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To put this claim in perspective, we are still unable to simulate a single cell by modeling everything we know from biochemistry, even if we ignore molecular dy

To put this claim in perspective, we are still unable to simulate a single cell by modeling everything we know from biochemistry, even if we ignore molecular dynamics. Mostly this is because we don't know what many genes and the proteins they encode do. This matters, for example, if we want to simulate neuronal plasticity or the effect of antidepressants. We're an incredibly long way from a full simulation, which would also require integration with the rest of the nervous system.

gwern 13y ago
> To put this claim in perspective, we are still unable to simulate a single cell by modeling everything we know from biochemistry, even if we ignore molecular dynamics. Mostly this is because we don't know what many genes and the proteins they encode do. To me, this mostly shows that naive beliefs about difficulty aren't really accurate ('but it should it harder to simulate a brain than a cell, because it's bigger right!'). But of course, progress is being made on simulating cells: http://lesswrong.com/lw/drk/paper_simulation_of_a_complete_cell/ http://lesswrong.com/lw/drk/paper_simulation_of_a_complete_c... It's a high-level enough model that you can do it with only 1 core per cell.
- foobarbazqux 13y ago
  Sure, but that's also for a bacterial cell. We have 50 times as many genes and you can't easily culture humans on a Petri dish for experimentation. A single gene can take years of work to understand. Yes, you can simulate anything if you abstract away enough. But if the goal is a convincing replication, you'll need to include lots of intracellular effects. In the end, I believe that practical simulation of a whole brain that you can have a conversation about its existence with is more difficult than the development of quantum computing powerful enough to break all existing crypto. The work is still interesting, if only because it pushes the limits of what we can do. But I might want to start with an ant brain.
- Dylan16807 13y ago
  Why does it show that the belief isn't accurate? This isn't simulating a brain, it's simulating the connections in a brain and pretending the neurons are about as complex as wires. That is a model that is possibly correct, but there's certainly no evidence it's correct.
  - gwern 13y ago
    It shows, at a minimum, that 'simulating' is not a binary either-or proposition, and that the higher-level a simulation, the easier/more efficient the simulation can be, and so it is perfectly possible to have a high-level simulation of a 'big' thing which is easier to run than a low-level simulation of a 'small' thing - both of these points, as obvious as they may seem to you or me, are badly underappreciated by a lot of people.
    - dnautics 13y ago
      then why is the modeling attempting to recapitulate biology? Why not run a simulation at a level higher than 'cells'?
    - Dylan16807 13y ago
      When people say 'simulate a brain' they mean a very specific thing: simulating it in enough detail that it can have thoughts in fundamentally the same manner as a fleshy brain. >it is perfectly possible to have a high-level simulation of a 'big' thing which is easier to run than a low-level simulation of a 'small' thing While this is true, it's not being shown here until we know that this particular high-level simulation actually works. If it doesn't work then it's more of a failed attempt at creating a simulation.
- dnautics 13y ago
  I happen to work in the synthetic biology lab at the venter institute, although not on this project - two of our researchers are coauthors on this paper - and my personal opinion is that this paper is a joke. Note that the guys who made the simulation didn't even pick the correct organism. The cell that we have synthetic control over is M. mycoides, not M. genitalium. Lest this seem like a nit-pickey detail, until they rewrite their software for mycoides, in broad strokes the model is essentially untestable, since we don't have broad-scale control over the genitalium genome like we do mycoides. Also note that: "The model accounts for previously observed gene essentiality with 79% accuracy." This is REALLY bad. Considering they are 'seeding' the model using a biased structure that automatically "knows" that certain genes are essential (for example, they have a 'module' for replication that probably zeroes out if you are missing an important replication component, as opposed to simulating how those genes work at a low level) this is probably somewhere close to as good as flipping a coin.
  - gwern 13y ago
    What did your colleagues make of your criticism?
    - dnautics 13y ago
      A common theme where I work is me making a vociferous criticism, being ignored, and the things I say coming true later. (this is not to say that all of the objections I make wind up being correct)
      - moocowduckquack 13y ago
        You didn't refuse the advances of Apollo by any chance?
        deleted 13y ago
        [deleted]
deletes 13y ago
To correctly model a cell you would need to simulate every atom and there are about 10^11 to 10^14 (!) of them in a single cell. I think an interesting number would be how many atoms does it take to simulate one atom reasonably well. Then you could get correct results for some ( really ) small biological functions.
- jevinskie 13y ago
  Aren't you modeling a subset of the universe at that level? Isn't a model supposed to provide a higher level understanding/abstraction?
  - deletes 13y ago
    Atom is still an abstraction of sub particles ( that may be made of even lower ones, we don't know ) and their physical interactions so i think it is a model. And a reasonably good one.
  - frozenport 13y ago
    In cases where qualitative meaning is nontrivial, you don't know 100% what is going on, it is nevertheless possible to implement parametric studies for some target parameter.
- lvs 13y ago
  Your point is valid, but many people are trying to "correctly model a cell" without making a total atomistic simulation (which is clearly not going to happen any time soon). It's all about what questions you're looking to ask of a model.
- foobarbazqux 13y ago
  Usually people modeling cells don't consider molecular dynamics, they consider concentrations of proteins, ions, and metabolites. A full MD simulation would obviously be superior, but useful predictions could be made without it. It's hard to say which is the better approach. On the one hand you have MD from which you could technically build an accurate model "from scratch", folding all of your own proteins as part of the simulation, but it is exceedingly expensive to do that. On the other hand, you have a model built at the level of biochemical reactions and molecular biology, which is computationally feasible, but then you don't have enough information from bench work to flesh it out.

gwern 13y ago

> To put this claim in perspective, we are still unable to simulate a single cell by modeling everything we know from biochemistry, even if we ignore molecular dynamics. Mostly this is because we don't know what many genes and the proteins they encode do. To me, this mostly shows that naive beliefs about difficulty aren't really accurate ('but it should it harder to simulate a brain than a cell, because it's bigger right!'). But of course, progress is being made on simulating cells: http://lesswrong.com/lw/drk/paper_simulation_of_a_complete_cell/ http://lesswrong.com/lw/drk/paper_simulation_of_a_complete_c... It's a high-level enough model that you can do it with only 1 core per cell.

foobarbazqux 13y ago
Sure, but that's also for a bacterial cell. We have 50 times as many genes and you can't easily culture humans on a Petri dish for experimentation. A single gene can take years of work to understand. Yes, you can simulate anything if you abstract away enough. But if the goal is a convincing replication, you'll need to include lots of intracellular effects. In the end, I believe that practical simulation of a whole brain that you can have a conversation about its existence with is more difficult than the development of quantum computing powerful enough to break all existing crypto. The work is still interesting, if only because it pushes the limits of what we can do. But I might want to start with an ant brain.
Dylan16807 13y ago
Why does it show that the belief isn't accurate? This isn't simulating a brain, it's simulating the connections in a brain and pretending the neurons are about as complex as wires. That is a model that is possibly correct, but there's certainly no evidence it's correct.
- gwern 13y ago
  It shows, at a minimum, that 'simulating' is not a binary either-or proposition, and that the higher-level a simulation, the easier/more efficient the simulation can be, and so it is perfectly possible to have a high-level simulation of a 'big' thing which is easier to run than a low-level simulation of a 'small' thing - both of these points, as obvious as they may seem to you or me, are badly underappreciated by a lot of people.
  - dnautics 13y ago
    then why is the modeling attempting to recapitulate biology? Why not run a simulation at a level higher than 'cells'?
  - Dylan16807 13y ago
    When people say 'simulate a brain' they mean a very specific thing: simulating it in enough detail that it can have thoughts in fundamentally the same manner as a fleshy brain. >it is perfectly possible to have a high-level simulation of a 'big' thing which is easier to run than a low-level simulation of a 'small' thing While this is true, it's not being shown here until we know that this particular high-level simulation actually works. If it doesn't work then it's more of a failed attempt at creating a simulation.
dnautics 13y ago
I happen to work in the synthetic biology lab at the venter institute, although not on this project - two of our researchers are coauthors on this paper - and my personal opinion is that this paper is a joke. Note that the guys who made the simulation didn't even pick the correct organism. The cell that we have synthetic control over is M. mycoides, not M. genitalium. Lest this seem like a nit-pickey detail, until they rewrite their software for mycoides, in broad strokes the model is essentially untestable, since we don't have broad-scale control over the genitalium genome like we do mycoides. Also note that: "The model accounts for previously observed gene essentiality with 79% accuracy." This is REALLY bad. Considering they are 'seeding' the model using a biased structure that automatically "knows" that certain genes are essential (for example, they have a 'module' for replication that probably zeroes out if you are missing an important replication component, as opposed to simulating how those genes work at a low level) this is probably somewhere close to as good as flipping a coin.
- gwern 13y ago
  What did your colleagues make of your criticism?
  - dnautics 13y ago
    A common theme where I work is me making a vociferous criticism, being ignored, and the things I say coming true later. (this is not to say that all of the objections I make wind up being correct)
    - moocowduckquack 13y ago
      You didn't refuse the advances of Apollo by any chance?
      - deleted 13y ago
        [deleted]

deletes 13y ago

To correctly model a cell you would need to simulate every atom and there are about 10^11 to 10^14 (!) of them in a single cell. I think an interesting number would be how many atoms does it take to simulate one atom reasonably well. Then you could get correct results for some ( really ) small biological functions.

jevinskie 13y ago
Aren't you modeling a subset of the universe at that level? Isn't a model supposed to provide a higher level understanding/abstraction?
- deletes 13y ago
  Atom is still an abstraction of sub particles ( that may be made of even lower ones, we don't know ) and their physical interactions so i think it is a model. And a reasonably good one.
- frozenport 13y ago
  In cases where qualitative meaning is nontrivial, you don't know 100% what is going on, it is nevertheless possible to implement parametric studies for some target parameter.
lvs 13y ago
Your point is valid, but many people are trying to "correctly model a cell" without making a total atomistic simulation (which is clearly not going to happen any time soon). It's all about what questions you're looking to ask of a model.
foobarbazqux 13y ago
Usually people modeling cells don't consider molecular dynamics, they consider concentrations of proteins, ions, and metabolites. A full MD simulation would obviously be superior, but useful predictions could be made without it. It's hard to say which is the better approach. On the one hand you have MD from which you could technically build an accurate model "from scratch", folding all of your own proteins as part of the simulation, but it is exceedingly expensive to do that. On the other hand, you have a model built at the level of biochemical reactions and molecular biology, which is computationally feasible, but then you don't have enough information from bench work to flesh it out.