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Persistence of Long-Term Memory in Vitrified and Revived C. elegans worms (liebertpub.com)
89 points by gwern on May 23, 2015 | hide | past | web | favorite | 40 comments



Cryonics is the low-temperature preservation of the deceased in order to grant them a chance at a renewed life when technologies for restoration are developed. One of the big outstanding questions is the degree to which a well-conducted cryopreservation successfully preserves the fine structure of the brain and thus the data of the mind. The fact that cold water drowning victims can live again after an hour or more of brain death tells us that memory is encoded in physical structures, with the current consensus (not undisputed) suggesting it is located in synaptic connections between neurons.

Scanning technologies have been used to show that cryopreservation via vitrification of cryoprotectant-infused tissue does indeed preserve the fine structure of brain cell connections. E.g.:

http://www.brainpreservation.org/content/competitors

So it seems reasonable to move forward with initiatives based on the theory that yes, cryonics is going to preserve the mind. Certainly all too many people are left with no other viable option for a shot at a longer life in the future. There is always the need for more and better proof, however. At the present time studies involving restoration of vitrified individuals must be carried out in lower animals, unfortunately, as researchers are still far from the point at which they can safely restore vitrified mammals. That said, restoration of a vitrified mammalian organs has been demonstrated, though even that is very early stage work in the grand scheme of things.


> cold water drowning victims can live again after an hour or more of brain death

They don't reach brain death. The cold causes a drop in the oxygen requirements, but the brain keeps on living.


Indeed. If by "brain death" you mean "massive ischemic damage", then cryopreservation under good circumstances also takes place before brain death.


Take this with a huge block of salt.

This PDF is of a paper recently accepted by an unremarkable journal. Further, the research is sponsored by a company that performs cryonics. If this is true, it may be exciting but we should wait for others to replicate these findings.


I don't see why we should be skeptical. It seems to lack the usual warning signs like small samples or questionable statistics, and, for all the skepticism most laymen have ('but how do we know vitrification does preserve memory even if it preserves everything else?!') this is what one should have expected, if only from related instances like comas and drownings - whatever memory is physically encoded as, exactly, it's clearly not ultra-evanescent.


I think there are a few causes for concern regarding this paper:

1. Rejuvenation Research isn't a widely-recognized biology journal. If this is the first time memories have been recovered from a cryopreserved organism, this should be in a top journal as it's great news.

2. The article was accepted on the day it was received[ref 1]. This doesn't inspire confidence in the strength of the associated peer review as such minimal review is unusual in biology. Indeed, the average review time for the journal is about 4 weeks[ref 2] (which itself is a short time).

3. This is pretty concerning - the key protocol used in the paper hasn't been published (see reference 14 in the PDF). While it's described in passing in this paper, there's no way to assess the full protocol.

4. There's a juxtaposition between the authors' new technique and an established protocol for freezing C. elegans. However, the authors only freeze C. elegans for 30 minutes in their protocol whereas they freeze organisms in the established protocol testing group for 2 weeks. There seem to be appropriate controls but this difference in protocol is stated very unclearly.

References

1. http://online.liebertpub.com/doi/10.1089/rej.2014.1636

2. http://www.liebertpub.com/DContent/Files/FastFacts/FastFacts...


> If this is the first time memories have been recovered from a cryopreserved organism, this should be in a top journal as it's great news.

Cryonics related research never gets published in top journals no matter its quality, so this is what you would expect. There is a long-standing war by cryobiologists on anything to do with cryonics - the old canards like the exploding lysosomes o' death may have been refuted but last I heard, they were still explicitly banning from membership any cryonicists.

> 2. The article was accepted on the day it was received[ref 1].

Look up the journal policies and note the dates: it was posted the day it was received, as part of Liebert Instant Online/LION http://www.liebertpub.com/forauthors/rejuvenation-research/1... but that doesn't mean it was reviewed or accepted in a day:

> To enable the release of new scientific findings as quickly as possible, the Journal has a policy of pre-publishing all manuscripts in their unedited format upon acceptance. The papers will have undergone full peer review but will not yet have been copyedited, typeset, or proofread/corrected by the authors. All accepted papers appear online within 72 hours of acceptance as a part of Liebert Instant Online (LION).

Given the editing gap is at least October 2014 - April 2015...

> 3. This is pretty concerning - the key protocol used in the paper hasn't been published

Reference 14 is to the SafeSpeed cryopreservation protocol, not to vitrification in general. They also tested out traditional vitrification. If you distrust SafeSpeed, you can throw out that entire part of the paper and the results are exactly the same: preservation of olfactory memory. (This was covered on pg3, I don't know how you missed it if you could look up the reference number...)

> However, the authors only freeze C. elegans for 30 minutes in their protocol whereas they freeze organisms in the established protocol testing group for 2 weeks.

? The 30 minutes refers to the traditional vitrification itself (this is why it's 'slow') where they're immersed in Ln2, but then they were all stored in some more regular freezers at -80 celsius (much warmer than LN2) for several weeks (pg11-12).


> Cryonics related research never gets published in top journals no matter its quality, so this is what you would expect.

In this case it's Aubrey de Grey's own journal, which is getting just a bit incestuous.

Unreviewed or barely-reviewed papers are common these days (e.g. arXiv); this paper's peer review really just isn't up to the peer review standards expected in biology, but that doesn't mean it isn't an interesting result in any case. I'm very glad someone did in fact do this obvious experiment at last.


Wrong! I don't mean to nit-pick, but why are you posting all this inaccurate information? It took several months for blind review of this paper by highly acknowledged scientists. And Rejuvenation Research is a valued scientific research journal. Please ask people directly who are involved with this work before making wrong statements.


> There is a long-standing war by cryobiologists on anything to do with cryonics - the old canards like the exploding lysosomes o' death may have been refuted but last I heard, they were still explicitly banning from membership any cryonicists

I'm not sure what to say here - politics definitely plays into biology publication but there are multiple well-respected journals to send 'small results', of which I don't believe Rejuvenation Research is one.

> Look up the journal policies and note the dates

I did exactly this. Unless Rejuvenation Research has an unusual application of the terms 'Received' and 'Accepted' (see ref. 1), I'm more inclined to believe the information on the article page than a general journal policy.

Weirdly enough, all the articles in the most recently published edition of Rejuvenation Research (http://online.liebertpub.com/toc/rej/18/2) had at least some gap between receipt and acceptance. I'm even more inclined to think something unusual has started to happen with the current batch of online-before-publication papers. This could, of course, be a bug with the journal's content management system.

> Reference 14 is to the SafeSpeed cryopreservation protocol

Publishing a reference to an non-peer-reviewed protocol is unusual, irrespective of the details. This is even more unusual when the protocol forms the core of the paper.

To be a bit more precise (using details from the paper):

Vitrification and slow-freezing are distinct methodologies for preserving specimen. The authors only use two methodologies for preservation, which they explain in the methods section:

    The cryopreservation methods included worms that were trained and cryopreserved by vitrification and worms that were trained and cryopreserved by slow freezing
> If you distrust SafeSpeed, you can throw out that entire part of the paper and the results are exactly the same: preservation of olfactory memory

I think this is part of why my original comment said we should wait for replication and be skeptical. Trust in science is a difficult thing to gain and an easy thing to lose. The choice of journal and the very-unclear description of the cryopreservation protocols make me a bit more skeptical of the results.

The SafeSpeed protocol seems to be under review at Nature Methods. If it's accepted there, the authors will likely need to supply supporting data which will only bolster the claims they made here.

Further, the slow-freezing result is a fairly cheap one to replicate; we're likely to see many people try it and they'll likely cite Alcor's work.

> The 30 minutes refers to the traditional vitrification itself

I think the authors were intentionally vague in comparing the two preservation methods, especially given how clear the rest of the report is.

First, note that only one vitrification technique was used, SafeSpeed. Additionally, only one slow-freezing technique was used, a standard approach that one of your sibling commenters references in passing.

The SafeSpeed-vitrified animals were stored in liquid nitrogen (LN2) for 30 minutes and then recovered. This is stated (unclearly) in the methods section (pg 8) and alluded to in the discussion.

> 30 minutes refers to the traditional vitrification itself (this is why it's 'slow')

This is counter to what the authors state - they explain that the SafeSpeed method is actually slower than 'slow-freezing'. See page 11.

Conclusion

I think that this will be exciting if SafeSpeed gets published somewhere more reputable. As you alluded to earlier, if there is a physical correlate to benzaldehyde training that isn't damaged upon freezing, we'd definitely expect it to be recovered after freezing.

This paper just isn't compelling enough to say that we've seen this occur definitively.

References

1. http://online.liebertpub.com/doi/10.1089/rej.2014.1636

    'Received' usually indicates receipt of a manuscript;
    'Accepted' usually indicates the end of scientific edits.
    Often, articles are held up (i.e., not published online) to coordinate 
    publishing with other labs/projects within a lab.


> I'm not sure what to say here - politics definitely plays into biology publication

This is well beyond regular scientific politics; the attacks are now older than a lot of people working in the field. I don't know why you would expect random journals to be unaffected (where do you get cryobiologist reviewers who are unaffected or fearless?).

> I'm more inclined to believe the information on the article page than a general journal policy.

The journal policy which explains what the dates mean?

> Weirdly enough, all the articles in the most recently published edition of Rejuvenation Research (http://online.liebertpub.com/toc/rej/18/2) had at least some gap between receipt and acceptance.

So are you even objecting to anything besides a software bug?

> The authors only use two methodologies for preservation, which they explain in the methods section:

I don't understand your objection here. OK, so one protocol is still upcoming. I don't think this is that unusual since I see plenty of references to publications in press in papers I read - econ papers spend years as preprints, I regularly comment on drafts, fast moving areas often do this, work which has been turned into multiple publications does this all the time because different journals move at different rates etc. I don't think this is a big problem but even if it was, they also tested out the standard well-understood procedure you cannot possibly have any objection to, so what's with this 'only' business? That's the method one wants them to test - and they did. And it worked the same for preserving memories. Which is the point.

> Further, the slow-freezing result is a fairly cheap one to replicate; we're likely to see many people try it and they'll likely cite Alcor's work.

That seems unlikely. No one wants to go near cryonics for the political reasons I mentioned and there's no funding for it. I have been saying for at least 5 years now that I really hoped someone would run exactly this experiment with seeing if training survived, and it took that long for any study to be done - despite always being cheap to run. Sometimes being cheap to replicate doesn't matter.

> This is counter to what the authors state - they explain that the SafeSpeed method is actually slower than 'slow-freezing'. See page 11.

I don't see any such claim. I think you are again confusing different stages of storage and revival.

> This paper just isn't compelling enough to say that we've seen this occur definitively.

I find it compelling. None of your arguments goes to the root, and most are tangential: it's not a prominent journal because of the very well known politics involved, the dates are due to quirks of the website or acceptance process, the new protocol is not well-described but seems to work as well as the older methods and the older methods suffice to prove the point, and some confusion about the details doesn't obviate the core claim either. The worms were trained, were frozen, were revived, and remembered. Which of your criticisms defeats this? This isn't some mushy social psychology paper with n=15 and the authors could have tried a thousand different analyses to pull out a p<0.05; the worms either remembered or they didn't, there's not many ways to slice the data.


I don't think we're going to agree on the quality of this paper, which is perfectly fine and a normal part of science.

Two things:

> I don't think this is that unusual since I see plenty of references to publications in press in papers I read - econ papers spend years as preprints

This isn't normal in biology. It's a stance that researchers are trying to change (see http://biorxiv.org/, notably), however.

> I don't see any such claim. I think you are again confusing different stages of storage and revival.

At a molecular level, the two processes may work differently (we don't, of course, have the SafeSpeed protocol). However, the article states:

"During this time, it is necessary to allow 30-45 minutes for vitrification processes, 15-30 minutes for slow freezing processes, and 24 hours for all processes to safely recover and verify the survival of the worms"


This paper was peer reviewed and it took many months for it to be published.


When I used to work with C elegans, whenever we would freeze the worms and try and recover them, we would be lucky to even get a few revived from thousands of worms. This result should also be made available in the paper.


Alcor is not a company, it's a nonprofit organization.


Non-profits are companies, too.


Not directly related, but it reminded me of this: http://everything2.com/title/The+ability+of+planarian+worms+...


well, today we can restore information - sound - from a photo of the gramophone recording media (https://mediapreservation.wordpress.com/2012/06/20/extractin...). Tomorrow - from a frozen brain.

So, i wonder, if i had enough money - may be instead of whole body or head cryonics, i should go for sub-micron thick slicing of my brain and making photo and various other wavelength scans of it and storing this digitized info somewhere (like Glacier :) Or may be i should just start a start-up offering just such a service to make money for my future cryonics :)


This is a good question. There's a lot of active research into chemical fixation and then doing brain scanning on thin slices to reconstruct the connectome and other features, with regular progress like "High-resolution whole-brain staining for electron microscopic circuit reconstruction", Mikula & Denk 2015 http://connectomes.org/pdf/mikula2015_.pdf . I have some more links in http://www.gwern.net/plastination

The upsides to chemical fixation or plastination is that you avoid issues with temporary interruptions in cooling (as far as we know, Alcor and CI have a nearly perfect record in maintaining LN2 coldness, but one could wonder how well that will work for the next century) since a fixated brain will be stable at room temperature, and you can have a much more quantifiable idea how much progress has been made in fixation and scanning through things like the BPF's prizes (http://www.brainpreservation.org/). So that makes this attractive.

The downside is that there is no infrastructure setup (there's no one you can go to and say "here's $10k, please wait by my bedside and as soon as I'm declared legally dead, dunk my head in osmium"), and the concerns about cryonics being too slow are magnified massively - people are worried about vitrification taking several hours and cryonics possibly being too late, but the current fixation solutions take more on the order of a month and don't necessarily fixate the entire brain volume. So you may get a great preservation which can be easily stored and imaged at high quality without any concerns about how to heat it back up... but what will you be imaging?

If I died tomorrow, I would go with regular cryonics hands-down no contest. But in 30 years? If Mikula, Hayworth, the BPF, Seung, etc keep on pushing forward this area, maybe then plastination will be equal or superior.


That would make brain perservation via digitalization a lot more viable. But just imaging the precise connection points and volume of neurons might not be enough if every cell's DNA is methylated in a slightly different way, i.e. depending on the memory is is part of not just the general brain region.

Then every neuron's DNA has to be specially sequenced to extract that information, and until such a technology can be applied to all the billions of neurons the brain has to be kept on ice.


I think you'd be a bit ahead of things trying scanning now given we don't really know how memories are stored. Quite likely as chemical changes which are going to be subtle to pick up. Also Glaicer's going to cost you - cheaper to chuck the head in the freezer.

If you're looking for a startup idea you could give plastination a go. It may also preserve memory information and gets around having to store liquid nitrogen and all that:

http://en.wikipedia.org/wiki/Body_Worlds


Frogs can do this too (and more in fact), so I wouldn't be surprised if it was true. That said it's a bit of a (ok, not such a bit) stretch to extrapolate from being able to freeze a worm which has absolutely minimal nervous tissue to how this finding will apply to the non-science of cryonics, though I can see why those with a stake in the game would want to make such connections as strongly as possible.

Not only are there differences in scale between frogs, worms and humans, there are also differences in complexity and structure.



The viability (or not) (and the incentives of different parties in) the field of cryonics was previously discussed here:

https://news.ycombinator.com/item?id=8241374


Cryonics is fascinating because it's the closest thing to a technological religion so far. (Scientology does not count, it's more like a pulp sci-fi religion.)

St. Paul eloquently described the upcoming Singularity and the raising of the vitrified minds:

"Listen, I tell you a mystery: We will not all sleep, but we will all be changed -- in a flash, in the twinkling of an eye, at the last trumpet. For the trumpet will sound, the dead will be raised imperishable, and we will be changed."


I often hear the "cryonics is a religion" claim, but a closer examination refutes this. Unlike religions, cryonics is not exclusive. A person can practice Christianity or Islam and be signed up for cryo. Cryonics makes no claims about morality or politics. There's no dogma about how to live one's life, or the origins of the cosmos, or what happens to consciousness after the brain is destroyed.

The most important difference between cryonics and religions is that religious people are typically convinced of the afterlife. In contrast, cryonicists rarely assign high probability to being revived. Most think of it like an experimental cancer treatment: Unlikely to work, but better than the alternative.

And like experimental treatments, research is ongoing. Since cryonics organizations were first founded, there have been many improvements to preservation protocols. Modern cryopreservation methods allow a rabbit kidney to function after thawing, albeit with some damage.[1] This is very promising, as parts of the kidney have poor vasculature. Brains are much easier to saturate with cryoprotectants.

1. http://www.21cmpublications.com/PubFiles/11/12FahyORG5-3[1]....


I will eschew Wittgenstein's advice and take the bait- I don't think the techno-religion claim is too far off the mark. Of course, the entirety of our argument is over the definition of religion.

| Unlike religions, cryonics is not exclusive.

I think we'd both agree that exclusivity isn't the principle quality of religion, though many religions are exclusive.

Religions typically have some core set of beliefs - some of which may be untestable, ceremony, dress, and often attempt to explain the mysteries of the universe. I'd also throw in the quality that religions advocate their followers either do something they wouldn't otherwise do or abstain from something they would otherwise enjoy. Its possible some religion lacks proscriptions for life, but I certainly haven't met it.

Cyronics certainly has a core set of beliefs (faith!?) that lead to action. I very much doubt that even if we were to develop sufficient technology to unfreeze all those heads, future humans would do so. Perhaps we'd unfreeze some heads for science and then a few more for the novelty. We both agree cyronics is unlikely to work and that there is no way to run this experiment within our lifetime - cryonics requires faith (by any other name) in humanity and technology.

|In contrast, cryonicists rarely assign high probability to being revived. Most think of it like an experimental cancer treatment: Unlikely to work, but better than the alternative.

I know Christians that would describe their experience in similar terms.

| The most important difference between cryonics and religions is that religious people are typically convinced of the afterlife.

Christians believe in an afterlife, but not all religions do, or even weigh in on the matter - Judaism immediately comes to mind. Apropos, cryonics proposes its own cycle of rebirth! Well, possible rebirth until the great robot wars, the sun explodes, or the heat death of our local cluster.

As for the other attributes I mentioned - dress, ceremony, and the like, cryonics offers bracelets, (non)ceremonial decapitation with ensuing vitrification, and requires its devotees to die somewhere convenient! OK, I agree, this doesn't exactly fit the bill.

Precisely defining religion and faith is tricky. At the very least, I would say cyronics is uncomfortably close to a religion.


> Cyronics certainly has a core set of beliefs (faith!?) that lead to action.

You could describe basically every mundane activity as having a core set of beliefs that lead to action, but ok.

> I very much doubt that even if we were to develop sufficient technology to unfreeze all those heads, future humans would do so. Perhaps we'd unfreeze some heads for science and then a few more for the novelty.

Not reviving cryopreserved people is equivalent to leaving them to die... Unless you're counting on future society to be completely 100% morally bankrupt, I would bet on there being eventually at least one person with both enough of a conscience and enough money to fund the revival of people in suspended animation (as the cost of revival should decrease over time with advancing technology). Not that this really seems relevant to any connection to religion.

> Apropos, cryonics proposes its own cycle of rebirth! Well, possible rebirth until the great robot wars, the sun explodes, or the heat death of our local cluster.

FWIW, unlike religion, cryonics does not really claim you can come back from death. Legal death, yes, but legal death is merely a convenient criterion that captures "the point at which we give up on treating a person with current technology". If you set a cryonicist on fire and destroy their brain's information, they are permanently dead, just like anyone else.

(ETA: Since physics is reversible, destroying information is technically impossible, but capturing and calculating reversal of the trajectories of smoke, soot, air and photons back into a whole brain seems thermodynamically infeasible, even for a civilization with Big Angelic Powers.)


iirc physics is non-reversible. Something to do with entrophy and possibly quantum physics.


Quantum Physics is reversible; see http://en.wikipedia.org/wiki/Delayed_choice_quantum_eraser . (Warning: amateur, may be misunderstanding.) You do have to be able to capture the complete environment of the quantum process, which is why decoherence is usually considered one-way.


Upvoted because there's no point in denying that Singularity-related topics do often sound like things in the Bible. But that's only because it stems from the basic human needs - we'd like to not die, not get sick, and to get our deceased friends and family back.

The difference between cryonics and resurrection is, however, fundamental, and we've been through similar processes many times. It used to be that only birds and angels could fly. Then we figured out how to do it ourselves.


Dictionary.com has religion as "a set of beliefs concerning the cause, nature, and purpose of the universe..."

I'm not sure cryo-preserving someone really counts - it's not a belief about the nature of the universe, more some tech to keep you aroud like antibiotics or the like.


Yeah, calling it religion is definitely overselling the case against cryo. At worst, I'd call it speculation.


To make definite claims about what will happen with cryonics patients, the Singularity etc is certainly a religious act. However, there is a distinction worth drawing between those and more moderate claims. I think the best argument for cryonics is 'we don't know the odds of surviving if you're frozen - but we do know the odds of surviving if you're dumped in a hole in the ground to be eaten by worms'.


(Replying to myself because edit doesn't work after a certain time.)

To clarify, I wasn't criticizing cryonics -- just observing that it's a field of technology whose offering is close to religion's traditional core: giving hope of life after death.


Matthew 10 8: Heal the sick, cleanse the lepers, raise the dead, cast out devils

Who else but the cryonicists are trying to raise the dead?

Cryonics is all about preserving information. And the bible tells us that god is information: John 1 1: In the beginning was the Word, and the Word was with God, and the Word was God.

Genesis 127: So God created man in his own image.

Since God is The Word, which is information, and if God made us in his image, then we are also information. 2 Corinthians 6 16 we are the temple of the living God.

1 Corinthians 3 17: If any man destroys the temple of God, God will destroy him.

And we cryos are all about preserving information.

Also: 1 Corinthians 15 25-26: He must reign until He has put all His enemies under His feet. The last enemy that will be abolished is death. Cryonicists are engaged in preserving the information that is our soul, saving God's temple from the decay of the grave.

If cryonicists succeed and raise the dead in the distant future through future science, we will be helping God achieve his final goal of defeating death.

There is much more in the bible that supports cryonics....


I'd argue that LessWrong is even closer. They even have a devil, who's name must never be mentioned!


If you don't know that's a lie, then please go and check. Roko's basilisk was overblown and now is just used by some people to score cheap shots against LW.


> was overblown and now is

Was overblown? Now is?

So, it's not a lie. It's just not an accurate picture of the current state of affairs on that site. Or is your position that it never happened in the first place?


Cold storage




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