[HN Gopher] An ultra-sensitive on-off switch helps axolotls regr...
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An ultra-sensitive on-off switch helps axolotls regrow limbs
Author : gmays
Score : 107 points
Date : 2023-07-28 16:49 UTC (6 hours ago)
(HTM) web link (scopeblog.stanford.edu)
(TXT) w3m dump (scopeblog.stanford.edu)
| qup wrote:
| This is the most important work.
| seydor wrote:
| ... if you re an axolotl
| Teever wrote:
| It really is.
|
| Imagine if we can get to a world where the difference between
| not having health insurance and having insurance means either
| you wait for your body to naturally regrow a limb or your
| insurance covers a more quickly lab grown one.
|
| Imagine a world where organ transplant wait lists aren't a
| thing.
|
| Imagine a world where Ukrainian landmine victims are walking on
| new limbs.
|
| We can have this, but instead our best minds are fucking around
| with optimizing web ads, or they're figuring out how to tweak
| assembly lines that shit out McDonald's Happy meal toys.
| taminka wrote:
| > Imagine if we can get to a world where the difference
| between not having health insurance and having insurance
| means either you wait for your body to naturally regrow a
| limb or your insurance covers a more quickly lab grown one.
|
| america moment
| [deleted]
| Teever wrote:
| Yes I'm trying to frame it in terms the audience of HN can
| understand.
|
| I'm not sure what's wrong with that.
| TaylorAlexander wrote:
| The issue as an American is that I would much rather
| imagine a world where everyone has appropriate health
| coverage.
| csdvrx wrote:
| >> america moment
|
| > Yes I'm trying to frame it in terms the audience of HN
| can understand.
|
| > I'm not sure what's wrong with that.
|
| What's wrong is that it's orthogonal to the problem, so
| it risks creating a pointless discussion about health
| insurance instead of focusing on the technology. The key
| problem is the ability to regrow limbs is not yet within
| our technological reach.
|
| Having (or not) health insurance won't get you another
| pair of legs if you walk on a mine. Maybe you'll get very
| fancy prosthetics, but it will not be flesh and bone.
|
| In a world where this is known technology, even if the
| costs may initially put it out of reach of people without
| insurance, should it just be a gene edit _AND_ we have
| the ability to gene edit like we now have the ability to
| 3d print, the cat will be out of the bag, and it will be
| like people buying 3d printers to 3d print guns in
| countries where gun ownership is forbidden, or people
| ordering drugs on the dark web: it may be illegal, but
| people with addictions (or here, without legs) may not
| really care about the legality.
|
| Or they will just do a road trip to Mexico, like how it
| is for dental work.
|
| Health insurance is rarely the #1 issue: I think even
| Europeans do similar trips when they want something
| immediately instead of accepting long waitlines or some
| procedures not being officially available in their
| country. The only difference is they don't go to Mexico
| but to Turkey, the Balkans or Eastern Europe.
|
| What we need is more technology, and fewer legal
| limitations, like how it was pointed out last week about
| how the FDA risk aversion costs human lives in a way
| that's impossible (or extremely hard) to measure.
|
| We're very lucky the Trump administration (and a few
| others around the world) decided to bypass the regular
| vaccine safety process during operation warp speed:
| regardless of what you think about Covid vaccines, we now
| have mRNA vaccine technology, which is already being
| tested for many other things.
| re_ed wrote:
| [flagged]
| Teever wrote:
| If I'm reading your comment correctly it appears youre
| just restating what I'm saying?
|
| Is that an accurate interpretation of your comment? What
| am I missing?
| csdvrx wrote:
| Then I have misunderstood you, I'll edit my comment to
| point it's about the technology by providing more
| examples.
|
| EDIT: done, also I see we may have similar opinions given
| how you submitted
| https://news.ycombinator.com/item?id=34327992 about 3d
| guns in Canada
| soulofmischief wrote:
| Something tells me that death is built-in feature of many
| nested systems in order to prevent stagnation / local minima
| or maxima. In the case of social humans, death prevents bad
| people from remaining alive forever, cementing in power
| structures and not providing the needed substrate for
| continual growth of a society.
|
| I don't mean to ascribe intention to nature, but rather state
| that social systems which get far enough for its members to
| discuss it freely on the internet likely converge on this
| feature.
|
| One could argue that eternal life unlocks the next phase of a
| civilization, but I am unconvinced that humanity is even
| properly equipped for the level of technology we have today,
| much less tomorrow.
| skeaker wrote:
| I would rather a hundred bad people live than let one more
| good person die if we can help it.
|
| > I am unconvinced that humanity is even properly equipped
| for the level of technology we have today, much less
| tomorrow.
|
| If you had 1,000 years to figure everything out, you would
| be more than properly equipped. Instead we all have to
| operate with this arbitrary 80ish years to just barely
| figure anything out and then most of us die before we can
| do anything with the knowledge. It is a horrible and unfair
| system. Imagine if Einstein were still around today and was
| able to keep building on top of the knowledge he had
| before. Surely in that time he would have gotten things
| done that the vast majority of people could not begin to
| imagine.
| mxkopy wrote:
| > We can have this
|
| Can we? I think a necessary step towards this direction is a
| complete genetic model of the human body, which we haven't
| even the ability to compute until very recently (if at all).
|
| I feel like we need to solve the bioinformatics thing before
| we're able to gcc new body parts. Which I think is incredibly
| solvable, though ofc it'll take decades.
| amelius wrote:
| Yes, but remember that humans need like 16+ years to grow
| limbs into their final shape and size.
|
| PS: those adtech folks are destroying the planet by boosting
| consumption
| Teever wrote:
| Most humans as they currently are may need 16 years to grow
| an adult size limb, but it doesn't need to be that way.
|
| An interesting question would be how long does it take a
| baby to gain the mass of a limb?
|
| Another interesting question would be how fast can an adult
| gain weight?
|
| Another interesting question would be if it takes a person
| 18 years to reach 6' and 160lbs and then they stop growing,
| how long would it take them to grow another foot or two if
| they didn't stop growing?
| puchatek wrote:
| I think i'd prefer a world where there are no landmines in
| Ukraine. I would even sacrifice the ability to regrow a limb
| of it helped us get there.
| nradov wrote:
| How specifically would you propose to reduce the rate of
| traumatic amputations in Ukraine? There are a wide variety
| of kinetic weapons being used beyond just landmines.
| re_ed wrote:
| [flagged]
| Teever wrote:
| But you know that isn't an option?
|
| Limb regeneration is useful for more than just landmines.
|
| Does the kind of comment you made really contribute to the
| conversation?
| westurner wrote:
| From TA https://scopeblog.stanford.edu/2023/07/26/how-an-ultra-
| sensi... :
|
| > _Axolotls, they discovered, have an ultra-sensitive version of
| mTOR, a molecule that acts as an on-off switch for protein
| production. And, like survivalists who fill their basements with
| non-perishable food for hard times, axolotl cells stockpile
| messenger RNA molecules, which contain genetic instructions for
| producing proteins. The combination of an easily activated mTOR
| molecule and a repository of ready-to-use mRNAs means that after
| an injury, axolotl cells can quickly produce the proteins needed
| for tissue regeneration._
|
| From "Reactivating Dormant Cells in the Retina Brings New Hope
| for Vision Regeneration" (2023)
| https://news.ycombinator.com/item?id=35871887 :
|
| > "Direct neuronal reprogramming by temporal identity factors"
| (2023) https://www.pnas.org/doi/10.1073/pnas.2122168120#abstract
| :
|
| > Abstract: _Temporal identity factors are sufficient to
| reprogram developmental competence of neural progenitors and
| shift cell fate output, but whether they can also reprogram the
| identity of terminally differentiated cells is unknown. To
| address this question, we designed a conditional gene expression
| system that allows rapid screening of potential reprogramming
| factors in mouse retinal glial cells combined with genetic
| lineage tracing. Using this assay, we found that coexpression of
| the early temporal identity transcription factors Ikzf1 and Ikzf4
| is sufficient to directly convert Muller glial (MG) cells into
| cells that translocate to the outer nuclear layer (ONL), where
| photoreceptor cells normally reside. We name these "induced ONL
| (iONL)" cells. Using genetic lineage tracing, histological,
| immunohistochemical, and single-cell transcriptome and multiome
| analyses, we show that expression of Ikzf1 /4 in MG in vivo,
| without retinal injury, mostly generates iONL cells that share
| molecular characteristics with bipolar cells, although a fraction
| of them stain for Rxrg, a cone photoreceptor marker. Furthermore,
| we show that coexpression of Ikzf1 and Ikzf4 can reprogram mouse
| embryonic fibroblasts to induced neurons in culture by rapidly
| remodeling chromatin and activating a neuronal gene expression
| program. This work uncovers general neuronal reprogramming
| properties for temporal identity factors in terminally
| differentiated cells._
|
| >> _Is it possible to produce or convert Muller glial cells with
| Nanotransfection (stroma reprogramming), too?_
|
| Muller glial cells and mTOR:
| https://scholar.google.com/scholar?hl=en&as_sdt=0%2C43&as_vi... :
|
| - "Genetic and epigenetic regulators of retinal Muller glial cell
| reprogramming" (2023)
| https://www.sciencedirect.com/science/article/pii/S266737622... :
|
| > _A number of factors have been identified as the important
| regulators in Muller glial cell reprogramming. The early response
| of Muller glial cells upon acute retinal injury, such as the
| regulation in the exit from quiescent state, the initiation of
| reactive gliosis, and the re-entry of cell cycle of Muller glial
| cells, displays significant difference between mouse and
| zebrafish, which may be mediated by the diverse regulation of
| Notch and TGFb (transforming growth factor-b) isoforms and
| different chromatin accessibility._
|
| From "Fiber-infused ink enables 3D-printed heart muscle to beat"
| (2023) https://news.ycombinator.com/item?id=36894749
| https://seas.harvard.edu/news/2023/07/fiber-infused-ink-enab... :
|
| > _In a paper published in Nature Materials, researchers from the
| Harvard John A. Paulson School of Engineering and Applied
| Sciences (SEAS) report the development of a new_ hydrogel ink
| infused with gelatin fibers _that enables 3D printing of a
| functional heart ventricle that mimics beating like a human
| heart. They discovered the fiber-infused gel (FIG) ink allows
| heart muscle cells printed in the shape of a ventricle to align
| and beat in coordination like a human heart chamber._
|
| > _"People have been trying to replicate organ structures and
| functions to test drug safety and efficacy as a way of predicting
| what might happen in the clinical setting," says Suji Choi,
| research associate at SEAS and first author on the paper. But
| until now, 3D printing techniques alone have not been able to
| achieve physiologically-relevant alignment of cardiomyocytes, the
| cells responsible for transmitting electrical signals in a
| coordinated fashion to contract heart muscle._
|
| Hydrogel and gelatin.
|
| Regenerative medicine:
| https://en.wikipedia.org/wiki/Regenerative_medicine
|
| Regeneration in humans > Induced regeneration:
| https://en.wikipedia.org/wiki/Regeneration_in_humans#Induced...
| myshpa wrote:
| This is a prime example of why biodiversity is so important, and
| in my opinion, why protecting it should be a top priority for all
| hackers.
|
| Genetic information is code - code that has been written over
| millions of years. Nature is full of such wonderful programs and
| hacks. We don't yet know how to write even the simplest one, or
| even know about most of them. Yet, we're turning a blind eye to
| the current destruction of biodiversity and not thinking twice
| about it.
|
| I don't understand why the Hacker News community isn't more
| interested in biodiversity loss, or why articles about climate
| change and biodiversity loss are not welcome here.
|
| We're in the sixth mass extinction event, defined as a 75% loss
| of species, primarily caused so far by animal agriculture or,
| more precisely, by our food preferences. This situation is soon
| to be worsened by climate change.
|
| But when someone mentions veganism around here, all those hackers
| flag his post to oblivion.
|
| What makes all those javascript frameworks so important, and the
| code created by nature unimportant?
| Shosty123 wrote:
| Never thought about it like that. Thanks for sharing that
| perspective.
| positus wrote:
| Genuinely curious, since almost all (all?) of your submissions
| to HN seem to involve the climate in some way: what do you do
| for a living? What causes you to gravitate towards these types
| of articles and discussions?
| myshpa wrote:
| > What causes you to gravitate towards these types of
| articles and discussions
|
| Is there anything more important in this day and age?
| [deleted]
| rollcat wrote:
| I think it's a mix of groupthink and "someone else's problem".
| It's hard to break through an echo chamber and it's hard to
| accept something that inconveniences you. (I would assume the
| parts of the world where most of HN's audience resides are not
| going to be impacted by climate change as soon and as hard as
| many others.)
|
| I do believe HN is full of intelligent and compassionate
| people. Perhaps it's compassion fatigue? (Too many horrible
| things happening, can I even make a difference through my
| individual actions?) Maybe we just needed you to make a good
| analogy, to illustrate the problem?
| worldsayshi wrote:
| This times a thousand. The amount of unique information that is
| encoded in any single species likely dwarfs the collective
| knowledge of mankind.
| kdmccormick wrote:
| Well said. I had not made the parallel between genetic
| diversity and preservation of code, but now that you've put it
| like that it makes so much sense. I mean, I'd always cared
| about conservation, but this gives me yet another way to
| understand and explain its importance.
| panabee wrote:
| could someone with expertise in regenerative medicine kindly shed
| light on this quote, please?
|
| quote:
|
| "It was a 180-degree flip when we realized that when an axolotl
| loses a limb, it actually increases protein synthesis despite the
| energy cost," Barna said.
|
| questions:
|
| what is the conventional wisdom on how limb regeneration occurs
| w/o increasing protein synthesis?
|
| inferring from other passages, it seems like conventional
| research focuses on mRNAs, not actual protein synthesis. why?
| grishka wrote:
| Whenever morphogenesis comes up, _especially_ with the usual
| "work from DNA and proteins up" approach, I feel obliged to
| mention Michael Levin. He _also_ researches morphogenesis, except
| his approach is on a higher abstraction level. He manipulates the
| electrical network that cells use to communicate with each other
| to organize their work towards multicellular goals. Do watch his
| lectures, it 's some really fascinating stuff. You don't need to
| touch genes at all to regrow limbs and organs. Neither do you
| need to operate on that low level to cure cancer. This whole
| "let's effect organism-level changes by observing and
| manipulating DNA and proteins" feels to me like "let's add a
| feature to a react web app by observing and modifying the
| behavior of individual transistors in the CPU". Doable given
| enough time, but you'd drown in complexity in the process.
|
| https://www.youtube.com/watch?v=Ed3ioGO7g10
| hereallofit wrote:
| Piling on; I emailed Michael Levin during lockdown and he
| replied with answers to some high level questions and a bit of
| documentation. Not sure what his pace is like these days but he
| seems open to sincere attempts at discourse.
|
| Let's fund this instead of shitcoins, layers of indirection
| around POSIX.
| echelon wrote:
| The code is there. It's a timing and signalling problem.
| UniverseHacker wrote:
| I think that analogy is very apt- the fact that we have such a
| hard time understanding and predicting the outcomes of
| bioengineering/synthetic biology suggests that we are still
| missing huge parts of the picture of how life works.
|
| It seems very likely to me that our views are too reductionist,
| and the much of the key information isn't even encoded at the
| level of DNA as previously assumed.
|
| The cells multicellular organisms are constructed from are all
| shockingly similar... "cells" are basically a solved problem
| for this type of life, and somewhat frozen in their
| functionality because major changes would disrupt the larger
| systems that they make up.
| deng wrote:
| > The cells multicellular organisms are constructed from are
| all shockingly similar.
|
| They are not. They vary greatly in structure and function.
| UniverseHacker wrote:
| What I said was a matter of opinion, I didn't quantify it
| in any way, so I'm not sure how you can say that, but I
| will elaborate more so you have something to really
| disagree with :-)
|
| Sure, of course the different multicellular eukaryotes
| vary, but the diversity is very low compared to what we see
| across all life, look at Figure 1 here for example [1].
|
| I am looking at it from the perspective of the structure of
| the metabolic network, as this is my area of research.
| There is a huge amount of diversity in the fundamental
| structures of metabolic networks, types of metabolites and
| enzymes produced, etc. across all life, but from that
| perspective the differences between one multicellular
| eukaryote and another are slight in comparison.
| Multicellular eukaryotes have evolved very different
| behaviors, shapes, sizes, etc. from a relatively conserved
| biochemistry. When taken out of the context of an organism
| in cell culture, the cells are similar enough that their
| behavior under diverse experimental conditions can be
| predicted by nearly identical metabolic models, whereas you
| would see nothing of the sort with distantly related
| bacteria- the metabolism can be massively rearranged.
|
| [1] https://www.nature.com/articles/nmicrobiol201648
| dekhn wrote:
| I can't see any way that you could regrow a limb without
| "touching genes". And Levin doesn't say that in his video. At
| the very least, limb regrowth would require synthesis of many
| mRNA and their protein products, under the control of
| transcription factors.
| grishka wrote:
| Yes, but _you_ don 't do that. The cells themselves do it.
| You only trigger that mechanism and you do it by opening and
| closing specific ion channels in specific patterns.
| deng wrote:
| The article is specifically about a difference in the mTOR
| protein, so in the end, a genetic difference. You will not
| trigger a limb regrowth in humans by opening and closing
| specific ion channels in our cells.
| grishka wrote:
| > You will not trigger a limb regrowth in humans by
| opening and closing specific ion channels in our cells.
|
| Levin's research begs to differ. He did successfully
| regrow an amputated leg in a frog.
| civilitty wrote:
| _In a frog._
|
| The genetic machinery for limb regeneration is highly
| conserved (see reptiles) and predates the appearance of
| lissamphibians. There's almost zero chance it's possible
| with endotherms.
| generalizations wrote:
| (Paywalled) article:
| https://www.nature.com/articles/s41586-023-06365-1
| Conasg wrote:
| Will we be able to genetically transfer this behaviour to, say, a
| mouse for testing, to see whether the mouse would gain the
| ability to regrow its limbs or tail?
| reflektoin wrote:
| IIRC Michael Levin has started limb regrowing experiments with
| mice. He might've mentioned it in some podcast he was on.
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