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Comment by ValleyOfTheMtns | Hacker News Reader

Something I've never understood is how the nucleotides arrive to be included in the DNA strand. These animations always just show them appearing in perfect sequential order when they're needed, which is of course not what happens.

How are they delivered to the polymerase in the first place? How do they "know" where to be?

Are there just so many of them in the cytosol that through sheer numbers, there's enough random chance they'll just shuttle into place when the polymerase needs them?

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I wrote a blog post a few years ago explaining how molecules get to the right place at the right time. The short answer is that cells are nothing like the nice, peaceful animations. Cells are extremely crowded and things move extremely fast. Glucose molecules, for instance, move around cells at 250 miles per hour and collides with something billions of times a second. An enzyme might collide with a reactant 500,000 times a second. And proteins can spin a million times per second. So as you suspect, by random chance molecules are in the right spot very frequently.

http://www.righto.com/2011/07/cells-are-very-fast-and-crowde...

Thank you for writing this. I used to wonder how flies have such terrific reaction times and whip around the air with insane agility. And then I wondered if we are just seeing them in fast forward, due to the relatively slow clock in our heads. I imagined it was why they had such a short lifespan of just several days. And I imagined them seeing us as glacially moving statues—"man this guy hasn't moved in years!"

Reading your description of cells as moving imperceptibly fast only fills me more with this sense—that we are very slow moving giants, waiting on the billions of "years" of inner machinery time to tick us forward ever so slowly.

Time for you to read "Dragon's Egg", a hard sci-fi book about a civilization that evolves on a time scale far shorter than humans ultimately leading up to interaction with humans and this civilization. Awesome book which explores different time scales.

https://en.m.wikipedia.org/wiki/Dragon%27s_Egg

Dude, that was awesome. Thanks a lot!

I haven't had a book this good in some weeks. Cheers!

There is supporting evidence for your intuition. See for example:

http://www.sciencedirect.com/science/article/pii/S0003347213...

thanks for the citation! I converted Table 1 to show timescales using the CFF column:

    European eel                    0.23x
    Leatherback sea turtle          0.25x
    Blacknose shark                 0.30x
    Tokay gecko                     0.33x
    Rainbow trout                   0.45x
    Scalloped hammerhead            0.45x
    Little skate                    0.50x
    Tiger salamander                0.50x
    Harp seal                       0.53x
    Japanese rice fish              0.62x
    Lemon shark                     0.62x
    Brown rat                       0.65x
    Green sea turtle                0.67x
    Loggerhead sea turtle           0.67x
    Great horned owl                0.75x
    Tuatara                         0.75x
    Guinea pig                      0.83x
    Cat                             0.92x
    American red squirrel           1.00x
    Homo sapiens                    1.00x
    Goldfish                        1.12x
    Anolis cristatellus             1.17x
    Short-eared owl                 1.17x
    Budgerigar                      1.23x
    Dog                             1.33x
    Green iguana                    1.33x
    Yellowfin tuna                  1.33x
    Chicken                         1.45x
    Common treeshrew                1.50x
    Rhesus macaque                  1.58x
    Common starling                 1.67x
    Rock dove                       1.67x
    Yellow-pine chipmunk            1.67x
    Golden-mantled ground squirrel  2.00x

I've been having this same thought lately, about the scales of time that exist below/inside what we perceive. I agree that smaller/simpler brains probably run on a higher clock speed than those that are larger or more complex, and that impacts perception. But even within the fastest little minds, the rate at which chemical reactions take place or electrical signals propagate make them seem glacially slow in comparison.

I was actually thinking about putting a little video together about these scales of time, with the video containing nothing more than a person's blink reaction slowed down 5,000x.

I wonder if we allow enough for this in our search for alien life? Are their other life-forms out there somewhere whose timescales are radically different from ours? How would we find or communicate with them if there were?

like forests? I cannot forget the statement in 'Avatar' describing the 'tree of life'. How is it that memories have not been encoded in massively networked aspen forests? Or may they're there and we just havent looked. And with large encoded memory stores, manipulation of that data is what we call conciousness.

https://www.youtube.com/watch?v=QCqxOzKNFks

Just to clear up a minor (yet undying and continually propagated) fallacy, the lifespan of house flies is actually around 28 days.

>Cells are extremely crowded

Thanks for the excellent blog post. This is something more people need to appreciate.

I never realized just how crowded until I saw David Goodsell's molecular illustrations[1] in Drew Barry's TED talk.[2] Goodsell's drawings show the actual density and diversity of molecules inside the cell.

[1] http://mgl.scripps.edu/people/goodsell/illustration/public

[2] https://www.youtube.com/watch?v=dMPXu6GF18M

Those are nice.

People get confused because they read that cells are ~99% water by molecule count. By weight they're only ~65-70% water. One out of three atoms being part of a non-water molecule means cells are tightly packed.

Thanks for posting. That was fascinating.

Thank you for this. I have always figured something like this must be the case but it's never really explained very well in school.

> So as you suspect, by random chance molecules are in the right spot very frequently.

With that in mind I'd guess the bigger issue is how cells avoid having to deal with molecules being in the wrong spot.

there are both active and passive transport mechanisms in the cell.

> Are there just so many of them in the cytosol that through sheer numbers, there's enough random chance they'll just shuttle into place when the polymerase needs them?

Yes. Everything at that scale is very small, very close together and moving very, very fast.

This kind of thing is very common at the cellular level: have a receptor/channel/process/thing that only one precise 3d molecule can fit into - and then just wait.

As long as there's a process somewhere to make/acquire that molecule, then one will be along in a few nanoseconds or so, depending on the concentration. In the meantime the recipient will just wait.

In this way otherwise independent processes can regulate each other, and respond in a concentration dependant way to changing conditions without any central control.

I always thought of it as a probability field of molecules.

> have a receptor/channel/process/thing that only one precise 3d molecule can fit into

But what if the molecule has an unexpected "tail" attached to it? How to prevent the process from getting stuck?

I imagine there are not many things with unexpected shapes at that level that aren't accounted for somehow. Anything that doesn't slot into it perfectly will get knocked away by collisions. Bad shapes do exist however (prions) and are a cause of diseases.

Generally bulky substrates are inefficient and require additional catalysts for binding. (Typically kinases.)

So something with an unexpected tail won't react. It will not occlude the receptor either because it won't bind with it reliably...

These things are very, very precise.

https://www.youtube.com/watch?v=VdmbpAo9JR4#t=0m51s [warning, the view is jittery, due to being bumped around like a protein]

Also interesting things, just for scale: see a bacterium and a cell nucleus: https://www.youtube.com/watch?v=mdhk_-o8_n8

And an actual protein diffusion measurement from inside a nucleus (via light emitting proteins): https://www.youtube.com/watch?v=cDxUmCPxP_E

So, we're still some time from getting a "real" picture of the nucleus. Mostly because it's so dense.

(Here's a video about single particle tracking on the plasma membrane https://www.youtube.com/watch?v=dlq3kkbskaA and the nucleus is at least a magnitude more dense/busy.)

Life is very much about density gradients. Ion channels, osmotic pressure, and so on.

40% of the cytoplasm is proteins (by volume), which is remarkably high, considering a naive lattice packing is just 34% (the tetrahedral lattice with a density of).

As you said there are a lot of them, and they move randomly at crazy speeds (see Brownian Movement), accidentally coming together.

Yes, and indeed, this is why life as we know it only works in a narrow temperature range: high enough for Brownian motion to drive reactions, low enough not to unravel the results too quickly.

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