I would like to understand how cellular biology processes actually work. Like, how do all the right modules and proteins line up in the right orientation every time? Every time I watch animations, it seems like the proteins and such just magically appear when needed and disappear when not needed [0]. Sometimes it's an ultra-complex looking protein and it just magically flys over to the DNA, attaches to the correct spot, does it's thing, detaches, and flies away. Yeah right! As if the protein is being flown by a pilot. How does it really work?
They don't. This is a pet-peeve of mine, and it's reinforced by animation after animation.
Everything is being jostled around randomly. The molecules don't have brains or seeker warheads. They can't "decide" to home in on a target.
The only mechanisms for guidance are: diffusion due to concentration gradients, movement of charged molecules due to electric fields, and molecules actually grabbing other molecules.
It's all probabilities. This conformation makes it more likely that this thing will stick to this other thing. You may have heard that genes can be turned on or off. How? DNA is literally wound on molecular spools in your cell nuclei. When the DNA is loosely wound other molecules can bump into it and transcribe it -- the gene is ON. When the DNA is tightly spooled, other molecules can't get in there and the gene is OFF for transcription. There's no binary switch, just likelihoods.
Everything is probabilistic, but the probabilities have been tuned by evolution through natural selection to deliver a system that works well enough.
Even diffusion isn't some magical force guiding chemicals through the medium. It's just random movement that statistically results in the chemical being spread out. This is the same principle that the 2nd law of thermodynamics is based upon. There's nothing magic to it, it's just the statistically likely end result over many particles.
Yes. It's interesting how powerful and clarifying this model of its-all-just-atoms-bumping-into-atoms is. It's interesting how many people take science courses, but don't really get this.
In the context of Covid19, I see so many people wearing PPE, but failing to act as though they understand that the actual goal is to prevent this tiny virion dust from entering your orifices. Like wearing gloves and a mask, but then picking up unclean item in store then using now unclean gloves to adjust mask and make it unclean.
People seem to think of things as having essences or talismanic effects. Like gloves give you +2 against covid and a mask gives you +5 when it's really all about preventing those virus things from bumping into your cell things.
People understand 'germs' we don't live in a magical culture. It's not that they don't understand contamination they just haven't thought far enough ahead when they adjust their mask.
> Masks are for keeping your own particles from spreading far, not the other way around.
Masks are for keeping your own particles from spreading far AND for lowering the probability of virions found in the environment from entering your respiratory system.
Masks lower the probability when all other variables are held constant. If someone thinks wearing a mask grants invincibility and in turn chooses to increase their exposure to high viral load individuals or environments, they're putting themselves at risk.
> Masks are for keeping your own particles from spreading far AND for lowering the probability of virions found in the environment from entering your respiratory system.
Both of you may be correct. I think the person you responded to may not have been precise in their framing.
I suspect that you had N95 masks in mind when you wrote masks, which doesn’t negate the point of the person you responded to, if they had surgical masks in mind when they wrote masks. Surgical masks are far more common than N95 masks since they are cheaper and do not provide protection against viral particles for the wearer.
Surgical masks do provide some level of protection against virus droplets and aerosol for the wearer they just are not as effective as N95. Even a teacloth or a scarf wrapped around your face will provide some level of protection to the wearer from virus particles entering their mucus membranes.
Sorry, my comment was not very clear and is prone to misinterpretation. I'm not saying masks don't keep infection out, but rather that the point of society-wide mask adoption is more to keep unwitting spreaders from spreading so widely. I mean it does both, but as I understand it, it's main value is to attenuate sources than vice versa.
I'm in Taiwan where masks are ubiquitous, and have been upset reading about the slow adoption of masks in the West because it was always from a selfish perspective ("do masks protect ME?") whereas here they're worn for a communal purpose ("how do I protect others?"). How effective they are at blocking incoming infection always seemed like a big distraction to me, since it's been clear from the start that it reduces spray from spreaders talking and coughing, which alone is enough of a reason to adopt it widely.
Man, you and the other what-are-fields post just started me thinking about whether diffusion and fields are just things bumping into things. I know that at the QFT level things like the classical E-field can be expressed as interchange of mediator particles. But then QFT says it's all fields. Hmm...
To clarify: a "point particle" is an object with no internal structure, that is, it can be fully described by its coordinates wrt time (ignoring relativity for now). This is a concept, a model which explains many phenomena, a model on top of which you can build many theories. It does not, however, explain the conjunction of QM with special relativity.
It would be great if they showed just one animation up front of the chaotic mess that actually represents reality. They could then show the simplified version so that we can actually see what is going on.
https://www.researchgate.net/profile/Nicolas_Bellora/publica... is one example of the chaotic mess. What that shows is many RNA polymerase molecules walking up a gene. The horizontal line across the middle is DNA. The vertical tails hanging off it are RNA being built as the DNA is transcribed.
What that image drove home for me is:
1) that DNA transcription isn't something that happens rarely, or once-at-a-time. DNA is constantly being transcribed; proteins are constantly being built. The scale and rate isn't something I'd ever been taught.
2) How RNA polymerase works must be taking into account a hell of a lot of congestion. Polymerase molecules must constantly be bumping into each other.
3) How the picture would make no sense whatsoever unless you already know what the mechanism is.
I think it does make sense to start with the idealised process, as long as you follow up with messy reality.
The best programmer analogy I can think of is: imagine a system where every instruction always runs concurrently and every output influences everything with varying probabilities.
It's not so much "magic" as it is the sheer rate of molecular collisions in the cytosol. There are so many collisions happening that at least one of them will do what you want. Here's a back-of-the-napkin example, admittedly with many simplifications:
A tRNA molecule at body temperature travels at roughly 10 m/s. Assuming a point-sized tRNA and stationary ribosome of radius 125 * 10^-10 m, the ray casted by the moving tRNA will collide with the ribosome when their centers are within 125 * 10^-10 m of each other. The path of the tRNA sweeps a "collidable" circle of the radius of 125 * 10^-10 m, for a cross-sectional area of 5 * 10^-16 m^2. Multiplied by the tRNA velocity, the tRNA sweeps a volume of 5 * 10^-15 m^3 per second. Constrained inside an ordinary animal cell of volume 10^-15 m^3, the tRNA would have swept the entire volume of the cell five times over in a single second. Obviously the collision path would have significant self-overlap, but at this rate it's quite likely for the two to collide at least once any given second.
Now, consider that this analysis was only for a single ribosome/tRNA pair. A single ribosome will experience this collision rate multiplied by the total number of tRNA in the cell, on the order of thousands to millions. If a ribosome is bombarded by tens of thousands of tRNA in a single second, it's very likely one of those tRNA will (1) be charged with an amino acid, (2) be the correct tRNA for the current 3-nucleotide sequence, and (3) collide specifically with the binding site on the ribosome in the correct orientation. In actuality, a ribosome synthesizes a protein at a rate of ~10 amino acid residues per second.
Any given molecule in the cell will experience millions to billions of collisions per second. The fact that molecules move so fast relative to their size is what allows these reactions to happen on reasonable timescales.
I'd love to see a form of physical analysis like this extended to a statistical analysis of the likelihood of abiogenesis.
I know 4 billion years is a long time and the earth has a lot of matter rattling on it at any given time, but if every atom in the universe was a computer cranking out a trillion characters per second, you'd only have a 1 in a quarter quadrillion chance of making it to 'a new nation' in the first sentence of the Gettysburg address. Seeing the complexity in even the most trivial biological system just makes me scratch my head and wonder how its possible at all.
I'm not invoking God here. I just see a huge gulf in complexity that is difficult for me to traverse mentally.
The issue with these animations is that they're getting rid of all the thermal noise. In reality, single proteins are flying around the whole length of the cell many times a second, just from their thermal motion. And when processes like DNA transcription happen, they're not like a regular conveyor belt -- a fraction of the time the machine will even accidentally run steps in reverse! However, if any of this were shown, the animations would become impossible to understand.
Yes to getting rid of thermal noise. No ish? to single proteins flying around the cell that fast. The cytosol is incredibly jam-packed and things are getting hung up on other things so we'd expect the mean free path to actually be quite small for the larger biomolecules.
this segment is not the worst, but the full version of inner life of the cell is terrible. Because they cheated, by reversing highly symmetrical processes, for example:
The artistic director has a ted talk where he talks about how beautiful biological processes are, and it's like no, man, you made it look that way.
If you want a really fantastic video that captures just how messy and random it is I recommend the wehi videos, like the one on apoptosis, where the proteins look way more derpy than the secret life of the cell: https://www.youtube.com/watch?v=DR80Huxp4y8 There's a couple of places where they have a hexameric protein where things magically snap into place, but I give them a pass because the kinetics on that are atrociously slow. Let's just say for the sake of a short video the cameraman happened to be at the right place at the right time.
Oh my that facepalm dreadful. Thank you! That gives me a new high-water mark for misleading biomolecular visualization computer graphics content. Snagged a copy.
When most everything is unmoving, it's "obvious"... well no, not to students, but... there's no pretense of doing anything other than stitching together an extremely selective set of "snapshots", to tell a completely bogus narrative of smooth motion.
Here it seems something like a Maya "jiggle all the things" option has been turned on. Making it sort of kind of look like you're being shown more realistic motion. But you're so not. It's the same bogus smooth narrative, now with a bit of utterly bogus jiggle. Those kinesin legs still aren't flailing around randomly. Nor only probabilistically making forward progress. And the thing it's towing still isn't randomly exploring the entire bloody space it can reach given the tether, between each and every "step". It still looks like a donkey towing a barge, rather than frog clinging to rope holding a balloon in a hurricane.
And given that the big vacuole or whatever should be flailing at the timescale defined by the kinesin feet, consider all those many much smaller proteins scattered about, just hanging out, in place, with a tiny bit of jiggle. Wow - you can't even rationalize that as being selective in "snapshots" - those proteins should just be blurs and gone.
And that's just the bogosity of motions, there's also... Oh well.
So compared with older renders, these new jiggles made it even harder to recognize that all the motion shown is bogus. And not satisfied with the old bogus motion, we've added even more. Which I suggest is dreadful from the standpoint of creating and reinforcing widespread student misconceptions. Sigh.
Yeah. One might for example reduce reinforcement of the big-empty-cell misconception by briefly showing more realistically dense packing, eg [1], before fading out most of it to what can be easily rendered and seen. But that would be less "pretty". Prioritizing "pretty" over learning outcomes... is perhaps a suboptimal for education content.
> better
But still painful. Consider those quiet molecules in proteins, compared with surrounding motion. A metal nanoparticle might be that rigid, but not a protein.
One widespread issue with educational graphics, is mixing aspects done with great care for correctness, with aspects that are artistic license and utter bogosity. Where the student or viewer has no idea which aspects are which. "Just take away the learning objectives, and forget the rest" doesn't happen. More like "you are now unsalvageably soaked in a stew of misconceptions, toxic to transferable understanding and intuition - too bad, so sad".
So in what ways can samplings of a protein's configuration space be shown? And how can the surround and dynamics be shown, to avoid misrepresenting that sampling by implication?
It can be fun to picture what better might look like. After an expertise-and-resource intensive iterative process of "ok, what misconceptions will this cause? What can we show to inoculate against them? Repeat...". Perhaps implausibly intensive. I don't know of any group with that focus.
Agreed; cool, seems a neat guy. And much of his work is CC-BY, thus great for open education content. Hmm, the Wikimedia Commons capture of his work seems to be missing quite a bit. Oh nifty, there's now an interactive version of his 2014 "Molecular Machinery: A Tour of the PDB".[1]
At least there is some water there. But what strange force is that holding proteins together when they are completely out of alignment, and keeping the water away from everything else?
Well, OP did say "even if it's impossible to understand" so if it is in fact in any way misleading, then my lawyers assure me that I may claim the full privileges of a contextual get-out-of-jail-free card for linking to it, and am hereby fully absolved of any intellectual harm caused to any and all individuals who may have viewed it.
Ha. I've wondered if increasing embarrassment might reduce long-term stable misconceptions in education content. Like astronomy texts getting the color of the Sun wrong. Or wing lift discussed elsewhere. But making textbooks liable for intellectual harm... wow. What might the internet, media, politics, thought and conversation look like, if we were all liable for negligent intellectual harm?
It would be pretty boring, proteins bouncing around randomly and occasionally honking up, substrates flying around like rifle bullets sometimes hitting the target, and everything smooshing around in random directions. If you’ve seen Brownian motion, you’ve seen what is happening to all the molecules but at 1/100 the length scale. Nothing stays put. Everything is moving fast and far on the scale of proteins and small molecules.
Any time something "magically lines up", it means that those molecules randomly float around until the right ones bump into each other.
Once they are in close enough proximity to bump into each other, intermolecular forces can come into play to get the "docking process" done.
For something like transcription, once they are "docked", think of it like a molecular machine - the process by which the polymerase moves down the strands is non-random.
There are also several ways to move things around in a more coordinated fashion. Often you have gradients of ion concentration, and molecules that want to move a certain direction within that gradient. You also have microtubules and molecular machinery that moves along them to ferry things to where they need to be. You can also just ensure a high concentration of some molecule in a specific place by building it there.
Float is the wrong word to use I think. Float implies gravity and water. At the scale of a cell gravity is not as important as intra-molecular forces like van-der-waals forces, and fluids do not behave like we think.
But in a nutshell, the animations are heavily idealized, showing the process when it succeeds, slowing it way, way down, and totally ignoring 90% of the other nearby material so you can see what's going on. Then you remember that you have just a bajillion of cells within you, all containing this incredibly complex machinery and... it's really kindof humbling just how little we actually know about any of it. Not to discredit the biologists and scientists for whom this is their life's work; we've made incredible amounts of progress over the last century. It's just... we're peeking at molecular machinery that is so very small, and moves so quickly that it's nigh impossible to observe in realtime.
1) Compartmentalizing of biological functions. Its why a cell is a fundamental unit of life, and why organelles enable more complex life. Things are physically in closer proximity and in higher concentrations where needed.
2) Multienzyme complexes. Multiple reactions in a pathway have their catalysts physically colocated to allow efficient passing of intermediate compounds from one step to the next.
3) Random chance. Stuff jiggles around and bumps into other stuff. Up until a point, higher temperature mean more bumping around meaning these reactions happen faster, and the more opportunities you can have for these components fly together in the right orientation, the more life stuff can happen more quicky. There's a reason the bread dough that apparently everyone is making now will rise faster after yeast is added if the dough is left at room temp versus allowed to do a cold rinse in the fridge. There are just less opportunities for things to fly together the right way at a lower temperature.
3a) For the ultra complex protein binding to the DNA, how those often work in reality is that they bind sort of randomly and scan along the dna for a bit until they find what they're looking or fall off. Other proteins sometimes interact with other proteins that are bound to the DNA first which act as recruiters telling the protein where to land.
The common theme there is constrained proximity. To give random chance more of a chance.
My favorite illustration was a video of simulated icosahedral viral capsid assembly. The triangular panels were tethered together to keep them slamming into each other. Even then, the randomness and struggle was visceral. Lots of hopeless slamming; tragic almost but failing to catch; being smashed apart again; misassembling. It was clear that without the tethers forcing proximity, there'd be no chance of successful assembly.
Nice video... it's on someone's disk somewhere, but seemingly not on the web. The usual. :/
> yeast
Nice example. For a temperature/jiggle story, I usually pair refrigerating food to slow the bacterial jiggle of life, with heating food to jiggle apart their protein origami string machines of life. With video like https://www.youtube.com/watch?v=k4qVs9cNF24 .
> Compartmentalizing
I've been told the upcoming new edition of "Physical Biology of the Cell" will have better coverage of compartmentalization. So there's at least some hope for near-term increasing emphasis in introductory content.
Coincidentally I'm previewing PBotC just now. It looks really promising. Do you know roughly when the new edition is expected? Or if you have any favorite books on how things work at that scale, I'd be grateful for the pointer. (I've read a popular book by David Goodsell and am halfway through a somewhat deeper one.)
I've found the bionumbers database[1] very helpful. Google scholar and sci-hub for primary and secondary literature. But books... I'd welcome suggestions. I'm afraid I mostly look at related books to be inspired by things taught badly.
The bionumbers folks did a "Cell Biology by the Numbers" book... the draft is online[2].
Ha, they've done a Covid-19 by the numbers flyer[3].
If you ever encounter something nice -- paper, video, text, or whatever, or even discussion of what that might look like -- I'd love to hear of it. Sorry I can't be of more help.
I studied bioinformatics and found the standard textbook, Albert's "Molecular Biology of the Cell"[0] to be one of the most captivating books I've read. It's like those extremely detailed owners' manuals for early computers, except for cells.
The amount of complexity is just absolutely insane. My favourite example: DNA is read in triplets. So, for example, "CAG" adds one Glutamine to the protein it's building[1].
There are bacteria that have optimised their DNA in such a way that you can start at a one-letter offset, and it encodes a second, completely different, but still functional protein.
I found the single cell to be the most interesting subject. But of course it's a wild ride from top to bottom. The distance from brain to leg is too long, for example, to accurately control motion from "central command". That's why you have rhythm generators in your spine that are modulated from up high (and also by feedback).
Every human sensory organ activates logarithmically: Your eye works with sunlight (half a billion photons/sec) but can detect a single photon. If you manage to build a light sensor with those specs, you'll get a Nobel Prize and probably half of Apple...
"The distance from brain to leg is too long, for example, to accurately control motion from "central command"
As a dancer, I have been fascinated by that fact. It means that dancers do not dance to the beat as they hear it - it takes too much time for the sound to be transformed by the ear/brain into an electrical pulse that reaches your leg. Instead, all dancers have a mental model of the music they dance to that is learnt by practice/repetition.
Dancing is just syncronizing that mental model to the actual rhythm that is heard. When I explained that to a bellydancer friend she finally understood the switch that she had made from being a beginning dancer to an experienced dancer who 'dances in their head'
You can clap your hands to a calibrated delay from the previous beat that you heard (predicting the next beat before you hear it). This is analogous to the principle of a phase-locked loop, which gradually adjusts an internal oscillator until it matches an external frequency. That internal oscillator can emit a beat just before the real one, offset just enough to cancel all the delays in the processing path.
This only works if the beat you're hearing is sufficiently stable.
Yeah, you often send commands several beats in advance. And then there's some lag too, because muscles are fairly viscous and take a bit of time to start up. You're basically dancing in the future, because you are behind. I think we just run pre-baked programs (from a lot of practice) and adjust their timings on the fly every few beats or a bar.
The Albert's MBoC is pretty much known as the reference textbook where I studied.
Note that the 4th edition is (sortof) freely available at the NIH website. The way to navigate through that book is bizarre though, as the only way to access its content is by searching.
Cells are tiny and the speed of sound is how fast air molecules move. Proteins are also not bouncing around as fast but it’s very still quick relative to their size. Next, often there are multiple copies of each component. That’s half the story, larger cells also have various means to clump things together to improve the odds. https://en.wikipedia.org/wiki/Endoplasmic_reticulum
PS: Speed of sound is 343 m/s, diameter of a cell nucleus is ~ 0.000006m to give an idea.
Yep, and speed of sound is lower than the average speed of individual molecules. But, I was aiming for an intuitive understanding rather than accuracy involving brownian motion etc.
From a physics perspective I bet you have two things happening:
1. These molecules are moving around a lot. The kinetic energy of molecules at room or body temperature gives them impressive velocity relative to their scale, and they're also rotating altogether and internally.
2. Compatible molecules are like magnetic keys and locks. They attract each other and the forces align with meeting points. The same way that proteins fold spontaneously.
So the remaining part is getting concentrations appropriate for what you want to happen - and that's a matter of signaling molecules and "automatic" cell responses to changes in equilibrium. It's a really chaotic system and it's a wonder it works at all.
I imagine that's also one reason life is imprecise, i.e. no two individuals are alike even with identical genes. There's a lot of extra "entropy" introduced by that mess of a soup.
there are some animations that show how fast molecules and proteins go around in a cell, it's basically a bunch of extremely fast collisions and interactions going at random that end up falling into proper configurations. The way Science is taught in molecular biology (as in, visually, with proteins binding to receptors just like if it were fate) is usually completely wrong.
By molecular structure alone Insulin is one of the simplest proteins, even (though it's complex in ways you don't see by looking at a static picture of it, lifecycle, oligomeric interactions)
[0] https://youtu.be/5VefaI0LrgE