension preserves synaptic
structures when done right and fast enough" because I am almost 
certain that the requisite experiments and technology that would allow
you to validly hold that view, without allowing wishful thinking to sway
you allocation of probabilities the unknowns, don't exist yet. 

I think you are doing a very typical human thing. I think that when you
are confronted by a complex matter with many aspects/variables in it
you are allocating a higher probability to those aspects/variables/unknowns
that accord with your desires than is objectively warranted. 

I think that if you and I continue to talk about this that I will undermine
your faith/confidence in cryonics.  But that remains to be seen ;-) 

> While I defend a lot of reconstruction methods below, my heart is
> more in analysing scanning and emulation methods.
>
> > On what basis do you think machine phase chemistry is
> >"definitely" thermodynamically credible?
>
> > I'm assuming you are aware of Smalleys fat and sticky fingers 
> > criticisms of Drexler. Life molecules like proteins assemble in
> > compartments containing water.  Machine phase chemistry as
> > I understand it is essentially watery-solution free chemistry.  
> > Without a watery solution how do you see machine phase 
> > chemistry managing the folding of proteins?

> You can always build hybrids. One simple model would be to assemble
> proteins in a watery environment and then transfer them to a machine phase
> environment (with water around them, if needed) for assembly if you are
> (say) restoring a frozen brain.

I would like to see you develop this line of thinking but do it within a controlled
way where you can't handwave away known scientific facts mostly facts about
cell structure, function, size and shape that I confront you with. (ie. In the other
thread).  You may use any creativity you can get from anyone else but I propose
to discuss this only with you because I won't have time to deal with all the 
true believers. You have not yet lost my trust unfortunately Robert who is 
knowledgeable and whom I like has. So you can use any of Roberts arguments
or references you like, but because I have to manage my time as a limited 
resource I ask that you only use stuff that Robert or others give you that you
understand well enough to endorse as coming from you. 

> Smalleys fat and sticky fingers criticism seems to be disproven by DNA
> repair enzymes, and they are working in a liquid environment. 

My view would be that (and Smalley recognized that) the liquid environment 
is a very special case where every water molecule acts like a finger. Water
is the only molecule that acts like water at physiological (ie. living metabolising
cell) temperatures.  Outside of physiological temperature (say roughly 45C to
40C in mammals like humans) water molecules don't even behave like water
molecules anymore, that is outside of the narrow temperature range, the 
special small and sticky finger capacities of water molecules are no longer
able to handle the biomolecules in the necessary ways.  

> Even if general atomic assembly is impossible or too inefficient it 
> is clearly possible to make more specialized forms of moiety assembly,
> it would just make the systems messier and less easy to do armchair
> design of.

>>> Given that frozen cells can be thawed with viability intact,
>>
> >I've frozen and thawed cells. Have you?

> No. But if you are referring to the fact that quite a lot of the cells die
> in the process, I don't consider that to be any form of counterargument to
> my previous argument. I was merely showing that there existed a method
> that had a high likeliehood of assembling a viable cell if implemented,
> not the best possible such method.


I do grant there exists a method whereby there is a high likelihood of frozen
(to -170c) cells (not organs, not tissues) surviving on thawing. 

When I took mouse ES cells to -170C I did it in two stages, taking them to
first -70C for 24 hours - for the moment I can't recall why something to do
with DMSO - I'll have to check, but I'm pretty sure that taking them straight
to -170C, would have disrupted their plasma membranes and killed them. 

> > It is important to get that the brain is an organ of a multicellular
> > life form. It grows as a result of the actions of cells but it isn't
> > just a big lump of cells. I  know you know that as a neuroscience 
> > guy but I don't know how well you know that and I don't
> > accept expertise on the part of others until I see evidence of it.
> 
> Well, you can always call me a theoretical neuroscientist. I know about
> the brain structure, but the closest I get is looking over the shoulders
> of experimenters doing rat brain slice work.


Okay. Theoretical neuroscientist it is. 

> Brain tissue is terribly complex and labyrinthine, and I think standard
> cryo suspensions do nasty things to it. That is why I'm not so much of a
> believer of bodily cryonic revival but rather in uploading - I can see how
> that could in principle be done, and it is even possible to get down to
> gritty details already to callibrate our predictions. 

>(actually, I really ought to be working on that paper right now)


I can imagine Eugen and Robert nodding furiously. But we each have to
prioritize as we see best.  

[snip]


> > Though we can grow cells in quantity in E.coli, 

[or yeast might have been a better example for me to have used]

>> we can't build as
> > opposed to growing just a single frozen cell. A growing cell can 
> > preserve the  integrity of mitochondrial membranes. You can't do
> > that working from the outside to built the membrane.


> Hmm, suppose you were putting down phospholipids in a matrix
> of vitrified water, starting from the bottom and adding layer after
> layer. Why couldn't you just print the inner membrane? 

Here's where we should switch over to the other thread. 

Its a three dimensional container, that can't leak in any dimension at
physiological conditions because its got to keep its inside separate
from its outside for the ATP pumps etc to work just to give one of many
reasons. The membrane proteins embedded in it mean that it wouldn't
be smooth like a sphere even at the scale of a couple of nanometres
it would be rough with the embedded proteins. 

I'm not sure what picture you have in you minds eye but the picture
I image *you* have involves an extruding device laying down molecules
of water and other molecules onto a grid that represents planes in
a 3D volume.  Is that right?

I mean do you think that individual water molecules are going to drop
or be fired out of the extruding device as if they were little frozen
lego blocks made of one oxygen between two hydrogens so that you
could place precisely each individual water molecule and also place
each individual hydrogen ion so you have the difference in concentration
of hydrogen ions on the inside and the outside. 

Is that essentially what you are thinking?

[Aside:  What I want you to do for the purpose of our discussion/exploration
is visualise the brain as a volume (1450 ml) containing matter that can be 
arbitrarily broken down into smaller cubic volumes. (other thread - then I
can impose cell physiologic facts into those volumes showing you the 
scales of whatever we are talking about).  This will get rid of a lot of the
handwaving I suspect.]

> It would
> be just like the 3d printing of the nested spheres in the middle of
> this page: http://www.georgehart.com/rp/rp.html


I looked but I can't see it what you mean. Could be I can see coz
I don't get it but I think its I cant see because I have a different
picture/representation of what a mitochondrial membrane looks like
at the nanoscale than you do. 

> > We can produce in vitro cell free systems to do research on. 
> > We can create liposomes - lipid enclosed spheres that aren't
> > cells. But we can't create a living cell as a manufacturing process.
>
> No, not yet. But unless you believe in vitalism, you would agree 
> that iF *somehow* the molecules making up a cell were just 
> placed in the right pattern it would become a living cell, right?

If *somehow* then yes.   I'm not a believer in vitalism. I'm a hard
core materialist. 

> Now it is just up to us arguing that it can be done to show that
> it is possible to achieve this using a physical system, and for
> the people arguing that it is likely to be done to show why
> such a system is likely.


Well that would be a first step to pursuading me sure. But we
need to proceed with some discipline.   

> > At this stage, we, science, don't know how for instance the first cell
> > that  was the progenitor of all life on earth formed. Not exactly. 
> > We don't even  know that much in principle yet.
> 
> Or even that it was a cell. 

Right.  Not a cell as we know cells today. 

>I'm pretty convinced that it was more akin to a ribozyme.


It can't have been just a ribozyme. The replicative machinery needed to 
be constrained in space to concentrate its raw materials for self 
assembly. Membranes with "filters" play a vital role in helping to
concentrate raw input materials. There have to be enough molecules
of substrate around that the enzyme can encounter them as they hit
it through brownian motion fast enough.     

> >>  Cells are pretty robust (otherwise they wouldn't survive, and
> >> temperature changes and thermal noise would instantly kill them), so you
>> > only need to get close enough to the attractor state(s) that correspond
>> > to
>> > a working cell to get it to spontaneously do the final pieces of
>> > selforganisation.
>> 
> > "only"   "attractor state(s) that correspond to a working cell" :-)
> >
> > So talk to me like a cell biologist. Tell me your protocol or point me to
> > a peer reviewed paper.
> >
> > "attractor state(s) that correspond to a working cell" sounds like
> > believer psuedo-explanation handwaving to me.

> I am a computational biologist. At best I can explain my thinking
> and results to you, but I dont do "protocols" and attractor states 
> are my bread and butter.


Okay.  Lets not get hung up on the word protocol. If you can outline
a series of steps each one of which makes sense and is intelligible
in its own right taking us from state a to f through b c d and e then
thats good enough for me in terms of you being able to "do" a 
protocol for our purposes. 

I've offered you a model (other thread, brain as volume containing
matter) into which you can propose a series of steps either for
scanning or for rebuilding the brain. I'm more interested in the
rebuilding side myself but both are problematic for cryonics. 

> A bilayer is an attractor state in the configuration space of phospholipid
> molecules in water (e.g. see S.J. Marrink, E. Lindahl, O. Edholm, and A.
> Mark. Simulation of the spontaneous aggregation of phospholipids into
> bilayers. J. Am. Chem. Soc., 123:8638-8639, 2001. )


Okay.  You found a paper and built trust. Thanks I looked at it.  I still don't
know what the words attractor state means exactly but it probably doesn't
matter I can find out if I need to to understand you if its important.

But for our purposes a flat bilayer in a plane like say fat might form on top of
a sink full of water isn't enough the bilayer of an organelle or a plasma 
membrane or even vesciles are all three dimensional bilayers like balloons
with insides and outsides. Its this capacity to keep whats inside separate 
from whats outside so there can be concentration differences etc that is 
critical to cellular life and cell function. Break the 3D integrity when the 
cellular machinery is doing its thing and your concentrations are gone and
your cell dies.  

> Membrane biophysics is not my field, but I'm pretty certain there are
> characterizations of how far lipids can be displaced before the structure
> breaks.  And I know there are molecular dynamics simulations of
> membranes (such as the one above) that would allow you to experiment
> with jittering their positions. So unless it has already been done, there is
> a nice paper in characterizing the probability of reforming properly from
>  different levels of positional (and rotational) uncertainty. In fact, one 
> could also try changing the simulation temperature to see if there is any 
> phase transitions or other troubles if one starts with a vitrified ice state
> and move up to physiological temperature (I'd love to do that paper if 
> I had the time, simulator and some more expertise).
> 
>
>  [In fact, given results such as the animation at the bottom of
> http://www.memphys.sdu.dk/~besold/research.html a more proper
> characterization would be: does this organisation happen fast enough to
> not cause significant leaks or topological defects of the membrane. ]


Cute animation. 

The issue though is spherical bilayers which can contain a volume within
a larger volume without leaking.  

> Locations of biomolecules is an interesting chapter. Given the rapid
> diffusion of most small molecules and proteins not bound to anything, they
> can essentially be put in the right compartment and they will extremely
> quickly spread out.

>  More care is needed for membrane-bound
> molecules that have to be placed on the right membranes and 
> macromolecular structures such as microtubuli.

They aren't placed on though they are embedded in. The amino acid
sequences of the proteins that are intended to be membrane proteins
itself interacts with translocation machinery of the cell (in liquid 
conditions) to place the proteins into the membrane. When cells (and
of course the tissues and organs made of them) are growing all this
protein trafficing into and through membranes can take place at 
physiological conditions with the water molecules acting as fingers.

> My guess is that it is
> the later that are going to be the most troublesome objects to 
> reconstruct. Again, if it has not been done yet it is not a terribly hard
> research project to characterize how much noise in position these
> structures can handle, and how quickly they relax into correct 
> (or incorrect) configurations.

I'm only tangentially interested in the attractor state stuff your are
talking about. 

So long as we are clear we are talking about 3D volumes not flat
bilayers like the ones in your links. 

> Cells are stable to thermal noise and other minor distortions due
> to e.g. mild sound waves. Most of this I would expect is because
> of the bilayers. 

> To me it makes sense to regard a living cell as a 
> particular set of points in the configuration space of all its molecules.

Whatever floats your boat. But please consider it in the context of the
brain volume of 1450 ml in the other thread. 

> We know small deviations from this set like an indentation of the
> membrane will relax away, so it is an attracting set. What needs to
> be characterized is the distance to the boundaries of the basin of 
> attraction for this set: if an intervention or recreation manages to 
> stay within that distance from the "true" cell it will converge back
> to the proper state.


> > You say that as though you have done it. But you haven't actually
> > done it have you. Had you done it you'd have had a lead paper 
> > in Science and  Nature.
>
> Them's fighting words. Let's race you to the cover? :-)

:--)

Recognizing that you haven't done it doesn't mean that I think I can.

But who knows maybe we'll amble in that direction together. 

> >  That sort of handwaving is highly characteristic of  what 
> > transhumanists do when they prentend to actually discuss
> > technology. It works to give the illusion of knowledge without
> > demonstrating any. It poo poos whats necessary to be done
> > without either demonstrating that it has been done and without 
> > giving a protocol that demonstrates that it can be done even in
> > principle.

> Have you seen Nick Szabo's essay on falsifiable designs?
> http://unenumerated.blogspot.com/2007/02/falsifiable-design-methodology-for.html
> I think he has a good idea for an antidote.


I hadn't. I just skimmed the first bit then. At present I'm not feeling the
need for assistance in falsifying designs. I'm feeling I can falsify other
people unsound designs already. Maybe later. I wouldn't agree that
Drexler and Kurzweil are "widely esteemed scientists and engineers" 
though.  I certainly don't widely esteem them as such and transhumanists
are the only folk that I know of that do.

I do esteem them both as creative and intelligent individuals.   

>>> To have a realistic chance of doing it right you first need to have
>>>  scanned a cell,
>
> > With current technology, cryo EM one can't scan a single cell. You
> > scan lots of them and get an aggregated averaged out picture. 
> > Fair warning handwaving about future technology will prompt me to
> > want to see what you know about the relevant small scale physics.


Actually, I mispoke there. You wouldn't scan a whole several micron scale
cell with cryo EM its used for much smaller structures.  

> I think cryo EM is changing quite rapidly, and given some of the
> references I'm adding to my paper it seems that making pretty good 3D
> models of single cells is within the near future. The biggest problem is
> that EM cannot distinguish protein types, and that is of course what we
> really want. Would you think Raman spectroscopy would enable that?

"within the near future" :-)  

I think cryo EM is only about 5 years or so old I'm not an expert I only just
started learning about it recently. We had to review a Nature paper from 
November 2006 that made use of it in a third year subject called molecular
aspects of cell biology I'm currently doing. 

You switch from talking about cryo EM to EM. With traditional EM the sample
is fixed. With cryo EM its in solution so the protein or particle (rnas may be
part of it) can still have close to its natural shape rather than being squashed
flat. cryo EM helps seen the shape of cellular machinery made of proteins and
rnas like translocons and signal recognition particles bound to nascent chains
on ribosomes etc.

Do I think Raman spectroscopy would enable the distinguishing of protein 
types? Not on the surface of whole cells, whole cells are too large. 

If your testing my knowledge of Raman spectrosopy I don't have much. 
I can get it if I need it but I don't need it right now, not yet, for my current 
purpose.  

I try to be a hardcore rationalist. This means I don't have to know everything
but I have to know what I know and what I don't.  

I am not an expert in cell biology, I'm a student. But even as a student
its my conviction that I already know enough cell biology to know that cryonics
can't work which is really the point of this discussion whether or not I am 
an expert in anything is irrelevant. 

>> picking it apart molecule by molecule and recording the locations and
>> type. If that can be done piling them together seems to be equally hard.
>
>
> I disagree. I think it is much much harder. I even think it is impossible.
> Because you have to get your manufacturing fingers around the cell
> clusters whilst the cells in the centre of the cluster have to be at the
> right temperature to act like  cells and bind to the other cells.

> My assumption was -170 C. It seems that your view is that cells at this
> temperature do not correspond to viable cells at all?


Yes. That is my view.  In order to take cells down to - 170 you take them
down to say - 70 for 24 hours or so first. You can't just plung them into
 - 170. 

You can do that slow stepped freezing with cells that are just cells, like
the mouse ES cells I've worked with (or pretty much any cells, that aren't
still in tissue form) because they have a small surface to volume ratio. 

> Your brain and mine would at one level be variations on the theme of homo
> sapiens male brains. But what makes me me and you you is in the
> nanoscale details. Knowing how to build Bretts brain as a manufacturing
> process wouldn't give you an algorithm for building an Anders brain. At
> the nanoscale where the synapse make their connections our individual 
> brains would be too different.
>
> Sure. The differences are actually far larger than nanoscale, you can see
> different folding patterns even in twin brains.

They are ALSO far larger than nanoscale, but that they are different at the big
scales is really beside the point. The point is that they are different at the small
scales where memories are made. In the 1450 ml volume of your brain and
my brain are lots of 50 nm cubic volumes. Our brains differ to the 50 nm scale
from each others and from what they would have been if our respective
genomes had developed and grown us in different enviroments so that we
had different experiences and learned different things. Our neural nets are
what they are in part because of our experience. To recreate the structure
we need to go down to the 50 nm scale where the smallest parts of cells
reach out and touch other cells to make new connections like memories.

>> Maybe it would be worthwhile doing a careful critique of nanoscale
>> dissassemblers?
>>
> >Biological or theoretical?  What nanoscale dissassemblers are you
>> talking about?
>
> Theoretical. Since many of the wilder projects discussed here tend
> to be based on the assumption that they can work, clearly analysing
> the underlying assumptions and constraints would help constrain the
> handwaving.


Indeed. 

> > That I think is ultimately what transhumanism is. Its not the 
> > successor to humanism its a cultural support system for cryonicists
> > and technological  religious types that can't find salvation in the normal
> > religions. Thats why  transhumanism doesn't produce anything except
> > writers and entertainers - although individual transhumanists do 
> > produce some things those things are in their capacities as people
> > not as transhumanists.

>
>  That is an interesting criticism. And one that I actually agree with to
> some extent. However, I'm much more hopeful about the usefulness of
> transhumanism.

Clearly. 

>> The wheels came off the transhumanist movement when transhumanists
>> did not take a strong enough stand when US political conservatives
>> turned into religious regressives.

> Actually, that might have been the breakthrough. Because it made 
> bioethicists much more transhumanist, and that will make a major 
> change in policy and funding in the long run.


No, I completely reject that silver lining interpretation. But that's another
topic. Arguably a more important topic, but I want to have that
conversation with others, because I want to have this one with you.  

>
>> That a lot of entropy is being pushed around (making unordered atoms
>> into an ordered cell) adds a bit to the heat problem, but can still be
>> managed by slowing things down or dividing the workpieces so that 
> >radiating the entropy into the environment is easy.
>
> No offense Anders but conversation needs a lot more credibility
> established before we can do the handwavey stuff.

> Excuse me, but where is the handwaving *here*?  You might slap 
> my fingers on cell biology, but it seems pretty strange that you find
> *these* statements handwaving.

My bad. 

When I post to Exi-chat on cryonics I expect to be beset by true
believers right and left and so I feel like I have to make very clear that
I am not going to waste my time or mince words.

You are perfectly right to call me on handwaving when you think I
am. 

>> > That molecules are dancing around isn't an enormous problem at -170,
>> > since the cryonic brain is essentially a crystal lattice with thermal
>> > vibrations are on the order of 0.01 nm.
>> 
>> The resolution of electron microscopes are about 2 nanometres from
>> memory perhaps 0.2. Its not the state of the brain when frozen as a block of
> >tissue thats the (or rather a) problem its that each brain is so massively unique
> >in its arborial structures to very low resolutions. Lipid bilayers are only
> > around 6 nanometres thick and if the bilayers are breached the ions leak and the
> > organelle will not work. You have to be able to manufacture to place your
> > lipids to that degree of precision whilst keeping the heat out that would
> > change the chemistry of the lipids. It can't be done not.

> Hmm, and why shouldn't I start to accuse you of handwaving and asking
> you to refer to peer reviewed papers here? 

You could, that would be fair enough. 

But scientists are hardly climbing over themselves to critique cryonics most
of them dismiss it out of hand. 

I'm giving you a shot at making a case for it and of making a convert that
would have the skills to make lots of other converts. But there is risk in
this for you because I may end up depriving you or a belief that you
would prefer not to be deprived of.  

Brett Paatsch

PS : I sent an attachment to the list but it seems folk don't want that
if you haven't got it and you want to pursue this then let me know
and I'll put it on a web site. 
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