[HN Gopher] New CRISPR-based map ties every human gene to its fu...
___________________________________________________________________
New CRISPR-based map ties every human gene to its function
Author : gumby
Score : 315 points
Date : 2022-06-10 15:54 UTC (7 hours ago)
(HTM) web link (news.mit.edu)
(TXT) w3m dump (news.mit.edu)
| loxias wrote:
| > New CRISPR-based map ties every human gene to its function
|
| The title would be so much better if s/its/a/.
|
| There is no way we'll have an operative map from "all" genes to
| function anytime soon. Sometimes hundreds of genes work together,
| interact with other microbiomes we contain or our environment to
| produce what might seem to be a "simple" quality like height.
| achenet wrote:
| There's an interview with Ken Thompson from about 2008 where he
| says that most of the work in CS has already been done, and he's
| advising his son to go into biology.
|
| I feel like CRISPR is the transistor of the 21st century.
| dekhn wrote:
| CRISPR is more like a machine to make large-node-size
| integrated circuits. Somebody else has to design the circuit,
| make it manufacturable, and integrate the circuit with a whole
| bunch of other hardware.
|
| I work in biotech at a company that is one of the few golden
| geese that lays 2-3 successful drugs with no competitors every
| few years. I have 30+ years of experience (deep experience) in
| machine learning, biology, and computer science.
|
| We are so far behind where we could be, in terms of turning
| biology into technology, that's almost shameful. Every day I
| see another system that says it can generate 10 times the data
| of the previous machine, but the actual amount of knowledge we
| are extracting for all that data collection is growing
| logarithmically. This is because for a long time biology has
| greatly underfunded computing and data.
|
| The one great shining light is AlphaFold. AF2 finally
| demonstrated to a wide range of scientists across many domains
| that a really great team using techniques that are barely known
| outside of FAAMG can work with some long-term experts to move a
| metric (quality of predicted protein structures compared to
| golden data) substantially further and faster than even the
| most wildly optimistic predicted. Not only that, some of the
| techniques they used didn't even exist several years ago
| (transformers, jax, various graph learning systems), and the
| work was replicated externally once the leading academic team
| had a hint of the direction to go in.
|
| To me, nothing about what I said is surprising to me; I
| predicted these outcomes a long time ago. Most of the reasons
| that it comes slower than it could are combinations of culture,
| incentive, morals/ethics, politics, innovator's dilemmas and a
| hundred different bottlenecks. Recently, the challenge has been
| that most of the really smart computational biologists
| disappear into FAAMG and don't contribute back the things they
| learn there to research.
|
| We're all waiting for that next moment when the cross product
| of Genentech and Isomorphic Labs announces that they have a
| computational model that can do end to end prediction of drug,
| from initial disease target to FDA approval post-phase III
| trial. That's been the dream for some time but we're nowhere
| near it still, and it remains to be seen whether some group can
| conjure all the necessary bits to solve the remaining
| underlying problems associated with that "far beyond NP-hard
| problem"
| Invictus0 wrote:
| AI?
| JKCalhoun wrote:
| Perhaps also future biology?
| jazzyjackson wrote:
| I'm still holding out for photonics and other optical-analog
| computers (where are my instantaneous trig co-processors?) but
| that does sound like good advice
| foobiekr wrote:
| The problem with this is that biology will likely end up
| dominated by China due to a willingness to conduct experiments
| that are otherwise non-viable in most countries.
| jeffreyrogers wrote:
| There's still so much basic research to be done that I doubt
| this will be a limiting factor for a while.
| ornornor wrote:
| > non-viable
|
| Did you mean unethical or are you talking about something
| else?
| mod wrote:
| Forbidden by law or fear of backlash (often due to ethical
| implications)
| jarenmf wrote:
| Yeah, it feels like most fields are stagnated except for
| biology and neuroscience. I am a postdoc right now but have
| considered seriously switching fields to work on something
| exciting.
| PartiallyTyped wrote:
| I fail to see how CS has stagnated since 2008, so I hope
| somebody could illuminate it for me.
| shimon wrote:
| I studied CS and now work in software systems for biomedical
| research. It's difficult to overstate how different the fields
| are, so I don't entirely agree with this statement. But I do
| agree there are going to be lots and lots of huge discoveries
| in biology in the 21st century.
|
| The main difference is that CS attempts to generate and study
| complex systems built from well-understood components, whereas
| biology attempts to understand and manipulate systems that
| evolved naturally over eons.
|
| Imagine dropping a fully functional internet-connected Google
| Home Hub into 1960-era humanity and asking them to figure out
| how it works so they modify it to sound like Walter Cronkite.
| There are thousands of problems on this order of complexity in
| biology. It's wild.
| tyre wrote:
| think of the tech debt in our legacy codebase
| elevaet wrote:
| 3.7 billion years of refactoring has kept it pretty clean
| and functional. We'll need to do a shit ton of unit and
| integration testing before we commit changes.
| jazzyjackson wrote:
| This is basically chaos engineering applied the the genome
|
| It doesn't say "this gene has this outcome" so much as it says
| "this outcome fails when this byte of data is missing"
| throwawaycities wrote:
| 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.
| tablespoon wrote:
| > 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.
| dekhn wrote:
| 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.
|
| You are probably referring to Mycoplasma genitalium JCVI-1.0
| ( (see https://en.wikipedia.org/wiki/Mycoplasma_genitalium)
| as worms are too complex to be minimialized
|
| See also
| https://en.wikipedia.org/wiki/Mycoplasma_laboratorium
|
| The work in this area is quite extraordinary, but typically
| gets much less attention than _anything_ that works with
| human genomes.
| gilleain wrote:
| Hmm wonder how Craig Venter is getting along with his
| project. He was making a lot of noise about it a few years
| ago.
|
| Seems like he sold a company in April of this year to the
| University of California.
| lgas wrote:
| Maybe https://en.wikipedia.org/wiki/Caenorhabditis_elegans#
| Use_as_... ?
| dekhn wrote:
| c. elegans is much more complicated. It has the advantage
| of eutely, but it's awfully complex for minimalist
| studies.
| mariebks wrote:
| Can you link to some of your favorite
| talks/conferences/podcasts? Thanks!
| bigbillheck wrote:
| "This Week in Virology": https://www.microbe.tv and sister
| podcasts.
| yellowcake0 wrote:
| 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.
| bigbillheck wrote:
| > 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...)
| afterburner wrote:
| > 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.
| ethbr0 wrote:
| Minimal genome -
| https://en.m.wikipedia.org/wiki/Minimal_genome
|
| 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.
| yellowcake0 wrote:
| You may also be interested in the Yeast 2.0 project,
|
| https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5894084/
|
| which is an attempt to redesign the genome of the model
| organism S. cerevisiae, i.e. standardize codons, remove junk
| DNA, etc.
| [deleted]
| pishpash wrote:
| 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.
| david_l_lin wrote:
| Not really?
|
| 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.
| jazzyjackson wrote:
| > 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)
| david_l_lin wrote:
| > "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.
| timy2shoes wrote:
| > 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.
| twic wrote:
| 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.
| dekhn wrote:
| 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"
| ramraj07 wrote:
| 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.
| Victerius wrote:
| Designer babies incoming.
|
| 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.
|
| $10M + options. Payable in monthly installments.
| zen_1 wrote:
| Turn on the Myostatin inhibitors!
| WitCanStain wrote:
| A new genetic aristocracy. Great.
| elif wrote:
| 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.
| cronix wrote:
| What do you think they would choose if they had the option
| for gender, orientation and sexual preference?
| Victerius wrote:
| Most wealthy couples with the means to afford designer
| babies would probably want heterosexual children. Gender
| would be left at their discretion.
| mcculley wrote:
| 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.
| lajamerr wrote:
| 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?
| DrudgeCorporate wrote:
| 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.
| blamestross wrote:
| 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.
| InitialLastName wrote:
| 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.
| fgkramer wrote:
| We just need to see Gattaca to be horrified at the results of
| such experiment.
| sneak wrote:
| 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.
| tablespoon wrote:
| > 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 _un_ engineered 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]."
| nescioquid wrote:
| > 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)?
| sneak wrote:
| Genetic engineering of one's own children is not
| eugenics. It's not even close.
|
| Most of my friends' children are smart. The ones not
| raised in the USA are generally well-behaved. Your sample
| size may need to be increased.
| rowanG077 wrote:
| Honestly I love this future. There are so many bad traits
| humans have that would help everyone a great deal if they
| would be eliminated.
| elif wrote:
| Consider that idea's other subscribers in history, the ones
| utilizing that exact rationality... Are you in good
| company?
| rowanG077 wrote:
| 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.
| atlasunshrugged wrote:
| $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.
| MontyCarloHall wrote:
| >$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.
| dekhn wrote:
| 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.
| daniel-cussen wrote:
| 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.
| ineptech wrote:
| 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.
| elevaet wrote:
| 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.
| dharma1 wrote:
| memes manipulating genes
| rootsudo wrote:
| This is cool, so in laymans terms - you can disable the bad
| "genes" and just express/enable/push the "good ones."
|
| So how do we define what is a bad gene? If we use crispr, can we
| turn it off on an actual, live, aging human being or only before
| they're "born" or such?
|
| Is there a good resource/book that gets someone from zero to a
| basic biological understanding and background of this and above?
| I _really_ have no idea, nor do I know who to ask. :(
| cvccvroomvroom wrote:
| Not in the field.
|
| Q: How can the human genome be "mapped" without sampling and
| sequencing genetic material from millions of individuals? Is it a
| sequencing of one individual?
| mdaniel wrote:
| > New CRISPR-based map(ping process) ties every human gene to its
| function
|
| Maybe it's because I'm not in that industry, but I was looking
| for a graphical gizmo that I could click on a gene and see
| functions but they mean "map" in its functional programming term
|
| Although clicking through the first link does say "Interactive
| Website under construction..." so maybe this was just submitted
| too early or something
| dekhn wrote:
| Here's a link to the gene they mention: C7orf26
| https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&lastVirtMod...
|
| To understand its function, it has its own wikipedia page(!)
| https://en.wikipedia.org/wiki/C7orf26 It's one of the remaining
| proteins whose "function" (to the extent that proteins can be
| said to have a "function") has not been reliably determined.
|
| There are sites for protein function, my favorite is Uniprot:
| https://www.uniprot.org/uniprot/Q96N11
|
| as you can see, they don't really know what it does: "Probable
| component of the Integrator (INT) complex, a complex involved
| in the small nuclear RNAs (snRNA) U1 and U2 transcription and
| in their 3'-box-dependent processing.".
|
| The integrator complex is an important bit of machinery that
| helps transcript DNA to RNA on its path to protein expression:
| https://www.embl.org/news/science/at-the-core-of-the-integra...
|
| In general, data presentation in biology is a pretty mixed bag.
| The field never attracted the level of UX investment that you
| see at ad-driven companies.
| lysozyme wrote:
| That's true, software for biology tends to be terribly,
| almost comically bad, with one-off file formats, brittle data
| interchange, and impossible-to-maintain code being the norm.
| With user interface and ergonomics being the most neglected
| aspect. Why do you think that is?
|
| Surely there is plenty of money in biology these days to hire
| a good designers to design good user experiences. Surely
| better user experience for biology software would lead to
| better understanding of biological systems and better
| outcomes in bioengineering.
|
| Where are the polished, powerful design tools for biology
| like those that exist for other fields like online
| advertising that routinely process and distill huge amounts
| of lightly-structured data?
| caycep wrote:
| it seems like that is a whole other skillset vs. biology
| graduate students...I know the Allen Institute employs data vis
| people to write visualisation tools like this in d3/react or
| whatever the web api du jour is, but they are separate from the
| science folks
| grej wrote:
| Another cool thing, their paper mentions that, "The specific
| implementation is based on the python package torch-two-sample,
| modified to use numba for improved performance." (
| https://www.cell.com/action/showPdf?pii=S0092-8674%2822%2900... )
|
| If you haven't checked out the numba package, definitely worth a
| look for custom numerical computing in Python!
|
| disclosure - have made a small contribution to the package.
| atlasunshrugged wrote:
| Anyone know where the state of the art is happening in applied
| 'designer baby' tech? I feel like there hasn't been much news
| since the arrest of the scientist who claimed to be the first to
| change the genes of live kids but I'm shocked there aren't some
| people out there pushing the envelope on this (and/or
| commercializing it).
| cauthon wrote:
| Never underestimate MIT's ability to oversell itself.
|
| (EDIT: see below, this is directed at the press release, which I
| perceive to be overstating the achievements presented in the
| paper, not the quality of the paper itself)
| warent wrote:
| Care to elaborate? This just seems like an empty criticism
| without any value or substance
| cauthon wrote:
| Sure. A genome-wide perturb-seq experiment is a huge (and
| expensive) technical accomplishment, but the authors did not
| "map every human gene to its function". (Nor did they claim
| to, it's press release hyperbole.)
|
| One, there's ~20k protein-coding genes in the human genome,
| and they screened ~10k, analyzing about 2k (fig 2a).
|
| Two, all the functional annotation is based off transcription
| profiles. They essentially looked for clusters of genes with
| correlated expression, and assigned function based on genes
| with previous annotations (fig 2d, S4).
|
| It's a good resource, but there's a lot more molecular work
| to be done to validate the function of these genes.
| timy2shoes wrote:
| > Two, all the functional annotation is based off
| transcription profiles. They essentially looked for
| clusters of genes with correlated expression, and assigned
| function based on genes with previous annotations
|
| This is an important point, because if you've ever worked
| with single cell data you'll know that the transcriptional
| profile is extremely noisy and your transcriptional profile
| to cell type map has many researcher degrees of freedom. I
| heard a story about a paper early in the single cell work
| that started with 53 cell types and after review ended up
| with 37 cell types. Are those true cell types? Did the
| experimenters validate that those cell types all performed
| different functions? Well, of course not. That's way too
| much work.
|
| Then add on technological biases, which make mapping
| between technologies difficult. I say this because they
| used a new sequencing technology that appears to have
| homopolymer bias
| (https://twitter.com/lpachter/status/1533875723995185153),
| which will bias the gene quantification.
| cauthon wrote:
| > I say this because they used a new sequencing
| technology that appears to have homopolymer bias (https:/
| /twitter.com/lpachter/status/1533875723995185153), which
| will bias the gene quantification.
|
| I believe they used Illumina for the results presented in
| the main text and then re-sequenced with Ultima and
| replicated a subset of the analyses (fig s13). The Ultima
| proof-of-concept didn't appear to be relevant to the main
| study/conclusions
| dekhn wrote:
| Is there a way to get the parent comment unflagged? The
| response from the commenter shows they have a lot to
| contribute, technically speaking.
| cauthon wrote:
| Thanks. I'll admit the first comment didn't contribute much
| and apologize for not including my thoughts from the
| follow-up. I just don't care for these sorts of hyperbolic
| press releases.
|
| It's part of the game, the big players are as good at sales
| as they are at science, but I've never been a fan of it.
| dekhn wrote:
| Useful book that any starting professor should
| understand, even if they don't want to admit they are
| playing a game. science-by-press-release is a technique
| to master if you want to both maximize the impact of your
| work, and get tenure.
|
| https://www.amazon.com/Winning-Games-Scientists-Play-
| Sinderm...
| Noumenon72 wrote:
| I have `showdead` turned on in my profile, and I saw this
| whole comment chain. Will people with it turned off still
| see the replies?
| wolverine876 wrote:
| You can click 'vouch'.
| dekhn wrote:
| Thanks, I didn't realize you had to click through to the
| comment to see that.
| coryfklein wrote:
| Wait do we even know that every human gene has a 1:1 mapping to a
| function in the body? I think the code analogy to this would be
| trying to map "C++ if statements" to a particular feature in your
| product. I'd expect something as complicated as the genome would
| have a much richer and complicated interaction with biological
| feature expression.
|
| I'm probably simply misunderstanding; maybe Weissman's data is a
| 1:N mapping?
| shpongled wrote:
| We already know that many genes have more than one function
| (especially when you consider that one gene can produce many
| protein products)
| elif wrote:
| I think mpeg encoding would be a better demonstrative than
| code...
|
| Where data is lost, details are lost, but the end result still
| typically renders into something recognizable. If you lose an
| iframe, you end up with a more serious deformity. Whereas code
| either does exactly what it says or does nothing at all, and
| knocking out a single statement is almost certain to break
| everything.
| astrange wrote:
| This kind of shallow presentation is common for genetics;
| compare reporting genetic traits by SNPs and implying the SNPs
| "cause" them, which is like diffing two versions of a program
| and saying X new feature happens because there's a letter 'n'
| in one program and not the other.
| axg11 wrote:
| There's not any type of mapping and this is what makes biology
| so difficult to study and understand. One gene can affect
| anywhere from zero other genes to every single gene. We also
| need to account for effects at every level of the central dogma
| of biology. Knockout of a gene can affect genetics, RNA,
| protein, and much more we don't even know about yet. The other
| underestimated complicating factor is that biology is very
| nonlinear. A 10% increase in gene expression could lead to no
| resulting effect, whereas an 11% increase in expression could
| upregulate downstream genes by 1000x.
| geysersam wrote:
| I'm not a biologist. Still, do genes really have "functions"?
| Guess some have, such as producing an enzyme to break down a
| particular kind of suger. But that this would be the case for
| _every human gene_ sounds unlikely to me.
| projektfu wrote:
| A gene is a DNA (or RNA) sequence that codes for some protein
| or RNA product. There are other functional sequences in DNA but
| they're not called genes.
|
| https://en.wikipedia.org/wiki/Gene?wprov=sfti1
| dekhn wrote:
| For your last sentence: that's right, to get any press
| attention today you have to basically say you've solved all
| cancer or done something pan-genomic, in a way that massively
| overstates the importance of the specific result and its impact
| on health care delivery.
|
| That said, Jonathan Weissman is a great guy who has pushed the
| field forward and the techniques they are using really are
| powerful.
| panabee wrote:
| thanks for all your comments and insights. can you recommend
| other people to follow on the leading edge of integrating
| technology and biology?
| commandlinefan wrote:
| > do genes really have "functions"?
|
| Makes me think of Douglas Hofstatder's "grandma neuron":
| https://www.livescience.com/grandmother-neurons-discovery.ht...
| radicality wrote:
| His explanation in GEB of how genes, DNA, and RNA function
| was probably the clearest one I've ever read. It's been a
| while and I forgot the details, but reading his analogies
| made everything click at the time. Maybe it's time to re-read
| GEB.
| david_l_lin wrote:
| All genes have a function. This paper helps us understand genes
| of unknown function (which is a LOT of them).
|
| Some of these functions are not intuitive: maybe they regulate
| the function of another protein, maybe they only function in
| the context of a particular stressor, etc. You can think of
| nearly unlimited scenarios to apply and you start to understand
| the complexity of understanding how a gene functions.
| dekhn wrote:
| "All genes have a function" <- this is a generalist statement
| that is wrong in its specifics, but also raises semantic
| question of what "function" actually means.
| pfisherman wrote:
| "All genes have a function" is analogous to saying, "All
| particles play a role in our physical reality". This should
| be uncontroversial.
| dekhn wrote:
| This is a bit of a semantic argument, but gene function
| is a fairly nebulous term. The essence of what I am
| saying is that there may be proteins that currently have
| no actual function, aren't under functional selection,
| yet are duplicated, transcribed, and expressed (not just
| pseudogenes).
|
| Function is a rabbit hole. Biologists get in big
| arguments about the semantics of this all the time
| (http://cryptogenomicon.org/encode-says-what.html). I
| don't really care. I care about the minimal set of
| necessary proteins for a model organism to exist and
| reproduce in a media-rich environment. And, whether there
| are actually subsets of mutually compensatory groups of
| proteins instead of a single minimal set.
|
| Protein function is one of those things that, at first,
| seems really simple to define, but the further you go
| down the rabbit hole, the more complicated it gets, until
| it's fractally complex and you realize that not only does
| the exception prove the rule, it's all exceptions.
|
| See also:
| https://en.wikipedia.org/wiki/Enzyme_promiscuity
| axg11 wrote:
| > All genes have a function.
|
| For the benefit of readers unfamiliar with the field: this is
| wrong.
|
| You can show this experimentally. Construct a gene that
| produces a non-human protein and introduce this to a human
| cell/genome. That gene would not have a "function" but still
| exists in the genome. This is actually happening all the
| time. Some viruses integrate their genomes when infecting
| cells. Viral integration is one of the factors that shapes
| genome evolution.
| eurasiantiger wrote:
| All human proteins are encoded in genes.
|
| https://en.wikipedia.org/wiki/Category:Human_proteins
| [deleted]
| Obi_Juan_Kenobi wrote:
| A gene is essentially defined as having a gene product, either
| an RNA or protein. So yes, all genes are functional.
|
| Genes that aren't translated into protein sequences (noncoding
| genes) can create structural RNAs as with Ribosomes, microRNAs
| that have regulatory functions, etc.
|
| There are lots of non-gene genetic elements that do things,
| though. Many are involved in gene regulation, affecting the
| transcription rates of nearby loci through a variety of
| mechanisms. There are also vast swaths of inactivated
| transposons, retroviruses, and other repetitive genetic
| sequence.
| imchillyb wrote:
| This is akin to taking an automobile apart piece-by-piece, not to
| determine its function but just to figure out if the automobile
| fails substantially by removing say a taillight, dome light, dash
| light, or wiper delay fuse.
|
| The car's not gonna fail for each piece, it'll take forever to
| determine what pieces are absolutely necessary, and it doesn't
| tell ya shit about what the pieces functions are.
|
| Neat, but ultimately inefficient and exceedingly limited in
| necessary detail to make the claim in the article's title.
| [deleted]
| throwawayarnty wrote:
| One model of how science progresses is a few pioneers breaking
| new ground and then everyone else rushing in to pick up low
| hanging fruit in the new field.
|
| Looks like Weissman lab has consistently been breaking new ground
| over and over again. Extremely impressive and very few labs in
| the world have such a track record.
| bryans wrote:
| An article from MIT:TR in the early 2000s always stuck with me as
| an example of how intricate and interconnected genes really are.
| Researchers using fruit flies found one born with white eyes, and
| they narrowed the mutation to a specific gene. They were able to
| modify it in vivo to reliably produce white eyes, but the change
| had an unexpected second outcome, which was that white-eyed males
| would only attempt to mate with other males.
|
| Years later, there was a group who cited that fruit fly paper
| when they proposed the same methodology to control mosquito
| populations, but I'm not sure if they ever recreated the male
| preference. The mosquito gene editing did pan out, but the method
| is different in that it doesn't allow females to survive, while
| males will go on to mate with other non-edited populations and
| spread the female-killing gene.
| jmyeet wrote:
| This is really amazing.
|
| Of course I was aware of the Human Genome Project and mapping DNA
| in general. I was also aware that figuring out all the proteins
| in a cell and what they do is a whole other problem.
|
| I didn't realize they'd made this much progress. It's not
| complete obviously but being able to figure out gene expression
| is a _massive_ step forward. The ability to switch off genes
| (this is where the CRISPR editing comes in) and seeing what
| changes is just astounding (there was an example of chromosome
| segregation).
|
| It's known that certain proteins mediate certain processes where
| the presence of that protein or the absence of it can lead to a
| condition or disease. The potential impact here for treating
| genetic disorders I think cannot be overstated.
|
| Between this an the technology behind mRNA vaccines, I really
| wonder if the 21st century will lead to the effective elimination
| of many diseases.
| tandr wrote:
| > Between this an the technology behind mRNA vaccines, I really
| wonder if the 21st century will lead to the effective
| elimination of many diseases.
|
| And, due to errors and human mistakes, possible creation of
| some new, or old-but-improved ones...
| jjtheblunt wrote:
| > The ability to switch off genes (this is where the CRISPR
| editing comes in)
|
| i think your wording is ambiguous : CRISPR can edit the
| sequence, but "switch off" has an association with methylation
| of items in the sequence, orthogonal to the sequence itself.
| Obi_Juan_Kenobi wrote:
| You misunderstand.
|
| We've being doing genetics for decades. Molecular biology
| without mutant studies wouldn't exist. It's the foundation of
| the field.
|
| All this is is a difference in scale. But it is a very crude
| tool; really understanding gene function involves studying it
| in relevant contexts. Looking at cells in tissue culture can
| give you some ideas or hints about how it functions, but the
| critical insight might require certain cell types or gene
| regulatory environments.
|
| What data like these do is inform hypothesis generation and
| refine the interpretation of genomic data. It is important
| work, but does not replace doing actual biology.
|
| What you're talking about is essentially saying we just
| invented molecular biology. Which is obviously not the case.
| Filligree wrote:
| > I didn't realize they'd made this much progress. It's not
| complete obviously but being able to figure out gene expression
| is a massive step forward. The ability to switch off genes
| (this is where the CRISPR editing comes in) and seeing what
| changes is just astounding (there was an example of chromosome
| segregation).
|
| The protein folding problem was solved earlier this year. You
| can expect a lot more coming in this vein... interesting times.
| dekhn wrote:
| the protein structure prediction problem was solved, not
| protein folding. Different field. Also, it wasn't really much
| "solved", so much as prediction got as good as the metric
| used to compare the predictions to reality, so we can't
| really say for sure whether the predictions are better than
| golden labels or not.
| hirako2000 wrote:
| The 21st centry may lead to the definitive elimination of
| humans, of desease i can only imagine their numbers going up,
| not down.
|
| "that's where CRISPR editing comes in". To edit the DNA of
| congeniality diseased people? I doubt the business will focus
| primarily on this category of patients, unfortunately. but I
| still hope the worst will be avoided when/if using this tech
| kind of tech.
| BurningFrog wrote:
| I suspect FDA regulations will have to be redesigned a lot to
| make most DNA editing treatments economically possible.
| hirako2000 wrote:
| If they approved the sort of recent treatment they
| approved, for that scale of deployment (billions of
| individuals within a year) it wouldn't surprise me they
| will approve anything, given enough lobbying. No worry to
| have with FDA becoming an obstacle.
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