Cells are fast and crowded places (2011) | Hacker News Reader

Cells are fast and crowded places (2011)

righto.com

294 pointsgmays117 comments

I find this initially unintuitive, but it makes sense when you think about it.

Look at any other system that produces aggregate emergent behavior out the behavior of smaller parts. For example, here's Conway's Game of Life implemented using... Conway's Game of Life: https://www.youtube.com/watch?v=xP5-iIeKXE8 It takes many many steps of the inner game of life to produce a single iteration of the outer simulation.

In general, with emergent behavior, it takes a lot of inner steps to produce a single meaningful step in the outer system. So it makes sense that our cells are much faster than we intuititively think of as "fast". Because our intuition about speed is itself the product an emergent system. We are that larger Game of Life there, so it looks incredibly fast to watch the inner one according to our own time scale.

what's interesting is that the GoL inception is (as far as I understand) highly sensitive to initial conditions and timing in order for everything to sync up properly, whereas the cell is really robust in terms of everything just jumping around randomly and yet still getting its tasks done

Yeah it feels as if the cell is a ridiculously parallel array of molecules where every molecule in the array is rapidly iterating through the array (colliding with every molecule in the cell as it diffuses) and type checking those items to see if it can operate on them (e.g. a protein breaking down a small molecule). It all works out because the operations are atomic (heh) (don’t need to worry about two proteins trying to break down the same molecule at the same time) and the type safety (proteins are highly specific on what kind of chemicals they target) means you don’t need to worry about trying to perform some invalid operation.

Turns out collision detection is real fast in real life!

What would happen if a cell were somehow to be optimized such that every operation occurs in O(1) time rather than having to iterate?

Cancer, probably.

This is probably what happened to Tetsuo in Akira.

Hm, well, it would require a "global" approach instead of what currently happens. Which is the opposite, local gradients, local diffusion, local parallel approaches. Many times things are being built, remodeled, moved, teared down, packed for moving, and unpacked for use. Everything is at the same time a tool for building bigger things and is just a piece of raw material if something else happens to disassemble it or use it for assembling something bigger.

So opposed to that there would need to be some kind of ordering, signaling, queuing, synchronization, etc.

Thanks to osmosis building block things are always pretty close when they are needed, and products are always getting spread out evenly too. (And there is a transport network in each cell that helps with those that need some help spreading.)

Of course there are certain things that work based on a kind of synchronization, like the waiting for all actin fibers and the two copies of each chromosome during cell division (probably the metaphase) to be in place so they can start pulling apart the cell nucleus (anaphase), and then the daughter cells can separate. Of course this also depends on signals (cyclins). The G1 cyclin slowly accumulates, and unless it's inhibited (by eg. signals get produced when "lack of nutrients" state happens around the cell) it'll start a cascade to ultimately split the cell in two.

Similarly there are certain genes that are environmental gradient dependent, usually these work when a stem cell differentiates into something specific. And the stem cell stuff is active because some parts of the DNA is conveniently exposed, certain signaling pathways are active - so the cell reacts to the gradient. And after differentiation those things get put away, locked down, coiled up, broken down, absorbed, etc.

Okay, so how could a cell skip all those iterations? It needs to know what to do and when, that's environment dependent (locally signaled by other cells, and sometimes signals arrive from far via special stuff in the blood, eg. hormones). Something like that could be probably implemented in cells. Eg. "simply" enumerating all the functions of a cell and making every process inside it depend on outer signals, and maybe leave the simple accumulators.

And when any process is about to start the cell would need to know if it has enough resources to go through with it. This would basically need yet another signaling and computational system. Or, sure, it might just start things and ... fail to finish it in time, but then it needs to disassemble whatever is half-finished. And basically that's already what happens. All the time. And if something is "really needed" it'll be finished fast. (Because signals inhibit things that slow things down, and also maybe slow down the cleanup crew too.)

So it's kind of like React hooks, except they are probabilistic and constrained by 3d geometry. And the things moving around fast inside the cell is the event loop. Fun!

Another analogy: molecule interactions are like proof of work operations that unlock cell actions when the right fit (hash) is found. trillions of molecule interactions are required to find the right fit.

the intricate network of transcription factors operate as a security system to unlock key processes in DNA regulation in eukaryotes. security must be maintain because the system is under constant attack from other information systems (viruses)

> the type safety (proteins are highly specific on what kind of chemicals they target) means you don’t need to worry about trying to perform some invalid operation.

You might want to look into the mechanics of heavy metal poisoning.

There is no type safety, and there's no type checking. Everything attempts to interact with everything it encounters. Those interactions usually fail.

The thing that is ignored here is that while molecules move fast ... they go nowhere. It's a random walk. It takes 6 hours for your small protein molecule to move 1cm ... at 250kph.

So while these molecules offering themselves up "automatically" works, it only works at very short ranges and it's a stochastic range. At 1nm they meet 100k times per second. At 1cm once per 6 hours. At 3cm once per month.

So there is in fact a lot of bookkeeping, keeping things tethered where they need to be and dragging things around to be done inside the cell where everything magically happens. People in this thread aren't correct that it's not necessary to do that. You don't need to get positions exactly right, as in you don't have to get the amino acids in every ribosome, but you DO have to get them "more or less" where they need to be. If for example if the amino acid concentrations near ribosomes ever get low, that's the end of you in about 2h (there's a fungus that causes that).

interesting. so the idea that this all happens just because every molecule interacts with every molecule many times per second, as advanced in the blog post, is not correct?

One big difference is the dimensionality, of 2d vs 3d. Even within the 3d space, quantum chemistry effects produce an even higher order of "effective" dimensionality. Finding stable paths that don't interact in 2d is hard, but easier in 3d. Its even easier in hyper dimensional spaces where other chemical properties can be used to provide pathways for only specific reactions.

It always bothered me that in the standard explanations of how these processes work it always seemed that reaction ingredients would somehow magically seek each other out, such as in videos like this where the amino acids arrive at the ribosome in order: https://www.youtube.com/watch?v=TfYf_rPWUdY

The molecules really do move randomly, not magically, and it's just that they go so fast and are so numerous and collide so often that even random chance puts the right molecules in the right place many times per second. This article was a revelation when I first read it and I'm quite disappointed that this was never explained properly in my entire school life.

Don't be disappointed. Most of the things you were taught in school were simplifications of reality. The curriculum is taught this way to make it easier for you to incorporate a lot of axioms from different fields into your fledgling, inexperienced mind. Once you have a number of these axioms at your disposal, you are equipped to leave the nest and go out into the world and make sense of new things yourself, at whatever depth and speed suits your circumstances and interests.

This isn't a simplification though. It's a complification. It's both more important and easier to understand than a lot of the biology stuff that I was taught. The curriculum should be rearranged to prioritize this higher.

Correct. In most class-based education, biology is treated just like history and math and everything else. All subjects are just collections of disconnected factoids handed down from on high. Intuition requires initiative, and initiative means asking questions, and asking questions takes away class time from the unintuitive students learning more factoids. The point is: go to your professors' office hours!

This is fascinating and new to me. I thought it was designed by say the DNA or the rna to behave in that coordinated manner and to seek specific molecules. But if it's just a random walk and somehow this success at this scale and speed, it is even more simple yet incredible to think.

Brownian motion dominates at the scale of a protein. In other words, the energy imparted by the ambient temperature is orders of magnitude greater than that that could be established through momentum of objects with that little mass. So everything bumps into everything, and the only distinguishing factor between various bumps is how long they stay stuck together. Most things just bounce right off. Sometimes they are repulsed, and in rare cases (when they've been selected for), multiple proteins can meet in just the right orientation that they stay stuck for a while (now scale this so that 3 or 4 objects must meet at the same time, and now you get into the 'regulation' of a cell at perception-relevant time-scales). This measurement of stickiness is called the "dissociation constant (Kd)" and is a measurement of what concentration of component A you need alongside component B such that half of component A is bound to component B. It is one of the primary drivers of most biochemical processes in a cell.

https://en.wikipedia.org/wiki/Dissociation_constant

Is there not some local disturbances in the circulation of cell contents that not all interactions are i.i.d? Some kind of repelling force on a large molecule that would keep similarly charged molecules at arms length. And in some cases act as a cell wide tidal force to diffusion?

I'm thinking of the atari pong ball where you can ricochet the ball between the top of the court and bricks repeatedly; is there some locality in the cell which takes advantage of positioning to increase likelihood of collision?

tl;dr very much so, yes

Cells are very subdivided, and the ease with which macromolecules traverse these spaces varies greatly. There are organelles and the nucleus that require only let certain proteins in and and out and at certain rates.

There are also kinds of tar-pits that keep certain proteins around for longer.

Stress granules and vesicles also gobble-up macromolecules into these fun party bags that burst in certain contexts.

Sometimes you even have complexes of macromolecules like ribosomes whose entire job is to intercept other macromolecules so that they might interact (there is a subtle difference between enzymes/catalysis here if I understand correctly)

> local disturbances in the circulation of cell contents that not all interactions are i.i.d?

Sure, in the sense that the cell isn't actually a single homogeneous compartment the way it's often portrayed.

There are numerous organelles, most (all?) separated by lipid bilayer membranes. (https://en.wikipedia.org/wiki/Lipid_bilayer) There are various transporters (ie protein machines) embedded in the different membranes that move specific things from one side to the other. There are also complex transport systems that move packets of things from one organelle to another. (https://www.nature.com/scitable/topicpage/endoplasmic-reticu...)

The end result is that the contents and chemical conditions of compartments are quite different from one another. As a concrete example, this is actually one of the ways that viruses know when to "wake up" and start doing things. (https://www.uniprot.org/keywords/KW-1170)

> Some kind of repelling force on a large molecule that would keep similarly charged molecules at arms length.

It's more that proteins get "sorted" into the appropriate locations where they aren't reactive with anything except their intended targets. If they react with things they aren't supposed to then (over generalizing to an absurd degree for illustrative purposes) everything stops working, that organism dies, evolution continues, and one way or another eventually we're back at that protein only reacting with the things it's supposed to react with.

What's also fascinating is that the shapes and biochemical properties of proteins and other molecules in the cell are so finely tuned that they can be flying into each other, and still have such a high degree of specificity (e.g. proteins interacting with certain other protein domains, substrates, etc) that life actually works.

I'm always awe-struck thinking about the fact we know this. For example the ATP synthase motors in the Mitochondria— we have figured out ways to discover these sorts of things without seeing them, just by chemical analysis, computer modeling, trial and error.

Moreover, this is just what we know, but there must be so much more we don't know. It's astounding to think just how much more might be hiding in these very complex systems.

To think that the machinery of the human body evolved from water and basic elements. It's hard to believe sometimes.

Most of life's history on this planet was single-celled. That's especially astounding when you consider the short generation time of single-celled life. The building blocks for these complex molecular machines existed before multicellular life was possible.

The first 2 billion years was single celled. Since then, life on earth has been a combination of single celled prokaryotic cells, and much larger (100x) eukaryotic cells.

The evolution of eukaryotes, which comprise all the plants and animals you see on David Attenborough's Life on Earth show, didn't occur until the Earth had developed an oxygen rich atmosphere.

What's amazing about eukaryotic cells is that they formed from colonies of prokaryotic cells, in a process called endosymbiosis.

There's a reason why the mitochondria in eukaryotic cells look like little bacteria like organisms. They actually were once separate prokaryotic organisms. Same for chloroplasts in plant cells.

How Two Microbes Changed History

https://www.youtube.com/watch?v=lhF5G2k45vY&t=343s

Search space for the first billion or so years was likely around atoms/chemistry. Search space for the next billion or so years was likely around mutations in well-defined genetic space (4 nucleic acids as building blocks, 20 amino acids as building blocks). Search space for the past 700M years has included 'recombination' (copy/swap/paste) of larger chunks of (existing) genetic code (in addition to the prior two mechanics). There are probably many such abstraction layers, including like you mention, copying/pasting of entire organisms, environments, biospheres...

> but there must be so much more we don't know.

I was pretty surprised at the amount of biology we don't know (I'm writing software to help geneticists, a recent development for me). We know a lot, but its astounding how complex these biological systems are.

It is kinda amazing we're alive.

Biology is unusual among sciences in that a five year old can ask questions it can't answer.

To get an idea about what life processes are like, you need to read endocrinologists like Robert Sapolski or Robert Lustig.

A lot of processes only work because there are so many moving parts each pushing only a little of the way, so that when something is wrong it doesn't all collapse.

> Biology is unusual among sciences in that a five year old can ask questions it can't answer.

You can do this in a lot of fields, but you're right, Bio is one where it's very easy to do.

I'm always struck by the 'pathways' side of mol-bio. It's not easy, but many grad students can come up with experiments that will lead to discoveries of new signaling pathways inside a cell. I'm sure someone has done a census of the number of pathways in their particular cell, but for all cells? It must be a gigantic number of proteins that interact.

And I'd hedge that we're no where even close to knowing how they all interact

Actually, the rotation of the ATPsynthase motor was observed under the microscope to be proven. The investigators attached a very small copper rod to the rotor to show that it indeed made a full rotation.

Reminds me of some Alan Kay talks:

https://youtu.be/YyIQKBzIuBY?t=1384

He actually mentions the book that is the source for the first illustration in the article. He also often talks about the speed of molecules and how it's counter-intuitive to the commonplace idea of cell operation.

Cell biology was an inspiration for original OOP (which wasn't much like Java/C++ at all).

When reading about Covid stuff and immunity, I often think how these mechanism could be imitated in engineering. I definitely believe there are some general principles that we could benefit from without trying to "simulate" biology.

Edit: Sorry, same author/illustrator, but different book.

Any chance you could provide a summary of how OOP was originally much more similar to cell biology? :)

Some of the ideas that were translated to reality are covered here:

https://www.youtube.com/watch?v=QjJaFG63Hlo

Some of them never got fully translated to reality at Xerox because of various reasons (e.g. memory limitation of hardware at the time). This is worth a read:

http://alumni.media.mit.edu/~mt/thesis/mt-thesis-Contents.ht...

OOP could only have been inspired by the then-available knowledge of cell biology, and it seems that even today we still have a lot to learn.

We know way less than we don't know. And much of what we think we know is wrong.

I think what made it click for me was thinking of explosions. Think of something like the detonation of ammonium nitrate. It is incredibly fast on a human timescale. It is just a chemical reaction. Chemistry can happen at insane speeds. Even the monstrous molecules of biology can interact at incomprehensible speeds. Think of all that needs to go on just to make a neuron fire, much less a million neurons forming a thought. It's amazing that our bodies manage to last as long as they do. That is an awful lot of stuff that has to go right or else we die.

If you want beautiful representations of what cells look like, highly recommend David Goodsell’s pictures. They’re highly regarded in the field of biotech

Link?

Some of them are at http://pdb101.rcsb.org/sci-art/goodsell-gallery/

Here's a profile that includes some of his watercolors:

https://www.sciencemag.org/news/2019/04/meet-scientist-paint...

His book, "The Machinery of Life", is just wonderful.

I also like his renderings of protein structures: http://pdb101.rcsb.org/motm

In case anyone missed the caption: the second picture on the page, "a representation of how crowded cells really are", is by Goodsell.

Goodsell's book, "Machinery of Life" is fantastic at giving a first-pass representation of the basic interactions in a cell that are otherwise invisible.

https://ccsb.scripps.edu/goodsell/machinery-of-life/

Does anyone know of resources or groups with a focus on educationally conveying a feel for foundational biochemistry mechanics: extreme violence; random; crowded; with locality and concentration enhancement?

For instance, there's a video of simulated viral icosahedral capsid assembly, where the panels are tethered together to maintain proximity, so you get to see realistic assembly and disassembly and reassembly, temporary misfits and irreversible fails, and just a whole lot of flailing and slamming around until something clicks. It's ok for showing 10 nm scale object violence, but I've never seen anything good for 1 nm or 100 nm scale violence. And for concentration enhancement, I've only ever seen nice slides in research talks.

Given how pervasive related misconceptions are, it'd be interesting to have a page to point to where the best available misconception antigens are slowly accumulated.

One issue is that the scales don't well-match. And there are actually many time-scales beneath us, not just a few (and that biology/life is working at them all - including those on the order of millions of years.

An event like a "protein folding" can take milliseconds, in a tube [1]. While atomic/biophysical/biochemical simulations have time-steps of femto-seconds.

[1] https://www.youtube.com/watch?v=gFcp2Xpd29I

From https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3890418/

"Traditional MD [Molecular Dynamics (protein folding)] simulations are limited in length by timestep limits. Studies by our group and others have shown that traditional MD is limited to timesteps of about 2 fs due to high-frequency resonance frequencies.1–3 Many biologically relevant motions occur on the microsecond to millisecond range, which is 9 to 12 orders of magnitude greater than the timesteps possible with traditional MD. Further, each step requires a costly force calculation (O(N) to O(N2)). As such, simulating medium-size proteins often requires months of computer time on a large distributed cluster such as Folding@home4,5 to simulate milliseconds of dynamics, while simulating a large protein (e.g. the β-2 Adrenergic Receptor) on biologically-relevant time scales (milliseconds through hours) using a standard desktop computer would take years. Thus, it is not feasible to simulate timescales of biological interest without substantial advances in MD methods."

12 orders of magnitude of difference in time is akin to the difference between causal events happening once per millisecond and those happening once per century. How do you show a movie capturing the nuance of someone's blink reflex, along with their birth life and death...

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

https://www.youtube.com/watch?v=VdmbpAo9JR4

> One issue is that the scales don't well-match. [...] many time-scales

Indeed, teaching of scale pervasively fails. Physical, temporal, and other. But it's also taught very very badly. Thus it seems an open question how well it might be taught, and to whom.

Might we teach it better? This[1] (mine) illustrates one speculative approach to teaching size down to atoms, for a young and outreach audience. And here's[2] an old attempt at helping develop a feel for torque, down to picoNewton-nanometers. Many years back I started on a temporal zoomer - don't know if it would have worked, but I've not seen anything similar since. I recall some work on teaching deep time in intro geology as being rather nice.

Interactives with physically realistic molecular motion are vanishingly rare, and I've never seen a one with temporal zoom. So I suggest we're not even trying yet to explore whether we can teach this well.

Those last two "Inner Life ..." videos are regrettably even more misleading than the original. Motion in the original was aphysical, but at least it was simple. Those two retain that aphysicality, and add aphysical jiggle, further obscuring how badly you're being misled.

Creating educational content to support an excellent understanding of science is ghastly hard. So much so, that I suggest we're not even really trying yet. Which would mean how hard it will be to teach, once such content exists, is necessarily an open question. I wish I knew of folks exploring it.

[1] first section of http://www.clarifyscience.info/part/Atoms (page loads slowly - was meeting prep, not intended to be public) [2] http://www.clarifyscience.info/part/ZoomB?v=A&p=CK6Ji&m=torq...

Very cool! I've actually built similar models for myself to build that intuition. They're so helpful and generally hard to find. I agree that scale is generally poorly taught.

I personally think having even a modest intuition for how to map physical knowledge to its appropriate 'scale' (time/space, from plank to universe) is one of the most straightforward ways to be "smart". And a great way to get to know the limits of our knowledge.

I still haven't seen a video that matches my intuition. Which is unfortunate. I want to build a version of your scaler there, but for VR that you can slide up and down along at least time/scale axes - and maybe additional ones too.

:) It does seem physical scale can serve as skeleton and scaffold to support learning and integrating knowledge of the physical world. I don't know of any attempts to really push on that.

> for VR

An unfinished lockdown project was a RL version of that hands-apart-to-zoom cartoon, with an atomic-bonding interactive, with realistic electron density, as content. Educational XR might eventually be so much fun.

> maybe additional ones too

Maybe Ashby diagrams in XR?! Someday.

I'd love an "measure explorer" - a densely fleshed out space of order-of-magnitude overviews. Length; velocity; accel; jerk; length/dollar; length/dollar^2; length/mass; etc, etc.

Years ago I prototyped an interactive where oom diagrams were tied with other content. So as you slide mass, you get different animals, and as metabolic rate scales with animal mass, you get heart beat. Life expectancy, etc. Heart to Hz, keyboard, and sound ripples spreading in space. Or explore equations: select ideal hand crank for torque, with a meter arm, a bacteria for mass, and a second later, hey, relativistic E. coli. :)

I've found the bottleneck on creating such to be finding usable media. Hopefully google will eventually do semantic scene indexing of youtube videos, and of images. If anti-trust doesn't break them. And sci-hub still exists. Finding "a bit of video with an X doing Y" is still prohibitively hard. And licensed for reuse? Perhaps structure the effort to survive being sued for aggressive use of Fair Use, or some country's similar exception, because copyright is a nightmare.

170 mV across a membrane only, what, 40 angstroms thick, is a field strength of >40 million volts/meter.

There's pretty video of bacteria with green-fluorescent-protein electric-field probes, flashing like (mostly on) fireflies, as they briefly drop membrane potential to dump charged waste without having to pump it against gradient.

"Membrane potential changes results from very small net charge movements across the membrane"[2], like 10^-4th or 10^-5th[1] of the potassium ions in a cell.

Bionumbers is a fun site: "membrane potential" https://bionumbers.hms.harvard.edu/search.aspx?trm=membrane+...

[1] https://bionumbers.hms.harvard.edu/bionumber.aspx?id=106433&... [2] https://bionumbers.hms.harvard.edu/bionumber.aspx?id=110762&...

I remember doing some back of the envelope calculations that showed the potential across the membrane was equivalent to only a few dozen potassium ions more on the outside or inside. Basically a countable number of atoms have to be moved by the cell to develop that potential.

Yeah, it's pretty mind boggling... Amazing that it "works". And I think debugging single-threaded code can be hard. ;-)

I mean, getting there took millennia of evolution, which is a long-time of brute-forcing. It's an incredible and beautiful thing to think about, and it's wilder than any one person's imagination, but I don't know that it's efficient ;)

I don't know... look at ATP Synthase, it's basically an electric motor made out of crazy nanotech from the future. Seems pretty efficient to me.

Yeah, pretty crazy that these things have been turning like mad for billions of years... ;-)

Whether the design is efficient is a different question than whether the design process is efficient.

Yes, this is precisely what I was trying to get at.

The process is inefficient in that it takes a long time for it to get to a workable solution, but the solutions are usually incredibly efficient.

Not saying it's efficient, in the way we would think of "coding" things.

One way I like to think of evolution is how long it takes to get from one state to another. So it took hundreds of millions of years for the first "life" to evolve-- perhaps close to a billion. This includes RNA, DNA, ATP, etc. Then it took about a billion-ish years to go from prokaryotic to eukaryotic life. Then about another billion-ish years to get multicellular eukaryotic life. Then it only took about a quarter billion years to have dinosaurs. It only took about 10-20 million years to go from the ancestors of all apes to having chimps, gorillas, and people. (!!!) And when you have people directing evolution, like with dogs or crops, you can make things happen very "quickly".

Efficiency tends to come at the cost of not being robust against the unknown. The crazy mutant random number generator might not go fast, but perhaps it's less likely to get stuck...

It's crazy what happens in there. It's as if other lifeforms exist at this cellular level, which wouldn't even care if they form part of a human or a plant, acting as if they have their own life, their own motivation and ability to execute it, their own purpose and will to live by it.

As if what applies to us individuals, with our thoughts and actions, also applies to these subsystems of a cell, in a different form.

What could be their motivation to build humans, to assemble brains that can reflect, eyes that can see, senses built to enable interaction with this world?

Where do these instructions come from?

With things like these I always like to visualize it backwards.

These things don't want anything. It's just the way things work.

If you manage to form an organism that survives better than other organisms, there will be more of you (and your cells). There is no "want" and "like" in evolution, just "works" and "replication".

It's more interesting to think that evolution is guided by the selective pressures that exist in the environment. That means that all of the current forms of life are finding the optimal design for their environment and interaction with other life forms. Human beings have evolved to fit this world and if we continue to expand beyond it we will continue to evolve to fit the solar system, the galaxy, and the universe. It's hard not to feel that there is some optimal thing that we are heading towards, the solution to the question posed by reality.

> It's hard not to feel that there is some optimal thing that we are heading towards, the solution to the question posed by reality.

depends how optimistic/pessimistic you are. I find it far more likely that humans will eventually hit some local maximum in a trough too deep to ever escape.

There are no platonic ideals for humans or beings in general; we explore a giant solution space for reproducing thinking-machines. For every utility function there's a globally maximal physical being or society, but there are also a lot of utility functions.

Don't you sometimes "want" to eat some chocolate, or an ice cream, or even better, a nice, juicy, salty steak? I definitely do, and I "like" what I feel when I get to eat it.

Yet I may be no more than a replicating machine whose purpose it is to build these new machines which may likely replace us one day, maybe keep us in a zoo, or as pets, if we get lucky.

I can't imagine what motivates these molecules to behave, to group the way they do; why the existing energies get channeled to make them move that way, since there is no need for the energy to do anything at all.

Something motivates me, and I see no reason why there isn't motivation in these molecules; what they do is already complex enough to be considered as something which may have a special purpose.

We do have consciousness. There is this something in me which sees and tastes, which experiences life. It's hard to believe that this is something material. To me it feels as if complex enough structures of molecules allow something to plug into this universe, to absorb its information and to feed something into it, like instructions which allow this "me" to interact with it.

The same could well be applicable to bacteria or to the most rudimentary lifeforms. Because a bacteria forms part of my body doesn't mean that it can't have its own consciousness; the same may be valid for all this stuff that (maybe) "lives" inside my cells. Lucky me, that I get to stand on its shoulders in order to perceive this universe the way I can and interact with it.

"Works" and "replication" isn't wrong, but removing the "wants" and "likes" from this equation doesn't feel right.

Sure, but the parent's claim was that there is no "want" and "like" in evolution.

You might want and like things; perhaps (perhaps) cells and bacteria might want and like things, but evolution certainly does not.

The fascinating question is where the line is between action and reaction and our qualitative experience of wanting and liking. Our wants and likes are (probably) physically implemented as a sequence of electrochemical reactions; almost certainly with nothing more than electromagnetism.

So which instantiations/states of the electromagnetic field experience feelings and desires? Are they held in the energy potential or in the energy transfer, or both? Is it enough to have a sufficiently complex feedback loop simulating/predicting itself?

The answer is likely to be both sort of simple but also profound. Eventually we'll have an a-ha moment studying electrocardiographs or FMRI or individual neural networks and be able to replicate experience in other electromagnetic substrates, and knowing precisely what we are, in a sense, will be pretty neat.

Then what will we really know about experience? Is it truly in the electromagnetic field or does it exist in the mathematical relationships that determine the evolution of the fields? That might be a question we never definitely answer from an outside perspective, but is endlessly fascinating to me.

Fascinating question indeed :)

> So which instantiations/states of the electromagnetic field experience feelings and desires?

Personally this is why I think that perhaps qualia is not an emergent phenomenon after all, and must come from outside the system. I.e. I suspect that philosophical zombies are possible

I find it utterly strange that drugs, hallucinogens, concussions, alcohol, electromagnetic stimulation, etc. could all reliably affect consciousness but that a brain identical to mine might be a pzombie. Like; who or what could possibly be doing the detailed-enough tracking to be sure to give my brain consciousness (but not my sleeping brain) while my molecular twin gets none?

> Eventually we'll have an a-ha moment...

Will we? How can we ever verify that our intervention produces this or that sort of qualia?

(For the record, I'm a fan of theories like IIT [0] that aim to answer questions in the neighborhood of these -- but we should be sober about what is even, in principle, knowable to us. We can verify that intervention X gives behavior Y, but I don't see how we could ever verify that intervention X gives qualitative experience Z (intervening on ourselves aside, which in any case will only tell us about our sort of conscious experience).)

[0]: https://en.wikipedia.org/wiki/Integrated_information_theory

You're onto something when you link "wants" with "energies".

Think back 4 billion years to some of the first lifeforms on earth, colonies of slime mould clinging to a rock in the ocean.

The first behaviour of these organisms was to respond to the movement of the sun overhead. They'd orient themselves to regulate their exposure to the sun's rays, arranging themselves in a horizontal plane on top of the rock when the sun was overhead, and vertically along the side of the rock when the sun was at an angle.

The first "desire" was the want of energy. The first behaviour was to move towards the sun.

The first communication was the signal that was passed through the colony of cells to coordinate the movement of the whole community into a mutually beneficial configuration.

The first conflict was when the colony became large enough and so diversely distributed that a part of the community "decided" it would rather not obey the signal to move and instead would move to its own preferred surface of the rock.

I think the main thing you’re looking for is “differentiation”. Unicellular organisms are generally homogenous, as each must be adapted to surviving on its own. Simple multicellular organisms are often just masses of individual cells. But, as you start increasing the number of cells, it becomes evolutionarily advantageous for some of them to take on more specialized roles, rather than have every one be capable of everything. That is differentiation.

As these organisms get more complex and develop more and more differentiated cells, mechanisms also evolve to prohibit cells from “regressing” to undifferentiated forms, and to tightly control aspects of cell growth. Unlike unicellular organisms, a functioning multicellular organism needs to have all its cells coordinate in order to survive. Human cells for instance contain a regulation mechanism which detects abnormal behaviour and directs the cell to commit suicide (a key protein in this mechanism, p53, is widely studied in cancer research).

So no, your cells don’t get their own “will”. They do what they are genetically fated to do. Those that don’t either die, or wind up as a cancer that chokes the life out of their host.

DNA is spaghetti code... but it all works somehow.

Literally, as even the tangling and folding ("packing") of DNA changes its behaviour.

How frequent are outages and operational issues with DNA?

Miscarriage is common.

Well, cancer is the second leading cause of death in the world.

let's take polymer, thermodynamics and statistical physics and make a new harder field out of these..

What's more interesting is its not just crowded but organized. We are starting to discover that large patches of cell membrane as well as the cellular volume might also be highly structured (p granules, etc) and gel like, and God knows what other mechanisms are involved.

Yeah that "crowded" cell picture is iconic. I remember my biochemistry teacher showing it several times in undergrad years ago, and really trying to hammer home the density of the cytoplasm.

Sometimes we have to reset our natural intuitions and I'm glad that professor did her job in making me more accurately imagine the interior of the cell.

Wow! So, molecular transports and reactions within cells happens to be probabilistic, and not mechanical. For me, this is new mind-blown level info.

What if, instead of monolithic chip we had "cells" filled by fluid with tiny chiplets in brownian motion. They would bump into each other or the wall to exchange packets of data or to recharge themselves.

You would have a computer that display the intelligence level of a bacteria.

Honestly, some of these, like the ATP synthase, spin/move slower than I expected. The ATP synthase spins at ~700 Hz. I'm not sure what I was expected, but it was in the tens of kilohertz.

Nice work by op. When I see the world and space, I cannot stop being awestruck by how everything is so beautiful. I am not able to explain all of this just based on randomness and Darwin’s evolutionary theory. I think there is God. Does anyone else get the same feeling? I also admit that I don’t know who the real God is. I also feel terrible sadness that the real God does not reveal himself to each individual when the expectation is that being the father he has responsibility to lead each individual.

Funny, I lean towards the opposite conclusion: That system based entirely on random coincidental collision of matter is more likely to have sprung forth from pure random chance rather than the mind of some individual omniscient being. No matter how all-powerful she might be.

There are multiple definitions of god. The crude one that is commonly used doesn't have to be only one. Its within the realm of possibility that there are entities that exist in a completely different substrate of existence. For us, time is experienced in a particular way because we also exist inside the same space-time. Maybe the 13 billion years of the universe, is like 13 billion cycles of a CPU which are tiny in our time-scale.

"Maybe the 13 billion years of the universe, is like 13 billion cycles of a CPU which are tiny in our time-scale."

That would be some hell of IPCs.

I've always felt that putting our universe inside some larger context is a punt (American Football reference). Weather that's saying we are a thing within some creators context, or that it's a simulation, all that does is push the questions of "what is all this" and "where did it come from" to a next level up that we can't see and have no hope of answering those questions.

If you think we live in the Matrix then all fundamental questions of existence can be asked about the "outer" world instead. It can't be turtles all the way down.

Oh, I didn't mean to imply that we should simply accept it as fact. I'm merely saying that we can have multiple theories. Certainly, we should only go where the evidence leads us.

Can we ever answer those most fundamental of questions? What pushing it one level up does do is show that we do not have enough information to answer it at our current level —- and if we ever create simulated universes of our own, it shows that perhaps you could never know the answer at any level.

If this system is all made from random mutation than I should expect my body could possiblely go brick every second. But it still works perfectly util now.

Please explain how the complexity of God arose independently of natural cumulative selection processes like evolution. The Blind Watchmaker might be an interesting read for you.

Not trying to pick a fight, just asking a question-- if you think the natural world as we see it could not have arisen "on its own" through the laws of nature, how did something even more amazing come to be?

The same way as everything else: On its own through the laws of nature.

To be frank, I have no idea. It would be folly for me to guess. Still, the notion of intelligent design explaining the awesome complexity of life by waiving it away with an additional, spontaneous and inexplicable divine entity of essentially infinite complexity just occurring out of nowhere makes even less sense to me personally than the spontaneous existence of a "basic" "unguided" universe with the potential for cumulative selection to cause complex life independently of a guiding hand. Intelligent design postulates that a divine entity spontaneously existed and all complexity is the result of that entity, whereas evolution explains complexity via long term cumulative selection. I struggle to rationalize the spontaneous complexity that intelligent design must justify.

I think you have the right approach. We all have to be humble and accept wherever science leads us. If god is part of the natural order, and we find evidence for this phenomenon, then it should be accepted.

Agree. The difficulty is that as we learn more, we often (not always) tend to believe that we have most of the answers and become less open to other possibilities with respect to God or simply more understanding. We have to keep in mind how much of our current knowledge has been acquired in perhaps the last one or two hundred years. In other words, we are probably complete neophytes with respect to our understanding of the universe as a whole. As a result we have to resist our more arrogant tendencies and try to keep an open mind to things that we may not yet be able to sense or measure. As scientists, I think we have to recognize that God may not exist, but we must also recognize that it may exist, keeping in mind that our definition of "God" is probably way off base from what we might eventually come to recognize.

Yes, and we have to guard against knowledge regressions (dark ages) too. It is critical that we preserve our human tradition of passing inter-generational knowledge to the next generation. As an example, I see several older nerds complain that the new generation keeps re-inventing the same-old same-old tech, and I do see a small grain of truth there, but by and large I think we have successfully managed to transfer our knowledge and experience to the new generation so that they can push the boundaries even further.

I remember reading (think it was Neil Tyson) that at some point in the future, if the universe continues at its current rate of expansion, we (earth) might arrive at a future state where we cannot detect the cosmic b/g radiation and other markers which confirm certain physical characteristics of the universe. I wonder if the future humans will accept that the humans who came before them really observed this phenomenon and that they can rely on that data :)

Studying this stuff puts me in a spiritual mood though for a different reason. At the sub-cellular level it’s just a bunch of chemistry. Molecules randomly bump into each other and stuff happens. It’s all “push”, not “pull”. Yet we talk of the whole cell as if it has agency (e.g. an amoeba is “attacking” other organisms; a bacterium is “moving” and “eating”); we definitely think that about still larger animals. The more time I spend thinking about this duality the weirder it gets.

"I don't understand" - "then call it god" is a false premise that was uttered many times in history:

https://evolutionspace.wordpress.com/2007/04/17/then-call-it...

Since you've identified what you don't understand, evolution, there is some hope.

Try a basic programming exercise: evolutionary growing 2d or 3d "walkers" on a simulation on a PC, or alternatively running core wars.

It's enlightening to see order, logic and machines arise from total randomness.

>It's enlightening to see order, logic and machines arise from total randomness.

https://en.wikipedia.org/wiki/Emergence

I had no idea.

I am really glad to see this piece. I've spent more than 19 years getting myself healthier while the world spit in my face and called me crazy. I did so by focusing on trying to understand my genetic disorder at the cellular level.

Most genetic disorder involve a miscoded protein. Your DNA serves as the blue prints for a complex factory called a "cell" and when there is a bug in the code of your DNA, the 3D printer mechanisms translating those instructions into physical reality create something broken.

That something broken is typically a bit of protein that normally gets folded up and used as a tool within the cell. When it is miscoded, it can't do it's job. It's sometimes kind of like a cog missing a tooth.

As the cell gets more chemically deranged from the tools misfiring, you see more misfolded proteins. If either salinity or pH balance are off, those proteins are more likely to misfold.

I think this accounts for what gets called "The normal progression of CF." It's a positive feedback loop -- aka a vicious cycle.

More broken proteins leads to worse chemical derangement and worse chemical derangement leads to more broken proteins and we are off and running on a highway to hell.

In cystic fibrosis, the protein that gets miscoded is known as the CFTR -- the cystic fibrosis transmembrane conductance regulator. It serves as a channel in the cell membrane.

You can think of it like a traffic light managing traffic into and out of the cell of certain proteins or an air lock and only certain proteins with the right ID card get to use it.

It causes the body to misprocess salt (NACL -- sodium chloride) and also sodium bicarbonate -- aka baking soda. I think the misprocessing of sodium bicarbonate is a large factor in why people with CF are so prone to being very acid.

I initially thought this my big discovery. It turns out everyone who knows anything about CF knows it causes excess acidity, including patients and doctors. They just don't bother to do a damn thing about it and act like it isn't clinically significant information.

"You are people are dying. We know you are too acid. Meh. Can't be related. Moving on."

Even though if you get ketoacidosis they promptly hospitalize you because you can be dead within three days.

Ketoacidosis is typically rooted in diabetes and people with CF are at high risk of developing a special form of diabetes known as Cystic Fibrosis Related Diabetes (CFRD). But lets not confuse any poor doctors and scientists with the facts. The slow boiling of the tissues of people with CF in acid couldn't possibly be anything like this extremely deadly condition for which they promptly hospitalize you. No. Let's just ignore the acidification of people dying of CF. Can't possibly be clinically significant.

The salt wasting we do has significant implications because as the salt gets sweated out at high rates, it drags other electrolytes with it. Reading up on Altitude Sickness was hugely helpful to my understanding of what was going on with my body and finally gave me a direct connection between the respiratory problems and the gut issues that both occur in CF.

When you are altitude and can't get enough oxygen, you begin peeing more. You do this because the body cannot breath out all of the wastes accumulating in your blood and your body starts shunting those wastes through the kidneys as a backup system.

So your blood chemistry directly connects what is going on in your lungs to what is going on in your gut. These are not "separate and unrelated systems that never interact." It is not "mere coincidence" that people with CF have both gut and respiratory issues.

Of course, a more fundamental issue is that CF significantly impacts all epithelial tissues and all mucus membranes and your lungs and gut both fall in both categories. (Your skin is also epithelial tissue, but not a mucus membrane.)

Anyway, glad to see cell biology getting some attention. This helps explain a lot about what I have accomplished and I am sort of glad I didn't get the memo earlier. Thinking of the cell in relatively simple terms was helpful to me, if only to make me feel less intimidated by the process of trying to get well while the entire world treated me abusively for not liking what was happening to my body and not wanting to quietly and meekly go along with their plans to gruesomely murder me so doctors and scientists could feel like they are smart and know things and former homemakers are clearly all "dumb blondes" or some shit.

Yes, I have baggage. No, I'm not apologizing. The world could have been less awful to me. It chose not to be.

That was really interesting, thanks for writing all that out!

Given this sort of knowledge and understanding, what do you do about your CF then? Is there a way to prevent your body from being so acidic, or to mitigate the effects of it?

The short answer is "I've made a lot of dietary and lifestyle changes."

I eat very carefully with an eye towards food chemistry. If you have no idea I have CF and I do this, you wouldn't notice that I eat any differently from anyone else.

For example, pizza is a staple part of my diet. But I mostly get takeout pizza from Little Caesar's.

They are the only national franchise that makes their dough fresh in house daily. Everyone else ships it in from elsewhere in frozen form.

They also use corn meal to help make it not stick. This was something I did when I used to make homemade pizza with a pizza stone.

The corn meal is more alkaline than wheat. Most wheat only crusts leave me too acid, but Little Caesar's pizza doesn't because of the addition of a small amount of corn meal to the crust.

I also avoid certain oils. It is well established that people with CF misprocess oils and I got very interested in the chemistry of oils.

They come in three forms: long chain triglycerides, short chain triglycerides and medium chain triglycerides. Medium chain triglycerides also get called MCT oil and it has long been established that MCT oil is medically beneficial for CF and certain other conditions.

This is the basis for why coconut oil is popular in some circles: it is high in MCTs. MCT oil has long been prescribed by doctors to people with CF and coconut oil has an even longer history of being medically prescribed for various gut issues, including stomach cancer (though I can no longer find the link supporting that statement, sadly).

I not only favor MCT oils, including butter which is a good source of such, I actively avoid long chain triglycerides because my body fails to break them down and it wreaks havoc and makes me really sick. So I avoid peanut oil, canola oil and some other things.

I am a butter fiend and I tolerate animal fats well, such as bacon (though bacon is high in something that is hard on the lungs and I had to be careful with it when my lungs were in worse shape).

So I pay a lot of attention to food chemistry and I do eat what other people see as "junk food" but one brand of potato chips is perfectly fine because they cook with oils I tolerate well and another makes me dog sick because they use different oils. If you don't know that, you see me eating pizza and potato chips and don't think I'm some kind of super extreme "health food nut" though I am.

I also am very careful about what I touch. Skin is epithelial tissue and people with CF are prone to aquagenic wrinkling -- aka we get extremely pruney in bath water. This is so extreme that they are now using it a cheap initial screening in rural clinics in India.

I've actually already written about the skin stuff so let me give a link rather than repeat myself on too little sleep and yadda:

https://atypicalcysticfibrosis.blogspot.com/2020/01/skin-and...

That even has a link to the PDF about the test they are developing (or have developed) in India for rural clinics.

I spent a long time taking $300/month worth of supplements. I now manage my condition with diet and lifestyle and I am mostly well, having resolved that backlog of malnourishment, chemical derangement, accumulated infections, etc etc. I'm trying to figure out how to solve my financial problems because I remain dirt poor and it sucks and I hates it.

I wanted to be an urban planner and now I am trying to figure out how to provide low cost services to small communities and I have fantasies the world will support my Patreon so I can pay my bills while doing a lot of stuff mostly "for free" for small communities so we can reverse this trend out in the world of everyone going to big cities and mostly hating it because that's where the jobs are and small communities shriveling up and dying. I think it is part of why our world is so dysfunctional.

I am very happy to be a supporter on Patreon.

I promise you will not regret joining.

Thank you.

Years of homelessness atrophied my social skills. I feel like I don't thank my Patrons enough. It's made a huge difference in my life.

It is enough thanks to find enlightening writing and see your byline on it.

Congratulations on taking the bull by the horns and learning enough about your condition to develop your own strategy to reduce its impact. I don't know anything about how medicine is practiced elsewhere, but it seems 'western' medicine is rapidly approaching a horizon where a single doctor is woefully inadequate to handle treatment of anything even remotely approximating chronic illness in a single patient.

I saw this far to closely and personally for a little over two years. I went to a very dark place for some time but ultimately decided that the healthiest attitude for me to take was that doctors are simply overwhelmed with information and overpowered with the risk of career ending litigation. I pray that I never have to go down that road again, but if I do there's going to be an extremely frank conversation up front and the doctors will have a choice if they want to ride shotgun or not.

In tribal cultures, "medicine men" or "witch doctors" are one part medical people and one part spiritual leaders. There is no clear distinction between body and soul.

Historically, doctors in a small community were some of the best educated people there and they knew people pretty well simply because it was small. They also took their little black bag and went to see you where you lived, which gave them enormous amounts of information about your life without saying one word and this informed their assessment of what exactly was wrong and needed to be fixed.

Then modern tech came along and now we go to see them because their office or the hospital is where the big fancy tools are for running diagnostics, as if what ails you is entirely about your body and your body is separate from your life. And they are little more than fancy technicians. They've lost that role of "village wise man" and we fail to see how valuable that was, how critical it was to the practice of good medicine.

I don't know how to fix it, but doctors don't do what they used to do and then we wonder why some things go so very wrong in a world with more "miracles of modern medicine" than ever before.

The diagnostics are amazing. Getting the right diagnosis was a big, huge deal. But then the treatment and attitudes were a huge disappointment and when I began getting healthier, my physician expressed zero interest in how and why that was. He just scheduled me fewer appointments because other patients needed him more than I did.

So when I moved, I didn't bother to find a new doctor. It seemed pointless. And then the internet decided I was some extremist anti-doctor nutcase when in reality it was doctors who basically wanted nothing to do with me.

That's some great insight.

Honestly I think there are some parallels with what we're seeing in law enforcement as well. In a drive to reduce costs and risks both roles have pulled back from that deep social contact into something just focused on execution (no pun intended ;) and it turns out the relationship that has been lost was incredibly important.

life was described as a miracle but facts like that make it even more so.. how organized processes emerges from this HF mess is .. surprising.

(2011)

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