4 ms·

Simulating a minimal cell in the browser

164 points by agnosis 3y ago

agnosis 3y ago
Have you ever wondered how life’s most basic units, cells, operate? As a programmer and cell biology enthusiast, I embarked on a journey to simulate the simplest cell using TypeScript.
- ClaraForm 3y ago
  In biology, there’s a whole field of research dedicated to minimizing cells and their complexity. If you message “John Glass” he might be interested in having you model his work! Edit: oops you’ve already modeled John’s work! That’s awesome. :D I’ve attended a few talks by John and I think he’d still be interested in seeing whether the modeling side of things can explain why he can’t get the minimal cell smaller.
- deleted 3y ago
  [deleted]
mtekman 3y ago
This is really amazing. I wonder if confounders such as transcriptional bursting[1] are modelled too? I did not check but I assume cell-cycle is readily modelled. 1: The tendency of a single cell to perform transcription in bursts of activity/inactivity, which averages in bulk tissue as a continuous variable.
- bglazer 3y ago
  They use a master equation for transcription, so they could theoretically get bursty behavior. But, my understanding is that the most well understood cause of burstiness is caused in eukaryotic cells by rearrangement of histones allowing transcription. Since this happens on a slower timescale than transcription you get bursts when the histones periodically get out of the way. Bacteria (like this minimal cell) don’t have histones but they do have bursty transcription, which is weird. Apparently it might be caused by DNA supercoiling and uncoiling [1], which is weird and cool. That said, they definitely don’t model that, so I’d be surprised if they got bursting transcription. If they did, I’d be interested in knowing what mechanism is causing the transcription bursts in the model. 1. https://www.cell.com/cell/pdf/S0092-8674(14)00739-9.pdf https://www.cell.com/cell/pdf/S0092-8674(14)00739-9.pdf
331c8c71 3y ago
Fascinating stuff, thanks! A recent workshop with recorded talks on such cells https://www.jcvi.org/events/minimal-cell-workshop https://www.jcvi.org/events/minimal-cell-workshop I am wondering if other researchers can procure or produce these cells or these are rather a know-how of JCVI?
- koeng 3y ago
  I gave a talk at that workshop! (I’m making the 61 codon version of JCVI-Syn3a) You can get the cells as a researcher, but basically forget about it for a commercial user or hobbyist. They’re also annoying as hell to grow. I’m trying to synthesize it from scratch for the precise reason of freeing it from MTAs (material transfer agreements)
  - DylanSp 3y ago
    Sounds like you're doing good work! Out of curiosity, can you give a layman's explanation of what makes them hard to grow?
    - koeng 3y ago
      Their media is real complicated and expensive (plus difficult to prepare: can’t just throw everything in an autoclave), and they don’t grow very fast, and they don’t grow to a high concentration. Basically that means that you can easily get contamination (like you would growing human cells), and even when you do get growth, it’s dilute.
  - charred_patina 3y ago
    I do some biology-adjacent programming work. I think protein and cell simulations would be a fun area to learn about. I am familiar with projects like OpenWorm. You seem pretty knowledgeable about the field. How does one get into computational biology? What prerequisite knowledge would I need to be able to write simulations like in this article?
gus_massa 3y ago
Does this model have operons like https://en.wikipedia.org/wiki/Lac_operon https://en.wikipedia.org/wiki/Lac_operon [1] ? I guess they are skipped to reduce the complexity of the model. [1] This operon was the first that was discovered, the idea is that the cell produce the enzymes to eat lactose only if there is lactose and there is no glucose.
- agnosis 3y ago
  At the moment it does not. As per the paper[1]: > We do not simulate any operonal structures for protein-coding genes and transcribe each gene individually. Once transcriptomics data becomes available for Syn3A to determine operonal structures, we can incorporate transcription of operons into this model. [1] https://www.cell.com/cell/fulltext/S0092-8674(21)01488-4 https://www.cell.com/cell/fulltext/S0092-8674(21)01488-4
koeng 3y ago
We don’t even know what like, 20% of the genes do. Simulations are neat, but they miss a lot of underlying biology that actually makes an impact on engineering. One of my favorite papers was published 40 years ago on this topic https://pitp.ias.edu/sites/pitp/files/morowitz-completeness_of_mol._bio._copy.pdf https://pitp.ias.edu/sites/pitp/files/morowitz-completeness_...
- hobofan 3y ago
  If you read the article you'd know that that's exactly why organisms such as JCVI-syn3A were created, where we know the (or at least some) function of 80% of the genes.
  - bee_rider 3y ago
    Oh wow, a RISC (reduced instruction set cell).
  - koeng 3y ago
    I’m well aware. I was in charge of designing and synthesizing the entire gene set, optimized for E.coli, in order for scientists to easily try to discover the function of these genes https://stanford.freegenes.org/collections/gene-sets/products/jcvi_syn3-0#description https://stanford.freegenes.org/collections/gene-sets/product... Out of the 100 or so unknown genes we had/have, only like 3 unknowns were actually used for research. Such is science sometimes.
- ramraj07 3y ago
  I thought you posted “Can a biologist fix a radio?” It’s also very pertinent to this topic: https://www.cell.com/cancer-cell/pdf/S1535-6108(02)00133-2.pdf https://www.cell.com/cancer-cell/pdf/S1535-6108(02)00133-2.p...
DylanSp 3y ago
Interesting blog post, based on an interesting paper. For a bit more background, there's been a couple of posts on the "minimal cell" concept on Derek Lowe's venerable In the Pipeline blog. This 2016 post [1] talks about the initial development of the JCVI-syn3.0 cell; this 2023 post [2] goes over a paper that studied the evolutionary dynamics of these minimal cells. [1] https://www.science.org/content/blog-post/smallest-viable-genome-very-weird https://www.science.org/content/blog-post/smallest-viable-ge... [2] https://www.science.org/content/blog-post/ground https://www.science.org/content/blog-post/ground
zkirill 3y ago
I wonder if it would be possible to simplify the task further, by removing cell reproduction processes? As far as I understand, an "immortal" non-replicating cell does not exist in nature, but there is nothing that prevents an artificial one from existing, especially if it has ways to repair cellular damage.
- majkinetor 3y ago
  Non-replicating cell is called a virus.
- dsign 3y ago
  > "immortal" non-replicating cell Many (if not most) end-of-lineage cell in higher mammals are non-replicating. They are, technically, not immortal, but some live a very long time, like neurons. I like your experiment idea though, and I think it would be really interesting. If you publish your results, I can already see critics coming out of the bushes and shouting "immortality is immoral!", "unnatural!!!" and "it's a virus! it's a virus!". Oh how we like our value judgements...

164 points by agnosis 3y ago

Have you ever wondered how life’s most basic units, cells, operate? As a programmer and cell biology enthusiast, I embarked on a journey to simulate the simplest cell using TypeScript.

ClaraForm 3y ago
In biology, there’s a whole field of research dedicated to minimizing cells and their complexity. If you message “John Glass” he might be interested in having you model his work! Edit: oops you’ve already modeled John’s work! That’s awesome. :D I’ve attended a few talks by John and I think he’d still be interested in seeing whether the modeling side of things can explain why he can’t get the minimal cell smaller.
deleted 3y ago
[deleted]

mtekman 3y ago

This is really amazing. I wonder if confounders such as transcriptional bursting[1] are modelled too? I did not check but I assume cell-cycle is readily modelled. 1: The tendency of a single cell to perform transcription in bursts of activity/inactivity, which averages in bulk tissue as a continuous variable.

bglazer 3y ago
They use a master equation for transcription, so they could theoretically get bursty behavior. But, my understanding is that the most well understood cause of burstiness is caused in eukaryotic cells by rearrangement of histones allowing transcription. Since this happens on a slower timescale than transcription you get bursts when the histones periodically get out of the way. Bacteria (like this minimal cell) don’t have histones but they do have bursty transcription, which is weird. Apparently it might be caused by DNA supercoiling and uncoiling [1], which is weird and cool. That said, they definitely don’t model that, so I’d be surprised if they got bursting transcription. If they did, I’d be interested in knowing what mechanism is causing the transcription bursts in the model. 1. https://www.cell.com/cell/pdf/S0092-8674(14)00739-9.pdf https://www.cell.com/cell/pdf/S0092-8674(14)00739-9.pdf

331c8c71 3y ago

Fascinating stuff, thanks! A recent workshop with recorded talks on such cells https://www.jcvi.org/events/minimal-cell-workshop https://www.jcvi.org/events/minimal-cell-workshop I am wondering if other researchers can procure or produce these cells or these are rather a know-how of JCVI?

koeng 3y ago
I gave a talk at that workshop! (I’m making the 61 codon version of JCVI-Syn3a) You can get the cells as a researcher, but basically forget about it for a commercial user or hobbyist. They’re also annoying as hell to grow. I’m trying to synthesize it from scratch for the precise reason of freeing it from MTAs (material transfer agreements)
- DylanSp 3y ago
  Sounds like you're doing good work! Out of curiosity, can you give a layman's explanation of what makes them hard to grow?
  - koeng 3y ago
    Their media is real complicated and expensive (plus difficult to prepare: can’t just throw everything in an autoclave), and they don’t grow very fast, and they don’t grow to a high concentration. Basically that means that you can easily get contamination (like you would growing human cells), and even when you do get growth, it’s dilute.
- charred_patina 3y ago
  I do some biology-adjacent programming work. I think protein and cell simulations would be a fun area to learn about. I am familiar with projects like OpenWorm. You seem pretty knowledgeable about the field. How does one get into computational biology? What prerequisite knowledge would I need to be able to write simulations like in this article?

gus_massa 3y ago

Does this model have operons like https://en.wikipedia.org/wiki/Lac_operon https://en.wikipedia.org/wiki/Lac_operon [1] ? I guess they are skipped to reduce the complexity of the model. [1] This operon was the first that was discovered, the idea is that the cell produce the enzymes to eat lactose only if there is lactose and there is no glucose.

agnosis 3y ago
At the moment it does not. As per the paper[1]: > We do not simulate any operonal structures for protein-coding genes and transcribe each gene individually. Once transcriptomics data becomes available for Syn3A to determine operonal structures, we can incorporate transcription of operons into this model. [1] https://www.cell.com/cell/fulltext/S0092-8674(21)01488-4 https://www.cell.com/cell/fulltext/S0092-8674(21)01488-4

koeng 3y ago

We don’t even know what like, 20% of the genes do. Simulations are neat, but they miss a lot of underlying biology that actually makes an impact on engineering. One of my favorite papers was published 40 years ago on this topic https://pitp.ias.edu/sites/pitp/files/morowitz-completeness_of_mol._bio._copy.pdf https://pitp.ias.edu/sites/pitp/files/morowitz-completeness_...

hobofan 3y ago
If you read the article you'd know that that's exactly why organisms such as JCVI-syn3A were created, where we know the (or at least some) function of 80% of the genes.
- bee_rider 3y ago
  Oh wow, a RISC (reduced instruction set cell).
- koeng 3y ago
  I’m well aware. I was in charge of designing and synthesizing the entire gene set, optimized for E.coli, in order for scientists to easily try to discover the function of these genes https://stanford.freegenes.org/collections/gene-sets/products/jcvi_syn3-0#description https://stanford.freegenes.org/collections/gene-sets/product... Out of the 100 or so unknown genes we had/have, only like 3 unknowns were actually used for research. Such is science sometimes.
ramraj07 3y ago
I thought you posted “Can a biologist fix a radio?” It’s also very pertinent to this topic: https://www.cell.com/cancer-cell/pdf/S1535-6108(02)00133-2.pdf https://www.cell.com/cancer-cell/pdf/S1535-6108(02)00133-2.p...

DylanSp 3y ago

Interesting blog post, based on an interesting paper. For a bit more background, there's been a couple of posts on the "minimal cell" concept on Derek Lowe's venerable In the Pipeline blog. This 2016 post [1] talks about the initial development of the JCVI-syn3.0 cell; this 2023 post [2] goes over a paper that studied the evolutionary dynamics of these minimal cells. [1] https://www.science.org/content/blog-post/smallest-viable-genome-very-weird https://www.science.org/content/blog-post/smallest-viable-ge... [2] https://www.science.org/content/blog-post/ground https://www.science.org/content/blog-post/ground

zkirill 3y ago

I wonder if it would be possible to simplify the task further, by removing cell reproduction processes? As far as I understand, an "immortal" non-replicating cell does not exist in nature, but there is nothing that prevents an artificial one from existing, especially if it has ways to repair cellular damage.

majkinetor 3y ago
Non-replicating cell is called a virus.
dsign 3y ago
> "immortal" non-replicating cell Many (if not most) end-of-lineage cell in higher mammals are non-replicating. They are, technically, not immortal, but some live a very long time, like neurons. I like your experiment idea though, and I think it would be really interesting. If you publish your results, I can already see critics coming out of the bushes and shouting "immortality is immoral!", "unnatural!!!" and "it's a virus! it's a virus!". Oh how we like our value judgements...