About 18-24months ago I went through a phase of listening to geneticists talks/conferences/podcasts for an hour or two a day during long runs, it’s so far outside my wheelhouse I’m probably mixing things up, but I thought I recalled cutting edge experiments using synthetic cells to create artificial life (a worm perhaps with a relatively simple DNA, maybe even a modified DNA further simplifying the genome to the furthest extent possible still resulting in life) with one of the goals of understanding the exact functions of all the genes in this “simple” DNA. Again I’m probably mixing up multiple discussions and studies into one, but I would have been very surprised if the function of every single gene in the human genome was known and understood, as suggested by the title.
I worked with mycoplasma genitalium which is a "minimal" organism- an extremely small number of genes, nearly all of which appear to be absolutely required for viability. It's sort of a unit test for model biology, except it grows so slowly it's more like an integration test in terms of performance.
This expert from the first link is very likely what I was poorly trying to regurgitate:
> Mgen still has the smallest genome of any known (naturally occurring) self-replicating organism and thus is often the organism of choice in minimal genome research. The synthetic genome of Mgen named Mycoplasma genitalium JCVI-1.0 (after the research centre, J. Craig Venter Institute, where it was synthesised) was produced in 2008, becoming the first organism with a synthetic genome.
> The work in this area is quite extraordinary, but typically gets much less attention than anything that works with human genomes.
In fairness laymen like me would just get us all mixed up with a worm genome anyway ;). In my defense I’m just a lawyer that likes to listen to foreign topics I find interesting while I run, but it is nice to confirm I have good instincts, because I really did find this work to be extraordinary and fascinating.
Well, depending on how broad your definition of life is, viruses have the most stripped down genomes of all. In the smallest viruses, with genomes of just under 10kb in length, nearly every basepair is dedicated to either infection or replication. In fact, they are often so compact that open reading frames are interleaved, in order to provide more functionality without increasing size.
Scientists often refer to viruses as "obligate", in order to sidestep the question of what is life, as most have no interest in the topics which occupy philosophers. In any case, they are non-cell based, for whatever that is worth. I imagine in a non-hostile environment, even the infection functional would be shed, and you would be left with just replication, which is the fundamental component beyond which no further reduction in complexity can be made.
> I imagine in a non-hostile environment, even the infection functional would be shed, and you would be left with just replication
A virus replicates by infecting another cell and taking over its actual replication infrastructure, so getting rid of infection gets rid of replication too.
> viruses have the most stripped down genomes of all
Giant viruses can have over 1M basepairs, substantially larger than a bacteria such as Mycoplasma genitalium, with substantial functionality (pretty much everything except the ribosome in at least some of them: https://www.virology.ws/2018/03/08/only-the-ribosome-is-lack...)
> I recalled cutting edge experiments using synthetic cells to create artificial life (a worm perhaps with a relatively simple DNA, maybe even a modified DNA further simplifying the genome to the furthest extent possible still resulting in life)
A worm seems super-complex for something like that. I'd guess they'd actually use a bacterium.
I thought some work on it made HN, but can't seem to find the article, about a research group that was continuing to strip things out and then test viability.
I wish I could be more helpful, but this was during a period I was distance running everyday for years without much concern on what I was consuming so long as I found it interesting.
In terms of popular podcasts maybe I could say Lex Friedman, but then I might search for one of his guests, or specific topics I wanted to learn more about, on YouTube and look for lectures or panel discussions in the results that looked like they might be high quality.
Not sure if you’re doing it a service or disservice calling it chaos engineering: at best it’s related. If you want to figure out what a complex system does where you have no ability to “see”, the only tool you have most of the time is to knock out individual components and see what happens.
As you might guess this is generally a blunt tool which can help you get to the first 30% of the understanding of the system but minimal extra data after that. The majority of genes discovered in this study would either be already known players in those pathways or unknown genes that would already have been guessed to play a role.
Until one of these massive screens tells us what the major vault protein complex does they should all be honest about what they are which Imo is just a minor addition.
It says that some genes result in the same outcome when knocked out as other genes, and identifies novel genes that putatively participate in the same pathways as others. This helps get at the potential function of genes without known functions.
So, people do this a lot and frequently make mistakes. For example, when you knock out a gene, you also damage any overlapping genes (yes, genes can overlap). most studies don't pay attention to the damage they do to overlapping genes.
The underlying physical model for how gene products interact to make phenotypes ends up being so hopelessly complex and latent that most conclusions in this area end up being "sufficient, but not necessary" instead of "necessary, but not sufficient"
> It says that some genes result in the same outcome when knocked out as other genes
a very useful map to make, but I don't see that this contradicts my comment - both genes in this case are dependencies to the outcome, without either of them, the outcome fails
this does not sound to me like we know the "function" of these genes, only that they're nessary for each phenotype
not to knock the research, just trying to make sense of what they're really mapping, in my own language of computer code (i suppose "function" has a different connotation in genetics)
> this does not sound to me like we know the "function" of these genes, only that they're nessary for each phenotype
But they're not even measuring the phenotype. They're using the transciptional signature as a substitute for phenotype/cell function (i.e. the bag of RNA model). This is a poor substitute if you try to apply this to practical applications such as cell engineering. Let's say I perturb a cell to match it's transcriptional signature to that of a neuron. Does that make it a neuron? Not if it doesn't function like a neuron.
I think this is a really important point. With a few exceptions (like the neat implied aneuploidy assay), they haven't measured an outcome or phenotype for the genes. They have measured the impact on transcription (well, mRNA levels, via transcription or some other effect). That is an extremely useful dataset, but it's not enough to say what the phenotypic effect of knocking out any given gene is, much less what the actual mechanistic function of the gene product is.
It's also important to note that there are loads of genes whose effects are not mediated by changes in mRNA levels. If you knock out Arp2, a cell can't move properly, because Arp2 is involved in assembling cytoskeletal structures needed to do that, but you probably won't be able to tell that by looking at the cell's mRNA.
> "this outcome fails when this byte of data is missing"
The outcomes here are not failures, they are measurable phenotypic differences, which they use to group genes into phenotypic outcomes. The typical "knockout -> failure to perform a function" is not what's being measured here.
It's kind of a dead end I feel. It can turn out that everything is used for everything. It's not designed so there is probably no clean decomposition nor is it necessary.
Turn off the genes that would make my child below 6'5 in adulthood, turn off the genes that wouldn't make him naturally muscular, turn off the genes that would give him an average intelligence, etc.
This doesn't really pass the sniff test; if there were any easy one-gene changes that resulted in unambiguously better results, it's highly likely that we'd all have them already.
Well, these aren't unambiguously "better results", not in a biological sense. Just better in terms of what our culture values, and not necessarily better survival and reproduction.
BCRA mutations: "It’s estimated that 55 – 65% of women with the BRCA1 mutation will develop breast cancer before age 70" [0]
ApoE4: "individuals with two versions of the ApoE 4 gene have a 50% chance of developing Alzheimer’s" [1]
HTT: The Huntingtons gene. If you have the wrong version of this gene, you will get Huntington' disease.
All that to say that, in these cases, sure _most_ people have positive traits from these genes, not all do and we could theoretically use CRISPR to change people with the negative versions of these genes to the positive versions of these genes.
It's embarrassing when self-appointed "bioethicists" do nothing but handwring about distant transformative technology - stuff that could confer such incredible benefits on humanity and that we are light-years from having.
It's so easy for them to posture as virtuous protectors of humanity, sowing FUD about things that are so far from existing that nobody even understands how they might work or what capabilities they might have or not have. So easy, when the benefits are nowhere near close enough to factor into anyone's near-mode thinking.
I'm cheering for the scientists. Give us the choice to have brilliant, strong, healthy children. Then laugh at how little anyone cares about the so-called "ethics", facile cloud-talk that never considered real people facing real decisions.
The "ethicists" had their chance to intelligently weigh the pros and cons and give real advice based in prudence, empathy, and a love for human flourishing. They chose to self-indulgently chinstroke about dystopia on the taxpayer dime.
$10M+ now and then in 20 years figure out that changing that gene sequence creates a dramatically higher likelihood for Alzheimer's or infertility. I personally am not against the modification of humans in practice, I think it's an interesting opportunity for humans to take control over the evolutionary process and optimize ourselves for the world we live in now (and future ones), e.g., what if we could minimize the amount of sleep needed, or our tolerance to heat so climate effects were somewhat mitigated, or so our bodies were less affected with long periods in space? The tie-in of capitalism to it creates a weird dynamic but I'm not sure I see an obvious better solution unless we want to outlaw everything except for government approved research and let the ideas be at the whims of whatever bureaucrat or political appointee happens to be in charge at the time.
>$10M+ now and then in 20 years figure out that changing that gene sequence creates a dramatically higher likelihood for Alzheimer's or infertility
Not only that, but any genes that are not selected against (e.g. your Alzheimer’s example, which occurs after reproductive age) are now permanently circulating in the population, with absolutely zero (humane) way of ever removing them.
In the short term, a lot of gene therapy focuses on the set of diseases where the repair really does seem to be "change this one base" and there are no side effects due to complex, unknown gene interactions or other unexpected phenomena. m And nearly all of it (I haven't looked at the details in a while) is just treatment (IE, injections of a gene therapy in a post-birth individual), rather than preventive by germline manipulation, which IMHO
It's likely that for the time being we'll only use gene therapy for things which are recognized as devastating diseases and the treatment is extremely reliable; germline modification for enhanced attributes in typical individuals is still a fairly out-there concept that would probably get panned in the media.
I have seen Gattaca and don't find human genetic engineering to be horrific. It's cool and exciting that people will be able to have better children than they would have otherwise.
> I have seen Gattaca and don't find human genetic engineering to be horrific. It's cool and exciting that people will be able to have better children than they would have otherwise.
Did you even pay attention to the movie? The horrific aspect was the human genetic engineering led 1) to the the unengineered to be turned into an underclass that was blatantly and unfairly discriminated against, and 2) that same discrimination would be turned against the engineered if they had an accident that caused them to fall short of the expected perfection.
I have little doubt that the reality of genetic engineering (that was is effective as that depicted) would rhyme with that movie. It's also nearly certain that any such technology would not be distributed in an egalitarian way, so the sentiment should be more like "it's cool and exciting that [well off] people will be able to have [genetically superior] children than [the plebs]."
I understood the intention of the movie, but I'm also in the camp that thinks engineering ourselves is the way forward, and a given. Genetic and silicon advances have a real potential to make us super/transhuman and immortal.
> It's also nearly certain that any such technology would not be distributed in an egalitarian way
This argument could have been made about early computers as well. But time and its economies of scale come into play. We can't limit our species based on shortsighted fairness, there's a longer view to take.
> I understood the intention of the movie, but I'm also in the camp that thinks engineering ourselves is the way forward, and a given. Genetic and silicon advances have a real potential to make us super/transhuman and immortal.
Techno-optimism hasn't really panned out as promised.
And I really doubt it will be "us." If trans-humanism pans out (though I suspect it's bunk), we'll be the Homo erectus populations to their Homo sapiens.
> This argument could have been made about early computers as well. But time and its economies of scale come into play. We can't limit our species based on shortsighted fairness, there's a longer view to take.
Capital got automation from computers, the plebs got distraction boxes that push ads.
Hrm. So what? How is that different from the uneven distribution of money/wealth/power/medicine/upbringing/private schools/university/"connectedness" today?
This will be just another currency. And there will be some flops, busts, unintended consequences. Just like with anything else.
> Hrm. So what? How is that different from the uneven distribution of money/wealth/power/medicine/upbringing/private schools/university/"connectedness" today?
Vague resemblance does not an equivalency make.
Right now, there may be an unequal distribution of wealth, etc.; but the wealthy by and large aren't actually better models of human. Genetic engineering has the potential to ossify that (both morally via "meritocracy" and physically) with biological superiority. It stops being Homo sapiens vs Homo sapiens, and becomes something more like Homo erectus vs Homo sapiens.
We have underclasses based on genetics now. Let's not pretend mate selection on Earth in 2022 is a meritocracy. It's mostly just racism, a slower form of deliberate genetic engineering of one's offspring.
If anything, this would increase the amount of opportunity in the world, as then your child could have whatever traits you (or your culture) deems superior. It would perhaps eliminate racism by rendering traditional race markers completely obsolete.
> It's cool and exciting that people will be able to have better children than they would have otherwise.
You know, I used to be wary of eugenics, but when you put in that light, yeah, I'm kinda tired of putting up with everyone's crap kids. If you could make them be quiet, sit still, and do as told, that would be a fantastic achievement! Oh, and maybe make them smarter, too. Ever try to actually talk to one (the newer ones are really pretty stupid)?
People will balk at this, which is funny in contrast to how much human energy is poured into ego, signaling and mate selection as proxies for perpetuating favorable genetics.
- this is performing an irreversible procedure on a person without their consent. Justifiable for a disease but less so for vanity traits.
- genes are pleiotropic and modifying multiple genes could have unexpected effects. An easy example is that taller people have a higher risk of cancer. Barring some great advance in predicting the effects of genetic changes, this will remain a problem.
- it has a homogenising effect, optimising for traits a culture finds appealing and that can be easily measured. You will eventually get a eugenic army that all look like swimwear models and score highly on IQ tests.
At the same time, I think that modifying the organism is the only way to get rid of diseases like heart disease and cancer.
Given that people already travel for IVF to cheaper locations abroad (Ukraine was one of them until the war), it is going to be more like $100K+ in the future.
Medicine is practised outside the US as well, including high tech medicine. And for a much more reasonable price tag.
I think so. Alexander Graham Bell, Helen Keller, Winston Churchill, Plato and there are countless more. Just because we didn't have the technology to implement it humanely in the past doesn't mean it can't be done in the future.
In fact. I would consider a society, that has the capability to noninvasively eliminate for example sickle cell anemia or Huntingtons and doesn't because some people one hundred years ago did horrible things, barbaric.
Helen Keller defended a doctor's 1915 non-intervention in the case of a child that was not capable of "the possibilities of happiness, intelligence, and power that give life its sanctity, and they are absent in the case of a poor, misshapen, paralyzed creature", and then later supported adoption of disabled children, such as the a case of an infant with tumor-induced blindness saying "blindness is not the greatest evil, it is only a physical handicap. that is life. the annals of progress show that much of humanity's finest work has been wrought by persons with with a severe handicap, that she may be spared to help open the eyes of ignorance"
I hope that she can help you to open your eyes as well.
Sorry if i hit a nerve, but obviously if i wasn't "arguing in good faith" why would i have so painstakenly avoided mentioning hitler for like 10 comments?
conversely, everything i've said has been a direct analysis of what you've said.
you referenced helen keller's non-intervention in an instance of infant mortality as evidence that she supported eugenics.
It is that erroneous conflation that introduced euthanasia for discussion. (also i would say that technically intentional non-intervention is not exactly killing, so thats not even what i was implying)
I provided evidence that keller, contrarily, saw value in genetic defects.
If you have another reason for believing that helen keller was a supporter of eugenics, you have failed to provide it.
Churchill had some virtues of leadership, but he was an abominable racist and colonialist, even by the standards of his time.
>"Churchill is on record as praising “Aryan stock” and insisting it was right for “a stronger race, a higher-grade race” to take the place of indigenous peoples. He reportedly did not think “black people were as capable or as efficient as white people”. In 1911, Churchill banned interracial boxing matches so white fighters would not be seen losing to black ones. He insisted that Britain and the US shared “Anglo-Saxon superiority”. He described anticolonial campaigners as “savages armed with ideas”.
Even his contemporaries found his views on race shocking. In the context of Churchill’s hard line against providing famine relief to Bengal, the colonial secretary, Leo Amery, remarked: “On the subject of India, Winston is not quite sane … I didn’t see much difference between his outlook and Hitler’s.”"
>"He referred to Palestinians as "barbaric hordes who ate little but camel dung." When quashing insurgents in Sudan in the earlier days of his imperial career, Churchill boasted of killing three "savages." Contemplating restive populations in northwest Asia, he infamously lamented the "squeamishness" of his colleagues, who were not in "favor of using poisoned gas against uncivilized tribes.""
Also, Alexander Graham Bell supported eugenics because he was worried that deaf people procreating created human and social divisions.
Any modern medicine gene modification program would create the exact human and social divisions he sought to avoid... Unless you are somehow able to suddenly do gene modification universally throughout the entire planet..
so he doesn't really support your position either.
it has taken us 2 years to give 60% of the planet a $5 shot despite having 2x world population of shots available.
"capability" should not be confused with "universal accessibility"
and "some people one hundred years ago did horrible things" is a fictional strawman. There are real and present reasons why practically eugenics will lead to stratified and unjust conditions for humanity in practice.
Not just wealthy couples. Most parents want their children to be heterosexual and bear them grandchildren. Having successfully procreated, they are more likely to have natalist genes and inclinations.
Why would they need to be heterosexual to successfully procreate.
If the future is designer babies/baby incubation pods. It doesn't matter what sexual orientation the kid is. The parent would have a designer baby, then why would the child eventually not have a designer baby as well?
You will always need an Egg or Sperm depending on which is missing in the relationship. Also, one of the parents would not have genetic code in the offspring since you can't splice two eggs/sperm together as far as I know.
We already selectively breed for natalists and look how that turns out. It actually makes an argument that genetic predisposition to natalism is currently rather weak and it is mostly memetic predisposition in practice.
The demographic trends we're seeing now (declining birth rates for affluent people in the developed world) could be due to our natalism level being mis-calibrated for our current circumstances.
It's good evolutionary strategy to reduce the birth rate to compensate for successful reproduction (i.e. more pregnancies that result in offspring that reach child-rearing age themselves), as otherwise populations will explode beyond the carrying capacity of the environment (or pay more of the fixed resource costs of raising children than is necessary).
What we see now, however, is that in situations where both pre-adult and maternal mortality rates are exceedingly low (such as has been the case for the last ~4-5 generations in the developed world), the strategy undershoots the replacement rate.
Yea human culture will find a new level of 'basic' combined with an inferred and understood if not blatantly codified position of social superiority... Sounds more like twilight zone than social progress to me.
This already is what happens with sexual selection. That is the purpose of sexual selection from the point of view of genetic integrity. People are designing their babies every time they have sex. There's huge amounts of money involved there too. And like how do I know the geneticist isn't slipping his own in-born DNA in my place, like that fertility doctor did or that criminal inseminator who broke into poorly-guarded sperm banks and substituted his sperm for that of astronauts with Nobel Prizes? Had like 660 kids that way.
Like there good reasons to do this are, OK genetic malformation, ie osteogenesis imperfecta, that's a SNIP, totally. Or you were raped, want to punish that rapist by making the egg have even less genes in common with him than it would ordinarily, making his rape counterproductive genetically. Another good reason, defensible. Or you want to protect rare alleles, considering weaknesses to be strengths, this is like a left-handed man marrying a left-handed woman, or freckles (I think something about freckles make children hate them til they're 19, rare exceptions, not even the iconic Lindsay Lohan accepted her own freckles). Preserving their identity and diversity. Don't pass laws as much as using judgment to decide, individually and collectively, what the future will be. Talk and think instead of setting up magic words for lawyers to copy-paste--an isomorphic problem to genetic design.
No fucking blind copy-paste, don't use copy-paste with your copy paste to copy-paste yourself.
It doesn't say "this gene has this outcome" so much as it says "this outcome fails when this byte of data is missing"