[HN Gopher] Virtual cells
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Virtual cells
Author : surprisetalk
Score : 109 points
Date : 2025-06-17 04:18 UTC (3 days ago)
(HTM) web link (udara.io)
(TXT) w3m dump (udara.io)
| nextos wrote:
| UConn coordinated a ton of work during the past two decades on
| mechanistic cell models. Mostly ODEs, PDEs, and stochastic ODEs.
| See The Virtual Cell at https://vcell.org.
|
| It's interesting how high-throughput perturbation assays have led
| to data-driven whole cell models. But these are not yet good at
| making robust predictions.
|
| Probably the future are hybrid neuro-symbolic models.
| donovanr wrote:
| Yes, this. A lot of work in this field is missing from that
| timeline. Just circa 2010-2020, Les Loew's VCell 3D PDE
| approaches, Faeder et al.'s BioNetGen / ODE work, Luthey-
| Schulten Shulten's grid based cell models, the Pittsburgh
| supercomputing center's 3D monte-carlo MCell, the image-based
| deep learning models at the Allen Institute for Cell Science...
|
| It's nice to see the idea of virtual cells make a comeback now,
| though the meaning seems to have shifted to transciptomics-
| based transformer / gpu-powered models (which have issues[0]),
| it's a fun field / problem, but I think it will make better
| progress if we take advantage of all the varied computational
| work that has come before.
|
| [0] Benchmarking Transcriptomics Foundation Models for
| Perturbation Analysis : one PCA still rules them all
| https://arxiv.org/abs/2410.13956
| udara wrote:
| oh that's interesting, I didn't come across these the way I
| was looking at it! thank you for informing us, I will read up
| on these and add it to the timeline!
| paulfharrison wrote:
| What a strange web page. Scrolling is thoroughly broken.
|
| I recently went to a two day workshop on whole cell modelling.
| I'm still trying to work out how much of the exercise is
| fantasy. I get that some of the chemistry is well enough
| understood to simulate from the ground up, but there's so much
| more to it.
|
| The oddest thing to me is the level of satisfaction in being
| able to run the model. I would think the model has to be very
| very fast, because of all the work that needs to be done with
| it to fit it to data and fully understand its behavior.
| jdonaldson wrote:
| Lol! Overriding basic scroll functionality on esoteric cell
| simulation software documentation pages is such a pointless
| gamble. Really calls the quality of the software itself into
| question.
| hobofan wrote:
| While it says this:
|
| > By 2021, these engineered bacteria could be simulated in
| unprecedented detail. Every gene, every major protein, and nearly
| every metabolic reaction in JCVI-syn3A.
|
| I think the crux is here:
|
| > Even after years of study, 91 of JCVI-syn3A's genes remain
| unannotated, of which roughly one-third are essential. Deleting
| any single one kills the cell, yet we have no idea what they do -
| representing some of biology's most fundamental unsolved puzzles.
|
| ---
|
| I think minimal cells and virtual cells are especially exciting
| as they open up a path to create fully controlled experimental
| environments for biochemistry from the ground up.
|
| Right now sooo much time in biochemistry goes into working around
| the limitations of what already happens to be present in an
| organism. E.g. we may know 5% of mechanisms that go on in a cell,
| but the remaining 95% percent of mechanisms that go on may still
| brick your experiment, and without knowing about them you
| essentially have to shrug and trial and error your way through
| them.
|
| In contrast in a synthetic minimal cell, we could start out with
| an organism where we know 95% of the mechanisms that are going
| on, and then study new mechanisms one gene at a time, steadily
| building up to bigger and bigger mechanisms.
|
| Strangely it seems to me that a lot of effort is going more into
| being able to simulate full cells that contain unknown
| mechanisms, rather than trying to use the capabilities to create
| hypothesis to uncover the unknown mechanisms. Yes, that probably
| expedites the path towards simulating much bigger human cells,
| but ultimately still leaves us in the dark on most fronts.
| suddenlybananas wrote:
| >Strangely it seems to me that a lot of effort is going more
| into being able to simulate full cells that contain unknown
| mechanisms, rather than trying to use the capabilities to
| create hypothesis to uncover the unknown mechanisms. Yes, that
| probably expedites the path towards simulating much bigger
| human cells, but ultimately still leaves us in the dark on most
| fronts.
|
| Seems the result of this general trend in science towards brute
| prediction and abandoning the goal of explanation or
| understanding.
| filoeleven wrote:
| Check out Michael Levin's lab for a refreshing and amazing
| example of a group that's bucking the trend.
|
| They are doing tons of experiments by starting with the
| premise that cells and their networks have intelligence, then
| using tools from behavioral science to convince them to do
| what the experimenters want (e.g. "grow an eye here"). I've
| been convinced by Levin's talks that this is a more promising
| area of research than genetics.
|
| https://drmichaellevin.org/
| TeMPOraL wrote:
| > _Strangely it seems to me that a lot of effort is going more
| into being able to simulate full cells that contain unknown
| mechanisms, rather than trying to use the capabilities to
| create hypothesis to uncover the unknown mechanisms. Yes, that
| probably expedites the path towards simulating much bigger
| human cells, but ultimately still leaves us in the dark on most
| fronts._
|
| I imagine it's much easier to create and test hypotheses about
| the unknown mechanisms, when you can view them in context of a
| larger system, with reasonable performance, allowing you to
| metaphorically "grab them in your palm" and tweak on the fly.
| We work better when we explore things, instead of immediately
| taking on problems that are at the limit of our computational
| tools, requiring individual brains (and tons of paperwork) to
| make up for the difference.
|
| In this sense, researching the nano-scale basics, and aiming to
| simulate micro-scale cellular systems, are actually aligned -
| as long as they're not cutting too much corners, the latter is
| creating space for former work to be done efficiently.
| moralestapia wrote:
| Great post.
|
| This is _exactly_ what I 'm an expert at, I even coined a term in
| the field [1], :).
|
| Since I started doing this 15 years ago (and I know the field
| predates me by much), one always has had this feeling that we are
| so close to a big breakthrough in biological simulation, but at
| the same time, progress has been kind of "slow". I think the
| reason for that is because pushing the envelope forward in this
| field requires mastering three (maybe four) different
| disciplines, your pick of [Bio, Chem, CS, Math, Physics]. Very
| few people reach this level of simultaneous understanding of all
| these pieces.
|
| I'm not trying to gatekeep the field, though, much of the
| progress here (including many of the papers mentioned in TFA) is
| work coming from PhD students. Anyone could jump into this, but
| you really need to sit down and try to make sense of it for a
| while, years. PhD gives one the perfect opportunity for that.
|
| Anyway, I hope this thing keeps going on forward, it's one of the
| ultimate goals of Biology and it would be extremely beneficial to
| the world.
|
| 1: https://www.frontiersin.org/journals/plant-
| science/articles/...
| _factor wrote:
| Thank you for your contributions. You are quite literally
| saving lives.
|
| Are there any good local (op-so ideally) tools and/or libraries
| one can experiment with? I have access to a couple HPC clusters
| and would love to learn more.
| moralestapia wrote:
| Sure!
|
| Take a look at SimTK [1].
|
| And I would try to reproduce Karr's model [2], paper here
| [3]; also mentioned in the linked page.
|
| This is the study that made me, and many others at the time,
| to actually take this seriously, lol. I was a student and was
| doing this as a hobby project, Karr's paper made me think
| "wait, this is actually possible, and _today_ ". It's really
| good if you want to learn and get your feet wet on this.
|
| If you want, you can reach out to me at hn @ moralestapia .
| com, and I'll be happy to recommend some more stuff!
|
| 1: https://simtk.org/
|
| 2: https://simtk.org/projects/wholecell
|
| 3: https://www.cell.com/cell/fulltext/S0092-8674(12)00776-3
| ulnarkressty wrote:
| A noob question, since the original article doesn't go into
| details - what is exactly being simulated here? I was under the
| impression that we can't even reliably do a single protein
| folding due to the sheer complexity of the task. So how do we
| simulate the zillions that are bouncing around in a single
| cell? And if we don't simulate it at that level, how are we
| confident that it is correct?
| andoando wrote:
| I assume same reason we dont need to simulate quantum physics
| to simulate a ball moving or even the weather.
| moralestapia wrote:
| You're right, they're only approximations at different
| levels, as a 1:1 reproduction of even a single cell would be
| unfeasible.
|
| Most of them are built around one specific, measurable,
| phenotype that they want to reproduce, like estimate
| metabolite input/output over time.
|
| Some others attempt to model the behavior of these cells when
| interacting with others, like in a colony or tissue. This is
| quite important because most of the phenomena that enables
| development, healing, regeneration, etc ... are emergent
| processes that only make sense when you study the whole
| tissue. One concrete thing you can measure/simulate here is
| "if I drop this hormone here, where is it going to be at time
| X and at what concentration" [1], which is super useful to do
| _in silico_ because measuring that in real tissue, without or
| even with markers, is much more complicated, expensive and
| time consuming.
|
| 1: I wrote one of the first models that was able to do this
| in realistic plant tissue. Realistic here means, bounded by
| the chemical/physical constraints found in real plants and
| using a structural scaffold that resembles them as well.
| udara wrote:
| Thank you! and it's awesome you can contribute to the subject!
|
| You're so right that it feels so difficult to make sense of
| because of how cross-disciplinary it is. I hope more people
| invest and work on this stuff as well. I'm hoping to learn more
| over the years!
| smj-edison wrote:
| This is exactly the field I want to enter! I really want to
| work on the tooling side for atomic simulation (I think I have
| a design that could complete each timestep in ~10usec that
| doesn't lose speed as it scales). I think it would be cool to
| automatically extract parameters for coarser grained models.
|
| I'm planning to go to college for electrical engineering (ASIC
| design), but swap out some of my requirements to focus on
| particle physics. The college I got into also has an
| undergraduate MD lab that I got invited to.
|
| Do you have any tips on what skills you've found most valuable
| as you've done simulation?
| moralestapia wrote:
| >This is exactly the field I want to enter!
|
| Please do!
|
| >I really want to work on the tooling side for atomic
| simulation [...]
|
| Please do x2. That's how I started with this.
|
| With respect to simulations, become as good as you can with
| the methods that enable them. ODEs, PDEs and how to compute
| (well ... approximate) them. Spend some time making sure you
| understand the math properly. You don't need to spend ages
| here, most of the equations used in the field involve no more
| than three variables. The trick is in how you solve them, but
| solvers already exist, ofc.
|
| Write your own FEM solver, this is a must. It's not going to
| be SOTA, but you'll get a good feel for all the fundamentals.
| Then you can move on to using whichever you need/want because
| you'll understand what they do. (I used deal.ii a lot, but
| there are many more good ones out there).
|
| I would recommend you work with C/C++ instead of Python (ofc.
| you can do both). The reason for this is that you'll kill two
| birds with one stone by getting a good sense of how a
| computer actually executes things. Python is too abstracted
| away from that, and in this particular field, you really need
| to know what the hardware is doing and how.
|
| Then move into GPUs. Actually, if you can write this FEM
| solver in something like CUDA or JAX, you will kill three
| birds with one stone.
|
| I would then try to join a research group doing this, even if
| it's for free, only a couple months. My personal preferred
| niche is what is now called morphodynamics. Just approach any
| of these groups and tell them "Hey, I'm good with CUDA/JAX, I
| wrote this solver, I made this small simulation, I'm
| interested in doing biological simulations and want to learn
| more", 8/10 will say yes, there aren't many people out there
| with this skillset, it's not crowded.
|
| I mentioned "even if it's for free", the thing is, everyone
| says yes to free, lol. Your goal is to get one paper out
| there with your name on it. It doesn't have to be your own
| idea/project, just help them build whatever they're doing and
| make sure your name is there. Then ... you're pretty much in.
| You can stay there or go to a different group, but now you
| can say "hey I worked on this project, here's the paper, I
| can do X" and you take it from there. :D
|
| If you want to be in touch email me hn @ moralestapia . com.
| My profile seems empty bc. our friend @dang hid it, but just
| send me an email.
| dang wrote:
| > _My profile seems empty bc. our friend @dang hid it_
|
| I actually undid that yesterday, after replying to you
| here: https://news.ycombinator.com/item?id=44321299. I did
| so because I didn't want to give the wrong impression of
| having punished you after moderating you, when in fact the
| two issues are unrelated.
|
| Since you brought it up, I'll clarify here: you're abusing
| your profile page to publish false and misleading claims
| about HN. Specifically, you say that "some users are
| favored so they get more upvotes" and "some users get a
| handicap, so upvotes to their accounts do not register".
| Both claims are untrue.
|
| I understand that HN's voting algorithm is hard to figure
| out from the outside--it needs to be, for several reasons,
| such as that people are constantly trying to game it. But
| that doesn't make it ok to publish damaging falsehoods
| about HN. A user who doesn't know this place well, who
| happens to read that, will come away with an untrue
| impression which could easily discourage them from
| participating here.
|
| Had you said those things in a comment, we could provide
| corrective information in a reply--but there's no way to do
| that on someone's profile page. Besides that, the About box
| isn't supposed to be for venting grievances or taking
| revenge on HN (as people are sometimes wont to do). When
| people abuse the About box in such ways, I think it's
| reasonable to hide it.
|
| Now that I've made it clear what the issue is, and that it
| is unrelated to the other moderation reply, I'm going to
| hide your About box again. If you want to edit it to take
| out the false claims, I'd be happy to reverse that again.
|
| ---
|
| Edit: it turns out that I emailed you when we originally
| did this back in March, and explained all of the above:
|
| " _This is unrelated to the moderation reply I just posted
| athttps://news.ycombinator.com/item?id=43520108, other than
| that I happened to look at your profile page while writing
| it._
|
| _I just noticed that you have this in the About box of
| your profile: "PSA: HN has a hidden algorithm that
| manipulates the vote count for specific lists of users.
| Some users are favored so they get 10x more upvotes, some
| other users get a handicap on them, so upvotes to their
| accounts do not register. So, don't take karma at face
| value, as it is not "honest". tl;dr, even HN is
| propaganda."_
|
| _That 's entirely false and badly misleading of others.
| I'm not ok with that being published on HN in a place where
| there's no way to answer or correct it, so I've turned off
| the About field in your public profile._
|
| _I have nothing against you and you 're welcome on HN, but
| not to make false statements like this which poison others
| against the site and the community. If you want to take
| that out of your profile and let me know when it's done,
| I'll be happy to restore your About field to public view._
|
| _Daniel (dang)_
| moralestapia wrote:
| Ok, I removed that bit.
|
| I'll check that email, also.
| dang wrote:
| Ok! I've removed the penalty on your profile.
| moralestapia wrote:
| Fair! :D
|
| Thanks @dang. I'm probably the most scolded user on the
| site, that's still alive, lol.
| smj-edison wrote:
| Thank you so much for the detailed reply!
|
| I've worked a lot with Rust, and a decent bit of C, but
| pretty much no C++ or GPU programming. Do you have a sense
| of whether it would be better to pursue CUDA or JAX?
|
| That's also encouraging to know that there's openings for
| computational simulation--I've been a little worried that
| there wouldn't be any openings for computational simulation
| since it seems like a rather small field.
|
| Off the top of your head do you know of any resources for
| learning FEM? Happy to look for it myself but it's always
| nice to have pointers.
| moralestapia wrote:
| If I had to choose I would choose CUDA. I recently got
| myself into JAX, I think it has a fair chance of being
| the dominant framework in 5-10 years; but also, a native
| version of CUDA is coming to Python so ... idk.
|
| deal.ii has a bunch of tutorials worth gold [1].
|
| I learned by following them and that's why I ended up
| using deal.ii for almost everything. If you know C well,
| moving to C++ won't be quite difficult. deal.ii uses a
| lot of templates, that would prob. be the most unusual
| thing to you, coming from C, but you'll get used to the
| syntax.
|
| 1:
| https://dealii.org/current/doxygen/deal.II/Tutorial.html
| RivieraKid wrote:
| > progress has been kind of "slow"
|
| Isn't it simply because it's a fundamentally hard problem that
| may not even be solvable? Simulating a 50 amino acids long
| protein in water for 1 ms on a top supercomputer using
| molecular dynamics would take about a week.
|
| Can the current approach lead to models that are even remotely
| as useful as a full molecular dynamics simulation? The current
| approach requires us to first discover the hard stuff, the
| myriads of tiny mechanisms happening in the cell.
| moralestapia wrote:
| Hmm ... a good analogy to answer your question would be.
|
| CFD exists and has been fundamental to shape the world as we
| know it (refer to Wiki page [1] to learn more about what it
| is and why it is important). CFD is also not a full molecular
| dynamics simulation, yet is useful.
|
| Another example could be weather models. None of them, afaik,
| simulate @RivieraKid typing a comment in HN, an action which,
| infinitesimally, affects the weather of the planet. And yet,
| they're still very useful.
|
| You work with approximations, some of them are good enough to
| give you 80% of the answers you want, and that 80% is more
| than enough to improve our quality of life significantly.
|
| 1: https://en.wikipedia.org/wiki/Computational_fluid_dynamics
| maltee wrote:
| Great article! Also, really nice site design, the referenced
| papers and annotations are a really nice touch!
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