/sci/ - Science & Math

>>15493056
genetics is antisemitic propaganda

>>15493058
No.

>>15493056
https://www.cell.com/cell/fulltext/S0092-8674(19)31210-3
Just read the research. Or start by understanding the fucking basics at least. Genetic modification is going to be nigh impossible for anything interesting because most of the traits you might want to select for, whether embryo selection or modification, are extremely highly polygenic where any individual SNPs have miniscule near or non-reproducible effect sizes. To such a degree that embryo selection barely puts a dent in something like IQ or height even in the abstract.

That gives you an idea of just how implausible genetic modification for the most popular traits would be. Maybe you can modify an SNP, but are you going to be able to modify thousands of them exactly how you want? At that point we may as well be the Gods of our own fashioning to do with ourselves whatever we wish. So genetic modification will have its uses, in baby steps, but you're not going to see anything "groundbreaking". Same for embryo selection and polygenic risk, which is a fuck of a lot easier than gene modification of an embryo nevermind attempting that in an adult.

>>15493081
>Maybe you can modify an SNP, but are you going to be able to modify thousands of them exactly how you want?
So it's an issue of quantity primarily? Surely that's not as major an issue as you seem to want to make out. We already have ways of collecting, assessing, and influencing vast amounts of data. Granted such oversight tends to be mechanical rather than biological, but even so.

>>15493119
>Surely that's not as major an issue as you seem to want to make out.
Let me just grab some figures. There are around 3,117,275,501 base pairs. If you accept one estimate upper bound, the functional base pairs would be 15% of that or 467,591,325 base pairs. Now modify that for each cell in the entire human body, of which there are ~37 trillion.

Granted there's all kinds of assumptions in the ballpark numbers, but I'm just trying to illustrate the scope of the problem. Even altering the assumptions and halving the number, or quartering it, you have to deal with an immense array of problems especially modifying past the embryo and sperm stage. The more cells post fertilization the worse it's going to get.
>So it's an issue of quantity primarily?
No, the quantity part is just the easiest part to understand without enumerating immunological factors and everything else ad nausea.

>>15493056
>the history of genetic modification
I liked Outer Limits of Life by John Medina, its dated but is a Philosphy approach to the implications of Genomics and not a Molecular Anaysis of said BioChemistry. I found it very fascinating as a child.

Otherwise I would suggest these books as they mostly cover natural Genomics in Evolutionary Biology context, not Chemistry.

>>15493186
Scratch out Regensis, its midwit garbage, and add I Contain Multitudes by Ed Yong

>>15493056
The Neu Age has dawned. The nucleus, neuron, and neutron will change humanity forever once we can master all 3.

Bump, this is an interesting topic

>transhumanist propaganda thread

>>15495696
sure, so mindbogglingly interesting that you aren't inspired to add any meaningful commentary to the thread

"Genetic Modification: History, Science, and Society" by Emily Anthes

>>15493056
A book? No. Read the research. Find review articles, and go from there.
>>15493081
Well, yes, but actually no. Why are you so focused on SNPs? We can add, subtract or change motifs, functional parts of genes, whole genes, developmental programs, we can modify promoters, enhancers, epigenetic silencing, we can duplicate whole genomic regions. Understanding developmental biology allows us to, with small modifications make huge and significant changes.
We are limited by the inefficiency of transgenesis by CRISPR or the inaccuracy of transgenesis by transposon systems, but we are making good progress on this front.
For cas9 with disabled endonuclease activity, high binding affinity can be made, and fusion protein of it can be made with a linker madiated transposase, which can sequence specifically (though witha 3/- of a few douzen bases for now) insert a gene of interest with a near 100% efficiency combining the streangths of the two systems.
As biotechnology and moelcular biology advance, and as our understanding of developmental biology advances we can make more and more radical changes. For instance we can now increase the lifespan of C. elegans 9 fold. We can make chickens greow 4-6-8 legs, we can make them grow 4 wings. And we can make animals see more colors. We can now grow brain organoids of neanderthal brains, or human brains with a different number of cortical layers, by modification of the novo1 gene. We can grow mice who are buff as fuck by loss of function in myostatin gene. The list goes on.

>>15496638
do we have a chance for AGI to sort shit out and like just input a full human DNA sequence and get a pretty good view of how it would look like, physically? say for example you could generate the 3D print code for like a limb/organ or something.

>>15493130
It's weird, because what you say makes sense, you seem to know what you are talking about, but also you are wrong in a few places. The human genome is 6.4x10^9 bp long, about twice of what you say. Also, about 8.2% is suposedly functional, though that is up for debate. Still, we arrive at a number of relevant bp about the same as what you say, around 6x10^8. The number of cells in the human body is 37.2 trillion as you say, but getting something into all cells (except for some special cases) has never been a particularly large challenge. Hormones do it all the time, and so do larger molecules via exosomes. That is pretty much what blood is for. To effectively deliver stuff to your cells.
So sure, if you want to make changes to several thousand basepairs one at a time, by say the CRISPR system, that would be hard, but why would you do that? If i want 169 bp changed in a gene, i would replace the gene with 1 system, instead of changeing the bases with 169 systems.
The immune part is actually far more interesting. Would transgenes products presented on MHCI cause an immune response? Well... if the transgenesis has happened on the follicular cells in which T-cells mature, then no. Because that would be selected against. But it is absolutely fair to say, transgenesis works much better and more easely at fertilisation stage than later.
That being said to write off genetic modifications as fancifull so quickly is wrong in my opinion.

>>15496652
>do we have a chance for AGI to sort shit out
No
>you could generate the 3D print code for like a limb/organ or something.
We already can kind of do that, look up organoid research. We can grow tiny brains, frog limbs, mouse spine, little kidney balls, etc...

>>15496638
Sorry to say all I could think of reading this was "no but no".
>We are limited by the inefficiency of transgenesis by CRISPR or the inaccuracy of transgenesis by transposon systems, but we are making good progress on this front.
I wrote the explanation for why >>15493130, in that it is the easiest thing for people to understand as well as understand how polygenic most of the traits your average person is interested in are going to be. For mendelian diseases and the like is one thing, for generally or broadly making significant gains in IQ or other complex traits not so much. Not least of which in determining more broadly the probability landscape for gene-environment interactions, adding even more dimensions to the already incalculable simulation.

If you don't like a simple example for people to readily begin to understand, even when it is explicitly stated that is the purpose for it, that's one thing. Don't "but actually no" me, only to then post a bunch of things entirely agreeing with the problems outlined as if they don't. Highly trait-dominating variants when very few people among the public are considering nor would care about them. Since I don't know everything, and you didn't cite literature or even an author to help me figure out which paper you refer to or even how it's relevant, I'm skipping to what I do know.
>We can now grow brain organoids of neanderthal brains, or human brains with a different number of cortical layers, by modification of the novo1 gene.
Growing tissues and with spliced sequences is an entirely different issue from the polygenic traits most people are interested in. It is the most immediately interesting and medically applicable, yes, but you're not "yes but no"ing anything I wrote before with this.
>We can grow mice who are buff as fuck by loss of function in myostatin gene. The list goes on.
In each and every case we're removing or replacing using a sledgehammer. You aren't disagreeing with me at all.

>>15496660
>look up organoid research.
I was curious more about bio 3d printing. Like in 50 years from now or something, something evolved from what Lee Cronin is working right now with the chemical printer stuff.

>>15496659
>It's weird, because what you say makes sense, you seem to know what you are talking about, but also you are wrong in a few places.
I see what you mean as to the genome length and the apparent strangeness as to trivia. I was tired and did not clarify, or think to. The genome length referred to is the human genome project draft genome if I remember right, and I should've posted the number for the whole genome instead as you point out. However, then I would've also had to more carefully review which paper estimate and whether or not the putative functional estimates were based on reference genome or not. It's complicated. Sufficed to say the precise accuracy of any figure wasn't important for the point anyway, as I explicitly stated, since the issue is one of dimensionality for complex traits. Also explicitly stated estimates on functional variants depends on what paper and methods you're using, whether it's 8.2% upper bound or 15% depends on which, or any other similar figure. Again, as stated, raw number or ballpark percentage did not matter so much for the point in the same ballpark.
>That being said to write off genetic modifications as fancifull so quickly is wrong in my opinion.
I think it is fair for the complex traits you almost always see being thrown about and discussed on /sci/. If you charitably interpret what I wrote and where I am writing it I think you'll understand why I wrote what I wrote. What scientists are talking about, and what the public thinks they're talking about, are almost never even in the same language family.

>>15496676
>I think it is fair for the complex traits you almost always see being thrown about and discussed on /sci/. If you charitably interpret what I wrote and where I am writing it I think you'll understand why I wrote what I wrote. What scientists are talking about, and what the public thinks they're talking about, are almost never even in the same language family.
This is very reasonable. I would agree, that the almost sci-fi things people expect from genetic modification are either impossible or centuries away. For instance, enhancing human intelligence seems so far off i'm not sure it's even possible. I mean even if iPSCs didn't go cancerous, even if we understood what intelligence actually is, and how it works, even if we could turn on adult neurogenezis... i still don't see how we could enhance human intelligence. And those ifs constitute like 50 years of research.
That being said rome wasn't built in a day. We are getting better and better at edditing the genome, and we are getting better and better at understanding poilgenic traits and developmental programs.
I think i may be rambling. The point i'm trying to make is, that though much of what the general public imagines or wants from genetic engineering is currently impossible, i see no reason amazing things could not be achieved. I know of no law of physics nor any mechanism which would prevent effective and groundbreaking genetic engineering from happening.

>>15496702
>And those ifs constitute like 50 years of research.
yeah. Near as I can tell you really do need a scalpel, and a lot of them, because you can't usually "just turn on" or sledgehammer your way to getting something neat out of it for complex traits. Not without being super lucky after a lot of hard work where removing or adding something causes a very complicated downstream chain of events, though that's usually the case with single-gene dominated phenotypes anyway as you see in diseases altering a lot of traits.

So for neurongenesis we're not talking about just "turning it on", but if doing so results in any modulating factors not working as they ought you're going to have far bigger more subtle problems. Since what you'd effectively be doing is further modifying, at a pace far above natural homeostasis depending on how strong the expression of the trait. The brain and other neurons have to not only teach, but prune to avoid errors, and could have all kinds of subtle problems that result from even not-sledgehamemring. May even result in paradoxical neurodegeneration keep in mind you also have finite resources, and lack of pruning or resource balancing will cause cell death. Probably an element to dementia if not a big component to which gene-enviro complex feeds into it like exercise.

You're kind of damned if you do damned if you don't.
>Explain using jargon and nobody understands
>Explain using both plus reference citations and nobody reads the citations and you're still left with retards screaming at you
I'll only really start talking about it if someone starts posting with genuine interest. Amazing things "could be" achieved, but we're talking about something analogous to high degree polynomial solutions, curse of dimensionality, etc. Plus the added issue of endogenous/exogenous environment interplays on the probability landscape of what you're working with. Going to be WAY easy for politicians to abuse, and the public to never understand.

>>15496716
Adressing the first part, the brain is a whole mess of it's own. There are so many aditional factors to adress compared to the rest of the soma. Just the fact that there is little to no cell prolifer, that it's immune priviliged, etc... makes it hard to work with. It's not my area of experties though, so i don't really have anything interesting to add.
Anyway, the legal landscape of it all will definitely be interesting. And anoying.
My research pretains to the mechanisms of ageing, and even there we encounter some ethical and legal problems. For instance we have identified a new epigenetic factor (not entirely new but the it's existance has been long debated, but we are publishing in nature in a month or so showing it exists) and developed a method for measuring it. With this, we can predict alzhaimers years before it developes as well as a few other things like insulin resistance. It's level is indicative of how long you have to live, and this is what we are about to start testing. The degree of accuracy in predicting how long one has to live. And the legal side of setting up this experiment is a fucking nightmare. All we want to do is take blood samples from old people, se who has levels near death, and follow up with the donors to see who lives.
Anyway, i'm still rambling, it's been a long day. Still i think my outlook on the whole thing is probably more optimistic than yours, it seems to me that though challenges abound, the road ahead is fascinating and full of interesting new discoveries. In my field especially, though my girlfriend works on organoids, and that field also seems to be making good progress.

>>15496638
Thought of Professor Michael Levine's Bioelectrical work?

https://youtu.be/XboYI_wxDr8

>>15496743
>It's not my area of experties though, so i don't really have anything interesting to add.
Think of it more analogously to the rest of the body. For example, with mechanisms of aging. The point made with respect to resource balancing points and homeostasis applies to many other areas and cells, and probably has a lot of intersections with non-communicable diseases (NCDs) and why exercise would ultimately seem to "be generally good at preventing everything". Degree of accuracy in such prediction is probably thus going to be off, at least as concerns NCDs, by the degree to which overall resource balancing is maintained as a matter of a probability function. In that the greater the likelihood of more frequent localized or generalized resource shortages and mismanagement the higher the likelihood of chronic self-reinforcing imbalances to occur.

I know I am just going long-form explaining homeostasis but homeostasis is most often treated as a cute cliche, except by relevant researchers. I believe, at least to my cursory reading occasionally, that aging related research often intersects with this.

Think of it this way: The reason to be "cynical" is not with respect to progress or pace, the reason is understanding the depth of complexity of managing what amounts to inevitable system entropy. You can't have adaptation without bifurcation, and you can't have permanent stability with bifurcation as a matter of thermodynamic management. If stuff is happening stuff changes, and stuff changing will change the balance points. How are you going to "cure" that?

>>15496747
>Degree of accuracy in such prediction is probably thus going to be off
This would be true, but keep in mind that whatever degree of exercise one des tends not to change much. Especially at the age group we will be observing. The point of this would be to tell people "you have 5 years to live, but with proper exercise and diet, you could live 8" or something similar. We will have to do the measurements. For now all we have done is age prediction based on this marker, which has been accurate to within 5 years (+/- 2.5yr).
But yes, i agree overall that resource managment is an interesting factor in all aspects of biology from supra to subindividual level.
>degree to which overall resource balancing is maintained as a matter of a probability function. In that the greater the likelihood of more frequent localized or generalized resource shortages and mismanagement the higher the likelihood of chronic self-reinforcing imbalances to occur
This is a good point. It is interesting, that most mechanisms of ageing ar known, but there is always a "general inefficiency causes minot errors which initiate the ageing cascade" caveat in all ageing studies.
That being said, the cascade can be modulated, the speed of it can be changed.
>aging related research often intersects with this
Of the 9 haulmarks of ageing, i'd say atleast 3 intersect. Mitochondrial disfunction and reactive oxigen species; Proteome integrity; and DNA integrity.
>managing what amounts to inevitable system entropy
The thing is, entropy and decay caused by resource mismanagement or random chance are such a low portion of ageing, that it is almost negligabel. Ageing is made of 9 or so layers of self and interstreangthening mechanisms, which increase the rate several fold. At the center of it all are transposons and senescence, but i don't want to go into detail (unless you want me to).
1/2

The point i'm trying to make through the example of ageing is, that though homeostasis is hard to maintain (probably impossible to maintain perfectly), that does not mean any change is impossible, nor does it require a full recalculation of what is needed to maintain homeosasis.
Similarly, add a new limb to the system and it will work mostly fine invertebrets keep adding and removing limbs like there is no tomorrow. Similarly, termites that have workers living for 2 weeks to two months add to the system transposon silencing and the reproductives live 20 years.
2/2

>>15497152
>This would be true, but keep in mind that whatever degree of exercise one des tends not to change much. Especially at the age group we will be observing.
Eeeh you really have to be careful of caveats. If we're talking people at end of life, you're talking about the very end point of homeostatic degradation. To the degree physical activity would help is therefore at its minima. I know you're talking in that case, or so I assumed and correct me if I did so wrongly, about elderly patients. My point was something more general about entropy and the inevitability of where bifurcation leads.

So in general another way to conceive of it is "the healthier you start and maintain consistently the better off you'll be". Which is hard to study since the counterfactual would require an identical "you" with the sole variable being something like exercise. Can't exactly get the ethical approval to control a twin like that, but there's cloned organs and such indicating a very strong causal effect IIRC. Do you know what I mean?
>That being said, the cascade can be modulated, the speed of it can be changed.
Absolutely. However, the general problem is I do not think the field, and I mean biology as a whole pertaining to things like medicine or such research like anti-aging, gives proper due for that hard problem. IMO it's the only interesting problem. Otherwise, at best, we'll be pulling a ship of theseus like replacing organs piecemeal and possibly inevitably even replacing portions of brain. Real life "repo men".
>The thing is, entropy and decay caused by resource mismanagement or random chance are such a low portion of ageing, that it is almost negligible.
Wait, really? I think my perspective was misunderstood, then. In my view at the level I'm conceiving it is wholly responsible for literally all of it. By definition. Each element, aspect, mechanism, etc, is all systemic entropy. An inevitability of, thought of more mathematicall as bifurcation toward catastrophe.

>>15497178
>Wait, really? I think my perspective was misunderstood, then. In my view at the level I'm conceiving it is wholly responsible for literally all of it. By definition. Each element, aspect, mechanism, etc, is all systemic entropy. An inevitability of, thought of more mathematicall as bifurcation toward catastrophe.
On a long enough timescale, maybe. But when talking about a few hundred years? No. The entropy and random error based ageing is so slow, it is only the first cause of a cascade which grows several orders of magnitude faster.
In short, DNA damage causes the ageing associated phenotype, and several aspects of the age associated phenotype cause DNA damage.
Entropy related errors may activate the first transposon, but that will then multiply itselfe within the DNA several fold with each cell division. This is an exponentially growing inbourn mutagen. If it happenes in the nuclear DNA, it causes degradation of the proteome. If it happenes inside the itochondrium, it causes exponentially growing release of ROS. ROS then contribute to the activation of further transposons, and further degradation of the proteome. Degradation of the proteome, causes further activation of transposons, further DNA damage, further release of ROS. All of this causes altered nutruient sensing, which also effects all of the above. Cytoplasmic DNA and misfolded proteins activate senescence pathways, which cause sterile inflamation via NF-kB signalling. The senescent cell secretory phenotype and inflamation both cause increased DNA damage and transposon activation. If the same happenes in stemcells, it causes stem cell exhaustion, cauing tissue degradation causing homeostatic inbalance which will cause further DNA damage, ROS dgraded proteome and transposon activation. ETC...
The point is, regular entropy based damage is orders of magnitude less than ROS or transposon caused damage, and we can knowck out transposons (though it is challenging as they are highly polymorphic)

>>15497283
>On a long enough timescale, maybe. But when talking about a few hundred years? No. The entropy and random error based ageing is so slow, it is only the first cause of a cascade which grows several orders of magnitude faster.
Right but it is the cause of the cascade. Hence the likelihood of "repo men" being morbid reality rather than gattaca or something else.
>The point is, regular entropy based damage is orders of magnitude less than ROS or transposon caused damage, and we can knowck out transposons (though it is challenging as they are highly polymorphic)
Let's assume that you can. How much time do you think it buys you to put out fires? Or do you think by putting out the fires you keep the rate of spontaneous fires steady? My thinking is you literally can't, and the number of fires will continue to escalate. Buying you time, but not stopping the process. Perhaps not if one ends up talking about "snap your fingers and DNA fixes itself back to perfect", but in any other case where you're talking attempted reversals causing their own errors, or wholesale macro organ replacements, etc, everything you do will do its own damage.

Still not sure if I am being understood on that or not.

>>15497337
>How much time do you think it buys you to put out fires?
Well quite a lot. I mean we are talking about a system that is multiple fold selfe streangthening. So removing some of the mechanisms can net you several fold your original lifespan.
Just knocking down the IGF-insulin signalling pathway to slow down cell turnover nets you an 8 fold increase in lifespan in the modeloragnism C. elegans.
Sure you are putting out fires, but it matters if the fire is a barrel of gas or wet wood. Something will break eventually. But fixing only a few things can net you several centuries.
I understand the principle you are talking about, but this is abstraction. The experimental results and concrete systems show we can get significan intcreases.
And what i'm trying to explain is, that your abstract approach doesn't seem to comport with reality at times. You said something along the lines of major changes would be impossible via genetic engineering. But we can do major changes already. Extra limbs, 3 times the muscle...
Also, you say replacing organs like that's a bad thing. But we can grow kidneys from induiced pluripotent stemcless, which are not rejected by the immune system, and are large enough to function in rats (growing them bigger is a challenge for now). I don't see how getting a new heart or kidney grown for you is a bad thing.
So i still think you are wrong about your pessimistic outlook on genetic engineering.
I may be missing something though, so please explain to me in more detail if you like, how major changes induiced by genetic engineering are impossible.

>>15497410
>I understand the principle you are talking about, but this is abstraction. The experimental results and concrete systems show we can get significan intcreases.
I suppose I am a lot more cynical about it given the lack of generalizability of a lot of examples. Case in point, C. Elegans. A lot of modifications do not just get you 8 fold increase, or the same modification gets you none or barely any. The other examples just don't seem relevant. I don't see them as significant improvements relative to the scope of the problem. Yes, they are significant relative to prior achievements, but not the scope of the problem.
>I don't see how getting a new heart or kidney grown for you is a bad thing.
Watch "repo men" if you haven't. The bad part is what people do with it. I did try to be explicit about that by the reference

HOWEVER- we can sweep all that aside. The problem is attempting to put out fires causes damage that, in turn, further shifts the fulcrum toward inevitable catastrophe. It is not that I am cynical about extension AT ALL, it is that I am dubious about how much time that buys you.

So without "finger snap magic perfect DNA repair" you will get those additive damages and errors. I am a bit dubious as to whether or not we can do anything better than what has evolved to do exactly that already, and probably the most effective thing would be just to use what the body already does and help it be better at it. Even then, the oldest by verification has been 122. That does buy significant time, if you could help the body along similarly, but your upper limit is still only in that ballpark if you do the equivalent of copy-pasting. Then with organ replacements, I'm not sure in the end that is really all that helpful for total life extension of some upper limit, though it'd absolutely get lots more people closer to it.

>>15493056
The title of those books always make me laugh.
My wife has a balanced chromosomal translocation t(8;12) and from doctors told us, it’s impossible to select embryos to make sure our future kids don’t have it.
If something so simple can’t be done, I’m curious to see how they will gene edit us into superchads.

>>15497579
W-will you Handmaid's Tale?

>>15495702
I am not seeking to promote anything. I want to learn more about an area of science that's becoming increasingly important.

https://arep.med.harvard.edu/gmc/protect.html

>>15497436
>generalizability
This is a fair point, the 8 fold increase based on the IGF pathway does not translate to an 8 fold increase in the case of mice. More like 1.6 if i remember correctly. So absolutely you are right on that one. It was just to illustrate a point, that whatever the system is that contributes most to ageing, interfering with that system can be largely beneficial. In humans, and mammals in general, the IGF pathway is far better optimized, and so is general DNA repair.
However, you can't deny that transposons play a crucial role in almost every aspect of ageing, and silencing them should cause significant increase in lifespan. If something speeds up ageing by several orders of magnitude in each aspect of the ageing process, it stands to reason, that silencing that mechanism would push out the inevitable breaking point in all of the systems it is involved with (which is all of them).
> The bad part is what people do with it.
Well sure, but that's true for all inventions. Isn't it? We can't stop inventing stuff because people may misuse them. That would put a hault to all human development.
>attempting to put out fires causes damage
I don't think i agree with this part. Removing the gasoline that soaks the wood may make the wood dry, but it will still be less flamable. And transposons and the senescence cascade are just that in tearms of ageing. Gasoline.
>how much time that buys you
This is going to be really interesting to see. You are right. We are putting out fires. Though i prefere the analogy of a barrel with planks of varying leangth. The shortest plank will let out the water. Put a new plank there, and the next shortest one will be the problem. I can make educated guesses, but that's it. We will have to see how reality fucks up my and your predictions.
>finger snap magic perfect DNA repair
Unfortunatly that really does seem completely impossible. Shame.
1/2

>effective thing would be just to use what the body already does and help it be better at it
Interesting that you should mention that. Consider the germline. The germline virtually does not age (especially with male line gametogenezis). This almost perfectly unageing nature is afforded to it via the use of the PIWI piRNA pathway. Similarly, cancerous cell lines tend not to age, you can maintain them ad infinitum. ALL cancers have activated PIWI piRNA pathway. The few "immortal" animals out there like planarians or hydra vulgaris or some acoels, all have somatically (or atleast stem cell line) active PIWI piRNA pathway. The function of this pathway is to effectively silence transposons, maintaining the integrity of the genome, orders of magnitude more effectively.
Similarly, the evolutionary adaptation that makes the difference between the 2 week to 2 month lifespan of worker termites to the atleast 20 years lifespan under lab conditions of termite reproductives is a partial somatic upregulation the PIWI piRNA pathway.
There are other cases, where things like zincfinger proteins designed to silence evolutionarily older transposons are upregulated causing significant increases in lifespan.
So we are infact trying to help the body better do what it already does, by attempting to use these mechanisms.
There are a few problems, namely that the piRNA biogenezis is complicated as fuck and is only partially understood (i hope to join a team working on this next year). Another problem is that transposons are very hard to ID and find, they are highly polimophic and transposase (the thing that reinserts the copyes into the DNA) is not sequence specific, its transposon recognition is also not fully understood.
Also, how exactly transposons activate over time is not fully understood, though we have recently made a breakthrough on this point (As i said we publish next month if nature stops dicking us around even though the article is accepted. Fucking assholes.)
2/2

>>15496659
The 6 billion figure is the length of the diploid genome, so a single copy of the genome is 3 billion base pairs

>>15499116
well yeah but he was right I should've specified which I was using

>>15497583
I will probably consider re-marrying if she can’t have kids. I’m optimistic we’ll have some eventually though.

>>15498625
The damage metaphor doesn't apply in that case as much no, was more for transcription related errors or organ transplants etc stressing the total system. Just a point about diminishing returns.
>ALL cancers have activated PIWI piRNA pathway.
>Similarly, the evolutionary adaptation that makes the difference between the 2 week to 2 month lifespan of worker termites to the atleast 20 years lifespan under lab conditions of termite reproductives is a partial somatic upregulation the PIWI piRNA pathway.
>So we are infact trying to help the body better do what it already does, by attempting to use these mechanisms.
See this is the problem I was having though. In humans if you do that you get cancers, for example. That is, the upregulation in termites? If you upregulate in humans, you develop cancer.

So the problem I'm having, conceptually, is that if you just splice something in, lacking all the other regulatory frameworks or other compensatory genes and functions, bad stuff happens. You end up with a problem that requires so many additional spliced in functions, and which would need to work along side all the others without causing still other problems, that it may in fact not be possible due to the complexity involved.

Thing is the problems you list, you don't talk about that. You're talking about difficulty in identification, and similar, but that is actually the easy problem. The hard problem becomes somehow figuring out the new homeostasis and what its implications are. I don't think I am completely ignorant of the relevant computational publications, but from where I'm standing we are NOWHERE near able to do anything like that. Way too many variables and way too hard to calculate what something will do placed in all those variables if it has subtle effects. In easy cases we can, sure, but IIRC not really unique cases of very high order complexity like would be required. So you get a lot of dead mice instead.

>>15500133
>In humans if you do that you get cancers
No, it prevent's cancer, as cancer is caused by mutations, and transpososnare responsible for the vast majority of mutations. Also, the idea is to activate it in stem cells, and spped up sensecence formation as well as senescent cell clearance (This would be a multilayer defense against cancer and it would also slow the ageing process). Once the cancer forms it activates this pathway to remain immortal, it does not cause cancer in of itselfe. Cancers also enhance vascularisation, yet we don't say vascularisation causes cancer.
>So the problem I'm having, conceptually, is that if you just splice something in, lacking all the other regulatory frameworks or other compensatory genes and functions, bad stuff happens. You end up with a problem that requires so many additional spliced in functions, and which would need to work along side all the others without causing still other problems, that it may in fact not be possible due to the complexity involved.
I understand this framework, but i'm not sure i agree. We are wll suited to changes in resource consumption, as without this evolution would be much harder. And we have evolved to evolve.
So for instance if you modify the hox genes of an invertebrate, to gain an increased number of segments, it will eat more, but it won't be much different otherwise. Which is exactly why evolution does just that, quite frequently.
1/2

>figuring out the new homeostasis
As long as cells can keep functioning as they have, without changes in uptake of material more significant than the upper limit of the endocytotic and chaneel pathways, i don't see why there would be a problem.
Lets stick with the example of ageing for now, as that is what i know in detail.
Somatic cells go senescent due to increased transposon activity, to prevent cancer, and cause neighbouring cells to go senescent too. This causes a senescence cascade, which can cause tissue degradation. The cascade is stopped by senescent cell clearance. As you age, increased transposon activity increases the rate at which cells go senescent, and decreases the rate at which they are cleared.
If at this point we increase clearance, replacement by stemcells needs to be increased. The signalling for that would come naturally, but it would increase stem cell exhaustion, as transposons act most harmfully at cell division. Introduceing the PIWI piRNA machinery to the relevant stem cells would solve that, but to make more stem cells, you need more material, enough to get all new stem cells well fed. They feed from the bloodstream. The material uptake rate per cell would not need to increase, but the material uptake rate over all would. However, this is no different than the fact you need more material uptake if you work out.
So where would the homeostasis be lacking?
And on a more general note, we add new genes to cells all the time, and it never seems to cause any problems. UAS-Gal4 systems, GFP. SImilarly, we add entire new areas or even organs to animals and they cause no significant issue. Much of developmental biology research depends on this kind of modification, but similar stuff is done in medical research. I mean the grew an entire human ear on a rat, and it didn't seem to mind.
I think i'm just not getting what you are trying to say, maybe i'm just retarded. Can you give me a detailed example?
2/2

>>15500629
>No, it prevent's cancer
I'm sorry, what? No it does not. If you upregulate it in humans it can cause other kinds of cancers. Sorry but you've completely convince me you don't understand the topic at all.

>>15501856
PIWI piRNA decreases mutagen activity. Mutagenezis contributes to the formation of cancer. There fore PIWI piRNA helps prevent cancer.
If a cell has almost gone cancerous, the only thing preventing it from doing so is the hayflick
limit, the active PIWI piRNA pathway will help it become cancerous.
If you have any evidence that this is not the case, i'm going to need a fucking citation.

>>15502624
>If you have any evidence that this is not the case, i'm going to need a fucking citation.
Sure. Most examples involve what you mentioned as cancerous cells upregulating/overexpressing hiwi (human piwi), but it is also directly tumorigenic
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3306289/
>However, the role of Hiwi in tumorigenesis has not been examined. Here we demonstrate that (1) over-expressing Hiwi in sarcoma precursors inhibits their differentiation in vitro and generates sarcomas in vivo; (2) transgenic mice expressing Hiwi (mesodermally restricted) develop sarcomas; and (3) inducible down-regulation of Hiwi in human sarcomas inhibits growth and re-establishes differentiation. Our data indicates that Hiwi is directly tumorigenic and Hiwi-expressing cancers may be addicted to Hiwi expression.
>Additionally, our data showing that Hiwi-associated DNA hyper-methylation with subsequent genetic and epigenetic changes favoring a tumorigenic state reconciles the conundrum of how Hiwi may act appropriately to promote genomic integrity during early development (via transposon silencing) and inappropriately in adult tissues with subsequent tumorigenesis.
>In conclusion, numerous recent reports of high levels of Hiwi in all cancers examined have raised important questions about the role of Hiwi in adult neoplastic tissues and seem to contradict its known roles in maintaining genome integrity in both germline and somatic stem cells. The data presented here are, to our knowledge, the first to define a causative oncogenic role for Hiwi in human cancer and to elucidate that DNA methylation dependent silencing of tumor suppressor genes accounts for the tumorigenesis. In doing so, we not only reconcile Hiwi's genomic protective and tumorigenic properties but also provide a therapeutic rationale for treating patients with Hiwi-expressing tumors epigenetically by means of DNA-methyltransferase inhibitors.

You can't just upregulate things.

>>15502708
>You can't just upregulate things.
This is true.
Ok, so the article. In the first half they tried to upregulate HIWI in sarcomas, which are forming cancers. So this is exactly what i said.
The second part about transgenic mice with HIWI upregulated in prx1 promoter active mesoderm is actually quite interesting. Now if you recall i did say that activating the entire PIWI piRNA pathway in the soma is subomptimal, and that it ought to be, as in nature activated in stem cells. I would also argue, that a sample size of 51 is not exactly ideal.
That being said, the research is valid. However, you seem to be conflating two things. HIWI is a single protein in the PIWI piRNA pathway. Activating only HIWI without induiced piRNA geneis, without the factors that process it, is meaningless. You just showed me that activating a lone protein which helps methylate DNA, without activating the targeting mechanism will do more harm than good.
Which... yeah. But its irrelevant to our discussion.
There are sveral systems, proteins, several large scale changes you can make to animals, and they will be fine. And when i say the PIWI piRNA system acts against cancer formation, i am right. YOu showing me a piece of research showing that one element of the pathway alone may contribute to cancer formation does not disprouve that.

Bump

>>15498585
That`s the spice

>>15502854
>This is true.
That was my whole point. I don't particularly care as to the quibbling over whether some given example is evidence of the general concept if you already agree to the general concept. What would the point be to that? I disagree with your interpretation of the finding, and there are others indicative of general tumorigenesis, but it doesn't matter if you already agree on that.

The whole problem is what you've been writing left me with a very strong impression you have a rather simple view where you can just upregulate things as "thing do good now therefore turn to 11 do better". I am sorry if that seems very uncharitable, but in my experience that is the overwhelming majority of people arguing strongly for some optimism in genetic engineering.

>>15504400
>thing do good now therefore turn to 11 do better
This is obviously not ture. I understand that point.
But throughout this whole conversation you failed to adequatle explaing you point, and you have brushed off any instance in which you are wrong.
You claim a pathway to be tumorgenic, and you show me research where the effector of a mutagen silencer withouth being targeted to the mutagen is harmfull. This is an instance in which you clearly were wrong, yet you brush it off. I give you examples where large scale genetic changes can be made like the myostatin loss of function, and you brush it off. I give you exaamples where an intracellular transgenesis has no negative effect like the UAS-Gal4 system (though there are countless other examples like full metabolik changes such as the hydrogen sulfide pathway being inserted into cells), and you brush it off.
I get your point. Changing expression patterns will have an effect on the core functioning of the cell. And something being identified as having some positive effect in an increased concentration doesn't mean you can over express it even more and more and expect a linear return on gain in whatever the benefit.
But to pretend this is some insurmountable barrier to significant genetic modification, or that we are facing some complexity so vast we can't hope to overcome it is just... silly.

>>15493056
from what i gather as a guy who has never read a single book about it but he remembers the regulations bullshit they put onto cloning research id say ethical boundaries are the thing holding back research into the field of altering organic stuff, i'm surprised we can even make organs lab grown much less tamper with humans on that level
hearsay during the time when they were cloning the sheep was that they had ran into some kind of wall on genetic modification and found their soft cap limit on what they can do with it without fucking people up with ripple effect, take that with a grain of salt i was young back then and it could have as well been some bar talk

>>15493056
Why are jews like this?

>>15504481
I don't think Cobb is a Jewish name.

>>15504484
well historically jews have been famous for taking any last name that benefits them, just look at their time in germany and how they all became bergs and steens

>>15504464
>This is obviously not true. I understand that point.
Your examples so far have been "look we can blindly upregulate things and produce multiple limbs and other circus tricks". Stop treating my raining on that silly parade as if I am James Tour.
>You claim a pathway to be tumorgenic
Dysregulated metabolic pathways can be. Water is also wet. As written already.
>and you show me research where the effector of a mutagen silencer withouth being targeted to the mutagen is harmfull
The context is, your examples were very simple, macro changes like extra limbs. Now when shown the same simplified model where "look we can grow ears on mice" doesn't work in reality, you claim I'm clearly in the wrong... when my point was those simple examples were wrong to use in the first place. You don't get it both ways. Either your earlier examples aren't examples by your current standard, or you accept my example refutation of that simplification.
>I give you examples where an intracellular transgenesis has no negative effect like the UAS-Gal4 system [...] and you brush it off.
Because while impressive relative to prior progress, the scope of the problem looms large. I wrote that already, so claiming I am "brushing that off", you must have brushed off my criticism of such examples. et tu brutus?
>But to pretend this is some insurmountable barrier
Treating me like James Tour doesn't make your bad examples arguing for optimism and magical ponies any less bad. Ignoring the context of what was written before to act shocked and appalled as if I've suddenly changed what I've been writing, or you wrote something different than what you wrote earlier, is only going to trick people who don't read the conversation. Or apparently have sleep induced amnesia as you now seem to. Re-read the fucking thread please.

And stop depicting me like James Tour.

>>15504493
>>15504464
And since you're being such an uncharitable ass with such a convenient memory, obviously when I write here "doesn't work in reality" that is in context of the reality of the START of the whole line of conversation about public interest in complex phenotypes, as well as complex diseases.

>>15504493
>>15504496
Ok, so intracellular changes (where you only adress the usa-gal4 system and BRUSH OFF the hydrogen sulfide pathway) can be made, and we can grow ears and new limbs, but those are circus tricks for some reason. Also you shfit the goalposts in the tumorgenesis case to dystegulating metabolic pathways. Yes, disregulating metabolic pathways can be tumorgenic, but that's not what we were arguing about. Pointing that out is not undcharitable.
>simple, macro changes like extra limbs
Simple? Ok, so what is an example of a complex change? YOu never explaing your point, you dance around it. Or project or i don't even know what you are doing. What is your point? Give me an example of a kind of change you think impossible. (I have asked you several times and you refuse to do so)
>simplified model where "look we can grow ears on mice" doesn't work in reality
I don't even understand what you are saying here. Did researchers not grow ears on mice? What do you mean doesn't work?
>my point was those simple examples were wrong to use in the first place
How? Explain to me in detail how these are wrong. Make a fucking point already.
>Because while impressive relative to prior progress, the scope of the problem looms large. I wrote that already,
Where?
>Treating me like James Tour
I have no idea who that is, but you clearly seen to be arguing that large scale genetic changes are impossible. Are you not?
Your entire initial point was "too many nucleotides need to be changed in the case of polygenic traits". How is that even a rational argument to make, when we obviously don't do genetic modification one nucleotide at a time.

I want you to clearly describe what you think is impossible, why, and how my examples are not refutations of their imossibility.

>>15504510
>where you only adress the usa-gal4 system and BRUSH OFF the hydrogen sulfide pathway)
Yeah okay kid I'm not going to bother on a back and forth where I reference portions to save time and text limit and you twist that into some little victory for you.

You have fun with that.

>>15504518
So no argument, no answer, no aknowledgement of where you were wrong, nothing. You even refuse to illustrate your point. You are the problem with the scientific community.

>>15504545
>So no argument, no answer, no aknowledgement of where you were wrong, nothing. You even refuse to illustrate your point. You are the problem with the scientific community.
uh huh hey I wonder if I humorously predicted your continued bad faith misrepresentations oh right hang on >>>15504496
>And since you're being such an uncharitable ass with such a convenient memory, obviously when I write here "doesn't work in reality" that is in context of the reality of the START of the whole line of conversation about public interest in complex phenotypes, as well as complex diseases.
You: >>15504510
>I don't even understand what you are saying here. Did researchers not grow ears on mice? What do you mean doesn't work?
I'm psychic.

The problem isn't the scientific community. You need to look in a mirror.

>>15493056
>genetic manipulation
Not real until people transform like Rick and Morty. And then? It will be mundane.

>>15504488
I don't think studying genetics is a bad thing. Genes are a fundamental part of life. Obviously it's something you've got to take very seriously and be very careful with, but to demonise people who want to learn more about genes smacks of obscurantism.