Zebrafish protein unlocks dormant genes for heart repair(hubrecht.eu)
hubrecht.eu
Zebrafish protein unlocks dormant genes for heart repair
https://www.hubrecht.eu/zebrafish-protein-unlocks-dormant-genes-for-heart-repair/
64 comments
It's all just chemistry, and the chemistry is extremely conservative all the way back to the first eukaryotes. Once our kind of life figures out a way to do something it's very uncommon that the fundamental pathways change - not by any means impossible.
Cells that have novel things happen to them nearly always die. Others become cancer, which is a career-limiting move for multicellular life at least. So the process of changes to basic chemistry of life is very slow. That's why omnivores can eat almost anything and be fine with it - imagine if different branches of plants and animals had really novel things in them, like a critter with nerve gas for a circulatory fluid.
There's been some discussion of mirror bacteria lately, which have opposite chirality in all their molecules, which would be substantially problematic since we really don't have defenses against that kind of thing. That just shows the degree to which you'd have to rejigger biochemistry to get a truly whole new thing going on.
Cells that have novel things happen to them nearly always die. Others become cancer, which is a career-limiting move for multicellular life at least. So the process of changes to basic chemistry of life is very slow. That's why omnivores can eat almost anything and be fine with it - imagine if different branches of plants and animals had really novel things in them, like a critter with nerve gas for a circulatory fluid.
There's been some discussion of mirror bacteria lately, which have opposite chirality in all their molecules, which would be substantially problematic since we really don't have defenses against that kind of thing. That just shows the degree to which you'd have to rejigger biochemistry to get a truly whole new thing going on.
Like all plants that produce sugar produce left-handed sugar molecules. And all animals that can digest sugar can only digest left-handed sugar molecules. There was no meeting, this is just the way it worked out.
The meeting was the animals who evolved to not be able to consume this, lived in more harsh conditions than those that had the readily available sugar. Evolution.
Yeah, having the reward function baked into the runtime is a sure way to eliminate any nonsense!
Our physiology can still interact with other chiral molecules though right?
Just for example, both the stereoisomers, dextro/levo amphetamine, in my limited understanding of pharmacological interactions, cause a reaction.
One being a powerful stimulant/psychotropic that can cause psychosis, the other benign enough to be sold over the counter as a nasal decongestant with stimulating effects, but orders of magnitude weaker.
Just for example, both the stereoisomers, dextro/levo amphetamine, in my limited understanding of pharmacological interactions, cause a reaction.
One being a powerful stimulant/psychotropic that can cause psychosis, the other benign enough to be sold over the counter as a nasal decongestant with stimulating effects, but orders of magnitude weaker.
You are correct. Protein chirality determines which direction they twist when they fold but the binding sites are all made up of the same functional groups, just arranged differently.
Realistically they have to be compatible because chirality is enforced by a D-handed chiral checkpoint protein that preferentially binds to L-amino acids, excluding the D-amino acids. All living organisms use the “wrong” isomer to make sure only the “right” isomer is used in protein synthesis. The amino acid cysteine is also present in both forms in mammals, so it extends to small molecules too.
Realistically they have to be compatible because chirality is enforced by a D-handed chiral checkpoint protein that preferentially binds to L-amino acids, excluding the D-amino acids. All living organisms use the “wrong” isomer to make sure only the “right” isomer is used in protein synthesis. The amino acid cysteine is also present in both forms in mammals, so it extends to small molecules too.
> One being a powerful stimulant/psychotropic that can cause psychosis
It can cause way more than psychosis. ODing on dextroamphetamine can kill you.
It can cause way more than psychosis. ODing on dextroamphetamine can kill you.
I don’t think mirror bacteria would do that well. They’d have to survive all the other handed chemicals already out there and to be able to use the other handed proteins and sugars for food to become pests. Furthermore immune systems can create antibodies which bind to arbitrary proteins as I understand it.
> ... chemistry is extremely conservative all the way back to the first eukaryotes. Once our kind of life figures out a way to do something it's very uncommon that the fundamental pathways change
Why don't most effects cross species barriers? Plenty of viruses, for example, affect some species but not others. When developing medical treatments, I thought that researchers had to carefully choose animal species analogs to humans for testing, and even then it was very unreliable.
Why don't most effects cross species barriers? Plenty of viruses, for example, affect some species but not others. When developing medical treatments, I thought that researchers had to carefully choose animal species analogs to humans for testing, and even then it was very unreliable.
so do you think interacting with aliens is possible given the chemistry side of things? The more I think about it the more concerned I am that that will end badly because our microbiology will act benign until it figures a way to use the foreign life as a food source and then boom one of us dies off.
Well, if they evolved differently then maybe not. But they'll have the same fundamental building blocks in terms of atoms, and there's a limited amount of energetically favorable ways to slice that particular bread.
I would be surprised if we ran into any extraterrestrial life that wasn't carbon based. They may choose a different chirality but there's very little chemically as versatile as carbon carbon bonds. And based on just prevalence levels in the universe carbon-hydrogen-oxygen-nitrogen is a pretty solid bet evolutionarily.
I would be surprised if we ran into any extraterrestrial life that wasn't carbon based. They may choose a different chirality but there's very little chemically as versatile as carbon carbon bonds. And based on just prevalence levels in the universe carbon-hydrogen-oxygen-nitrogen is a pretty solid bet evolutionarily.
we aren't made of carbon directly though, we are made of amino acids that are made from carbon and a few other things (plus polysacharides and a bunch of fatty acids), so I wouldn't exactly say we are made of the same fundamental building blocks, as I expect there is way more than just our set of amino acids that will work (I would expect a number of different grouping of amino acids to work as separate groups and how the first proto amino acids happen to be put to use by chance to determine which grouping then goes on to evolve further and dominate because if you have to break something down and rebuild it as what you need it is way costlier than just dissasembling to aminos and reassembling so given enough time one should becomethe monopoly)
It is a protein that exists in mammals. Presumably they produced the murine version to put in the mouse. Science journalism screwed up the paper's language, calling it a zebrafish protein, when it is a protein that is conserved for all vertebrates. But the function of the protein, and its role in heart regeneration, was identified in zebrafish.
> Directly after LAD ligation during MI surgery, hearts were injected twice with 15 μl of AAV9(CMV:GFP) or AAV9(CMV:HA-Hmga1) (1 × 1012 virus particles per mouse) in opposing regions bordering the area at risk of ischemic injury.
The paper doesn't say whether the viral vector (AAV9) used the murine or zebrafish Hmga1 sequence, but it is more likely that they used the murine.
> Directly after LAD ligation during MI surgery, hearts were injected twice with 15 μl of AAV9(CMV:GFP) or AAV9(CMV:HA-Hmga1) (1 × 1012 virus particles per mouse) in opposing regions bordering the area at risk of ischemic injury.
The paper doesn't say whether the viral vector (AAV9) used the murine or zebrafish Hmga1 sequence, but it is more likely that they used the murine.
Well it's important to note that all organisms (almost certainly) descend from a single common ancestor (https://en.wikipedia.org/wiki/Last_universal_common_ancestor) and the organisms we work with often are quite close on the inheritance tree (really, a graph if you include horizontal gene transfer).
When you collect the same exact protein from a bunch of close species, their underlying sequences often differ by very little and those differences are really just random mutations that occurred and were tolerated. Some proteins got "locked in" as useful and could not really change since so many things depended on them. For example, eukaryotes like humans have a protein called "actin" that is incredibly well consereved across all mammals, and we can even see what appear to be very distant cousins in bacteria- those two parts of the tree of life diverged billions of years ago (you think legacy computing is bad?)
If you start to study biology through the lens of evolution/development (IE, looking at the similarities and differences in close and far related organisms) it starts to become a lot clearer. Many organisms with very different phenotypes actually just contain slight modifications to the parameters of common generator functions- for example, wings and arms seem to derive from the same ancestral body part. Most of the genes that make them are in common, it's just how and when the different genes get expressed that determines the finer details (I'm glossing over a lot here).
So since nearly all the players are the same, it's often not that hard to move a protein from a close relative (mice are pretty close to us) to another without any real loss of function or major change in phenotype. However, there are some fundamental differences that make comparing mice results to humans and sometimes we modify mice to appear more human to make them better model organisms.
(even after working in this field for some 30+ years, I remain constantly amazed any of this works at all. I felt the same way about Google's production environment, which in many ways resembled a very simple organism)
When you collect the same exact protein from a bunch of close species, their underlying sequences often differ by very little and those differences are really just random mutations that occurred and were tolerated. Some proteins got "locked in" as useful and could not really change since so many things depended on them. For example, eukaryotes like humans have a protein called "actin" that is incredibly well consereved across all mammals, and we can even see what appear to be very distant cousins in bacteria- those two parts of the tree of life diverged billions of years ago (you think legacy computing is bad?)
If you start to study biology through the lens of evolution/development (IE, looking at the similarities and differences in close and far related organisms) it starts to become a lot clearer. Many organisms with very different phenotypes actually just contain slight modifications to the parameters of common generator functions- for example, wings and arms seem to derive from the same ancestral body part. Most of the genes that make them are in common, it's just how and when the different genes get expressed that determines the finer details (I'm glossing over a lot here).
So since nearly all the players are the same, it's often not that hard to move a protein from a close relative (mice are pretty close to us) to another without any real loss of function or major change in phenotype. However, there are some fundamental differences that make comparing mice results to humans and sometimes we modify mice to appear more human to make them better model organisms.
(even after working in this field for some 30+ years, I remain constantly amazed any of this works at all. I felt the same way about Google's production environment, which in many ways resembled a very simple organism)
I think what you are getting at is that life is all very similar. Most species have very similar genes. Why you can study genes in flies and yeast and worms and have it be relevant to human genetics.
In very simplified biology genes just make proteins.
There is a fair amount of software to find these similar genes across various species called “orthologs” https://en.m.wikipedia.org/wiki/Sequence_homology#Orthology
I’ve run some of these tools. They can be a little rough, but generally they work.
You are right though, it’s totally amazing it works. Amazing being alive.
In very simplified biology genes just make proteins.
There is a fair amount of software to find these similar genes across various species called “orthologs” https://en.m.wikipedia.org/wiki/Sequence_homology#Orthology
I’ve run some of these tools. They can be a little rough, but generally they work.
You are right though, it’s totally amazing it works. Amazing being alive.
> If you start to study biology through the lens of evolution/development (IE, looking at the similarities and differences in close and far related organisms) it starts to become a lot clearer.
Any suggestions on literature? Paper, survey article, text, whatever? Or any examples/thoughts of using that as a pedagogical framework?
I've an oddball interest in exploring what science education content might look like if crafted with far far greater interdisciplinary expertise and resources. So I've wondered what an intro bio might look like with a more... "veterinary + engineering" flavor - broad scope, comparative and cross-cutting, systems concerns, solution vocabularies, etc.
As an illustrative bit (years old so maybe now invalidated), perhaps highly-conserved regulatory micro-RNA might be used as a "available complexity" metric to create a much simpler "tree of life" for orientation. Or energy budgets as a lens. Or design themes (eg compartmentalization). Or conserved-outward (eg 16S to RNA to). Or emotive ("yay diffusion, and surfing just above the thermal-noise molecular mosh pit from hell" vs (an Analog Devices engineer's heartfelt) "Brownian motion is the devil. The DEVIL!!"). Or someone's picture book of motifs in cellular and embryonic development (eg perching pigeons spacing themselves evenly along a wire). Or ... .
Most everyone is quite reasonably focused on the students and resources and objectives at hand. But that leaves the heavy lifting of exploring for long-term transformative opportunities rather unincentivized. Making it hard to envision just how much potential is being left on the table.
Any suggestions on literature? Paper, survey article, text, whatever? Or any examples/thoughts of using that as a pedagogical framework?
I've an oddball interest in exploring what science education content might look like if crafted with far far greater interdisciplinary expertise and resources. So I've wondered what an intro bio might look like with a more... "veterinary + engineering" flavor - broad scope, comparative and cross-cutting, systems concerns, solution vocabularies, etc.
As an illustrative bit (years old so maybe now invalidated), perhaps highly-conserved regulatory micro-RNA might be used as a "available complexity" metric to create a much simpler "tree of life" for orientation. Or energy budgets as a lens. Or design themes (eg compartmentalization). Or conserved-outward (eg 16S to RNA to). Or emotive ("yay diffusion, and surfing just above the thermal-noise molecular mosh pit from hell" vs (an Analog Devices engineer's heartfelt) "Brownian motion is the devil. The DEVIL!!"). Or someone's picture book of motifs in cellular and embryonic development (eg perching pigeons spacing themselves evenly along a wire). Or ... .
Most everyone is quite reasonably focused on the students and resources and objectives at hand. But that leaves the heavy lifting of exploring for long-term transformative opportunities rather unincentivized. Making it hard to envision just how much potential is being left on the table.
one of the earliest and my personal favorite chymeric animals, were bioluminesent jellyfish monkeys, 2001 or before. The only one to glow visibly in normal light didnt live long, but some of the rest, that only glowed under infrared/black lights, did ok.
So the zebrafish thing just might work.
Also done by some mad scientist experimenting on themselves, was the injection, into there eyes of
a chemical produced by deap sea ?squid I think that humans dont produce any apreciable amount of, but we have the receptors for, and gives supper enhanced night vision to humans who are mad enough
to give it a go.
Ah, are you talking about Chlorin e6? I’m not sure if it’s squid inspired.
https://www.sciencealert.com/scientists-have-figured-out-how...
https://www.sciencealert.com/scientists-have-figured-out-how...
I assume we only hear about the cases when the protein does something interesting, and not the 999/1000 cases when it doesn't.
> Whatever weird programming language life is made from it seems to be a surprisingly forgiving environment.
Either that, or we truly are more similar than we seem to ourselves. It makes sense that humans would have a greater sense of discernment at the sensual level genetically nearer to us than further from us.
Either that, or we truly are more similar than we seem to ourselves. It makes sense that humans would have a greater sense of discernment at the sensual level genetically nearer to us than further from us.
I mean, quantitatively we are quite similar, when it comes down to the total possibility space dna allows, all life on earth is practically identical, statistically
> I wonder if the leap between a fish and a mouse is less than the distance between a mouse and a human?
No, mice are mammals just like humans. Fish were around long before mammals even existed.
No, mice are mammals just like humans. Fish were around long before mammals even existed.
genetic distance and taxonomical distance aren't that correlated
This is mainly due to errors in the taxonomy being based on phenotypic similarity which often does not correlate with actual relatedness (although, many would argue with this statement). It's not uncommon to see taxonomic reclassifications after enough species are sequenced.
Incredible work, I wonder how many other genes like this are dormant in mammals that are activated in other species. There are tons and tons of fun conserved structures/proteins: https://en.wikipedia.org/wiki/Rhodopsin is probably one of my favorites.
Can we start to ban/discourage "in mice" replies? They are seriously not in good faith or useful to any study that we see. All biochemistry is done in mouse models, this is the state of the art whether you like it or not. Would it be fair to reply "on computers" to every tech article we post? Probably not!
Can we start to ban/discourage "in mice" replies? They are seriously not in good faith or useful to any study that we see. All biochemistry is done in mouse models, this is the state of the art whether you like it or not. Would it be fair to reply "on computers" to every tech article we post? Probably not!
“In mice” is a very important lesson to learn about scientific reporting, but it’s also a very simple and reductive lesson. Most experimental results don’t translate to human studies. That’s it, thats the lesson to learn.
So, maybe someone here doesn’t know that, but it adds so little to the conversation to just repeat this widely known fact over and over again.
Now, let’s talk about the mouse models. Some models are better than others. Many experiments are conducted in mice that don’t have an immune system. Some mouse models have a “disease” that bears very little resemblance to the human condition and was induced through means that are very different from the human natural history. Some mouse models have a genetic defect in a gene that is very well conserved and mimics symptoms of the human condition and are thus excellent models that can tell us a lot about human physiology. All that nuance is lost by “in mice”, which makes it particularly frustrating when that’s used as a blanket reason to dismiss any mouse study.
So, maybe someone here doesn’t know that, but it adds so little to the conversation to just repeat this widely known fact over and over again.
Now, let’s talk about the mouse models. Some models are better than others. Many experiments are conducted in mice that don’t have an immune system. Some mouse models have a “disease” that bears very little resemblance to the human condition and was induced through means that are very different from the human natural history. Some mouse models have a genetic defect in a gene that is very well conserved and mimics symptoms of the human condition and are thus excellent models that can tell us a lot about human physiology. All that nuance is lost by “in mice”, which makes it particularly frustrating when that’s used as a blanket reason to dismiss any mouse study.
I hope one day mice can access the incredible amount of treatments we have developed for them.
There's a whole book and movie about it
https://en.wikipedia.org/wiki/The_Secret_of_NIMH
https://en.wikipedia.org/wiki/The_Secret_of_NIMH
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Hmga1 reduces repressive histone marks (H3K27me3), effectively unlocking genes typically silenced after embryonic development. This process seems to tap into an evolutionarily preserved "blueprint" encoded in the DNA. By reactivating these dormant pathways, differentiated cells like cardiomyocytes regain some of the plasticity and regenerative capacity characteristic of embryonic cells. If we combine this with the work coming out of Dr. Michael Levin's Lab at Tufts (https://www.youtube.com/watch?v=XheAMrS8Q1c)showing the existence of electrical blueprints that orchestrate life, we should see, as we do in this study that the regeneration observed was precisely tailored to the injury, avoiding pathological outcomes like cardiomegaly or uncoordinated growth. This preserved blueprint exists in all differentiated cells.
“…in mice” would be a helpful addition to the title.
To be fair, the gene also repairs heart damage in Zebrafish
which is more than just "in mice".
I understand the reasons behind the meme "in mice",
but on the other hand dismissing valid progress because
humans reflexively insisting on exceptional snowflake status
is counterproductive.
Plus, the jumo from zebrafish to mice is a lot larger than the jump from mice to humans. If it still functions across that large of a jump then it's very likely it'll also work in humans.
Apropos: "Analysis of animal-to-human translation shows that only 5% of animal-tested therapeutic interventions obtain regulatory approval for human applications" -
https://journals.plos.org/plosbiology/article?id=10.1371/jou...
Kind of makes you wonder what kind of biotechnology we could build if we didn't care about all that. There would be some pretty gnarly human suffering, but imagine if biological technology could progress at the same rate as electronics.
Morally abhorrent, of course, but there would be some benefits...
Morally abhorrent, of course, but there would be some benefits...
Although, even if it doesn't directly work in humans, it might be a stepping stone to something similar that might.
That won't stop Bryan Johnson.
His new zebrafish diet.
How easy are zebrafish to raise? What is their lifecycle? Can I raise millions of them in my basement or will I need to buy some warehouse? How long do they take? What do they eat? Any venture capitalists willing to fund my next business?
zebrafish are trivial, they are basically tropical fish that were repurposed for scientific research. temperature, ph, feeding, and cleaning the tank are the key steps.
Maintaining a population of zebrafish for scientific research is a bit more challenging; you need to maintain a continuous environment, adhere to a protocol, etc, to reduce all the variables that would your make your research results less reproducible.
zebrafish are imho one of the truly great model organisms- more interesting to work with and more convenient for many things. If I hadn't picked tardigrades for my microscopy/computer vision projects, I would have gone with zebrafish.
Maintaining a population of zebrafish for scientific research is a bit more challenging; you need to maintain a continuous environment, adhere to a protocol, etc, to reduce all the variables that would your make your research results less reproducible.
zebrafish are imho one of the truly great model organisms- more interesting to work with and more convenient for many things. If I hadn't picked tardigrades for my microscopy/computer vision projects, I would have gone with zebrafish.
https://zfin.org/zf_info/zfbook/zfbk.html
it is an open book ... no capital, but you are welcome to cut me in
it is an open book ... no capital, but you are welcome to cut me in
It's a common model organism in biology. One of the reasons is that it's easy to breed and keep in labs with fairly quick lifecycles. Raising millions of them is probably going to require a warehouse just like it would take to raise a million mice.
"...in mice, in a lab" as the saying goes
The scientific output from the Hubrecht institute is seriously underrated.
They only have like 20 or so researcher groups but the research quality and quantity rivals that of much larger departments.
They only have like 20 or so researcher groups but the research quality and quantity rivals that of much larger departments.
That is very exciting. Beyond the obvious applications in humans, it would be interesting to test whether love to see whether this could help reverse immune damage from cross-species heart transplantation.
Small comment, the Hubrecht Institute showing an "artistic representation" that looks exactly like actual histology data is very weird. They should make a cartoon graphic if they are trying to establish a model. How did they even make that? AI?
Small comment, the Hubrecht Institute showing an "artistic representation" that looks exactly like actual histology data is very weird. They should make a cartoon graphic if they are trying to establish a model. How did they even make that? AI?
I don't think the image is an artistic representation- I think it's an actual micrograph of fluorescently labelled cells. They may have called it that because some level of postprocessing was applied. In short, when this type of micrograph is taken, it's generated using a sequence of laser pulses, each laser pulse has a different wavelength of light designed to match one of the fluorescent labels, which itself emits a different wavelength of light. The images themselves are collected in grayscale and then a false-color image is created by coloring each grayscale image (mapping gray intensity to luminance) and compositing them. The color mapping does not recapitulate the underlying colors of the images that were taken although usually when these images are rendered, a color very close to the emission wavelength of the fluorescent label is used.
That said it's not impossible to conjure up prompts that would make a generative AI produce images that look a lot like a micrograph of cells. I skimmed the referenced paper and didn't see this image but I suspect the authors provided it in the PR package they must have distributed.
That said it's not impossible to conjure up prompts that would make a generative AI produce images that look a lot like a micrograph of cells. I skimmed the referenced paper and didn't see this image but I suspect the authors provided it in the PR package they must have distributed.
Yes, fluorescence imaging is a standard technique that I have performed a lot. The colors are arbitrary, and there is always post-processing - adjusting the signal intensity so that any background signal from negative control slides is removed. However, that doesn't make it an artistic representation, which is what their caption says.
I've seen that term used from time to time to describe false color imagery in astronomy.
Giving me some Rifters vibes here.
thanks fish
inverse prion protein?
those folding hacks are awesome. we know very little about it.
those folding hacks are awesome. we know very little about it.
*in mice
If we were mice this would be an amazing time to be alive.
Individual mice don't really live long enough to observe technological change though. Humans probably look like giant slow lumbering ancient wizards.
Yeah but I don't think mice are more similar to Zebrafish than us. If you were a little more brave you could inject it into yourself.
And no I doubt this will suddenly work in humans I’m more just fascinated by genetics proteins and life in general and just constantly amazed any of this works at all.