7 ms·

Biologists Rethink the Logic Behind Cells’ Molecular Signals

104 points by theafh 5y ago

hirenj 5y ago
The most remarkable thing about this article is that there are still people surprised that the lock and key analogy has limited utility. I’d even argue that the new model they highlight doesn’t even go far enough, and that a better model may involve promiscuous binding with receptors, coupled with mechanisms to amplify signals from binding events (through e.g., recruiting extra receptors to the place on the membrane where interaction is taking place)!
- hirenj 5y ago
  Thinking about this a bit more, I could also imagine that cell state could not only be encoded in the cell proteome, phosphoproteome etc, but also in the set of already activated (primed) receptors on the cell, so that the final signal only gets sent in cells that have been appropriately primed.
- lurquer 5y ago
  The analogies used to understand living systems always track technology. In the 1800’s when ‘fields’ were the new thing, folks assumed cells (or, more generally, tissue) has invisible vital forces that dictated morphongenesis etc. With the development of steam, internal combustion, etc, living systems were viewed in terms of energy and chemical reactions. Then, electronics... with digital, everything — from DNA on down — was viewed as, essentially, a computer program. Now, as we’re getting more comfortable with chaos and complex inscrutable systems (such as neural nets and the like), we view the mess of proteins less like a lock-key and more like a dynamic complex system. Not being critical... but, it’s worth noting the source of these analogies.
  - TeMPOraL 5y ago
    I never liked this hypothesis. The way I see it, we're returning to a "dynamic complex system" view from a brief infatuation with computing, and I'm not even really convinced the naive computing analogies were present anywhere else than in popular science and K-12 education. I'm having trouble imagining serious scientists believing there's a discrete, digital logic present in what's clearly an analog system built out of feedback loops - a conceptual framework that dates to the beginning of the 20th century if not earlier.
    - XorNot 5y ago
      HackerNews comments tend to build a contrarian narrative where the "young dynamic outsiders" are right and the "establishment" is crusty and old will be quickly superceded. This dominates in fields where the specialists tend not to post here (molecular biology) and gets shot down rapidly in areas where there's more people with domain expertise present (semiconductor manufacturing). It's a tech startup forum: the whole concept is based on this theory and the appeal depends heavily on ignoring the exceptionally high failure rate of start ups.
      - LargoLasskhyfv 5y ago
        OTOH citing Max Planck from there: [1] https://en.wikiquote.org/wiki/Max_Planck https://en.wikiquote.org/wiki/Max_Planck A new scientific truth does not generally triumph by persuading its opponents and getting them to admit their errors, but rather by its opponents gradually dying out and giving way to a new generation that is raised on it. … An important scientific innovation rarely makes its way by gradually winning over and converting its opponents: it rarely happens that Saul becomes Paul. What does happen is that its opponents gradually die out, and that the growing generation is familiarized with the ideas from the beginning: another instance of the fact that the future lies with the youth.
        ncmncm 5y ago
        Originators of new ideas are finally vindicated, and win awards, only after almost all of their opponents have died. The satisfaction is muted.
    - lurquer 5y ago
      > I never liked this hypothesis. The way I see it, we're returning to a "dynamic complex system" view from a brief infatuation with computing, I don’t know if there was much of the “dynamic complex system” stuff in the 1800s. (What a terrible way to describe it... but, I think you know what I was saying.) The theme seemed to be striving towards simplification. That is, as Newton transformed the convoluted epicycles and platonic spheres and all the other bizarro theories explaining astronomical movements down to F=MA with a nice simple inverse-squared law tossed in, I think scientists writ large believes a similar simplification would occur in other fields. This was justified to some degree; chemistry was beautifully simplified in a short time. As was, to some degree, medicine with the advent of germ theory. But, biology seems immune. I really don’t think many biologists were thinking in terms of complex dynamic systems. (Ironically, Turing — a computer guy — was with his paper on reaction/diffusion equations.)
popcube 5y ago
if this base on one research article, may I find in the beginning of article and hilight it? beautiful found! we can spend more time on try model subsystem of some molecular, fortunately, most of molecular biologist's work still do not need to change
VSerge 5y ago
I think (hope) that the deterministic model known as lock and key has been known to be a flawed view for quite some time. Books published in the early 00s (notably "Ni Dieu ni gène", by Kupiec and Sonigo) were already making this point in a popular science format, and explaining that even the concept of cells exchanging signals was flawed. A cell has no evolutionary reason to transmit signals. It will however eat molecules it can use, and excrete molecules that are no longer needed, because this allows the cell to survive and reproduce. A white blood cell eating a bacteria doesn't do so with an intention to protect some organ somewhere in the body, it does so like predator eats prey. Leukocytes who eat well, ie face a bacteria they can eat, then multiply, and end up eating all the bacteria, before dying off when there's nothing more to eat. So they protect the body and then remove themselves, not because they have the intention to do it for the greater good, or because they received a signal, but because they have evolved to prey on bacteria within the ecosystem of the body. Thinking of the body as a well ordered mechanism is a flawed view, there are no locks and keys, and most likely very few signals if any. Thinking of the body as a dynamically balanced ecosystem seems much closer to how cells behave and to the fantastically complex feedback systems that have evolved over eons and are now balancing the populations of cells in our bodies. We may be ecosystems of individually oblivious and dumb little cells, but isn't it wondrous that from this emerges a complexity that can say "I" and has consciousness of self?
- tines 5y ago
  But reproduction is a fundamental aspect of evolution, and (most?) cells in the body don't reproduce on their own, but rather they are manufactured. T cells for example are manufactured by bone marrow and the thymus multiplies them if I'm understanding correctly. So I'm not sure how that fits in with the view you explained in your post. In other words the T cell doesn't get feedback on its own fitness. The fitness feedback is at the level of the reproductive success of a human being (healthy humans can have more kids than sick ones), not the reproductive success of a T cell (because it has no reproductive capabilities and therefore cannot be subject to selection pressures). Correct me if I'm wrong.
  - UnFleshedOne 5y ago
thanatosmin 5y ago
This is the paper the article is covering: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5612783/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5612783/ It is beautiful work, but this breathless coverage really ignores that these properties have been previously characterized in other receptor signaling families like FcRs, cytokines, FGFR, TGFb, etc.
zosima 5y ago
The main problem is the old idea, that the message is the messenger. In a way that is still true, but its not one message per messenger molecule. The message is intimately connected to what other messenger molecules are around, what are they bound too, what composition of receptors are on the cell surface, what are those receptors connected to, what secondary messages are being sent intracellularly and what messages have the cells received previously. As we have understood the hormones passing loud, clear and overruling messages (like e.g insulin and thyroid hormone) we start discovering the much more specific and context-dependent hormones. And those are going to have effects that are much more dependent on the cellular state, and so are much more difficult to understand. It's extremely complex, because the state of the cellular machinery is huge, and quite a lot of things we can't really observe directly.
mensetmanusman 5y ago
In case you missed the photo competition, here is an amazing image of neurons: https://www.nikonsmallworld.com/galleries/2021-photomicrography-competition/microfluidic-device-containing-300k-networking-neurons-in-2-isolated-populations https://www.nikonsmallworld.com/galleries/2021-photomicrogra...
asdfman123 5y ago
Nature is messy and organic because no one needs to understand how it works in order for it to work.
rdlecler1 5y ago
if ( (BMPa & BMPB) & (Ra & Rb & Rc & Rd)){ //Do Something } ^This is the algorithm they describe. They make it sound like there is some mystic computation going on. This is how biological computation networks work. A lot of the complexity is just what’s needed to get an analog system to perform digital computation.
hikerclimber1 5y ago
hopefully millions of people die because biologists screwed up.
dilawar 5y ago
Probably nature doesn't care about the way we classify the mechanisms. There are lock-and-key mechanisms (receptors), weak interactions, combinatorial interactions, signals (neural signals), boolean networks (gene switching) etc. As an electrical engineer, who did Ph.D. in system biology, I wa s fascinated by the different routes biology takes to do seemingly same computation. As someone said, "Nothing in Biology Makes Sense Except in the Light of Evolution". If there is a way to select a mechanism that gives a real advantage to the organism, then it doesn't matter which bucket it falls into. PS: I was also amused by the lack of sinusoids and an abundance of sigmoids in biochemistry.
ncmncm 5y ago
Endocrinology recognizes whole other modes of action, where is it not just the presence or absence of this or that molecule or complex of molecules, but the rate of increase of concentration. Or, the rate relative to another rate, so which is rising faster is what matters. Maybe the effect of who wins depends on the immediate concentration of some other molecule. There is no upper limit to the complexity that biological systems are willing to use. They only have to work just well enough not to interfere with reproduction. Also: That endocrinology is even meaningfully possible to do is astonishing.
kazinator 5y ago
> But this lucid vision of circuit-like logic, which worked so elegantly in bacteria, too often fails in more complex cells. “In bacteria, single proteins regulate things,” said Angela DePace, a systems biologist at Harvard Medical School. “But in more complex organisms, you get many proteins involved in a more analog fashion.” How does "analog" rule out "circuit".

104 points by theafh 5y ago

The most remarkable thing about this article is that there are still people surprised that the lock and key analogy has limited utility. I’d even argue that the new model they highlight doesn’t even go far enough, and that a better model may involve promiscuous binding with receptors, coupled with mechanisms to amplify signals from binding events (through e.g., recruiting extra receptors to the place on the membrane where interaction is taking place)!

hirenj 5y ago
Thinking about this a bit more, I could also imagine that cell state could not only be encoded in the cell proteome, phosphoproteome etc, but also in the set of already activated (primed) receptors on the cell, so that the final signal only gets sent in cells that have been appropriately primed.
lurquer 5y ago
The analogies used to understand living systems always track technology. In the 1800’s when ‘fields’ were the new thing, folks assumed cells (or, more generally, tissue) has invisible vital forces that dictated morphongenesis etc. With the development of steam, internal combustion, etc, living systems were viewed in terms of energy and chemical reactions. Then, electronics... with digital, everything — from DNA on down — was viewed as, essentially, a computer program. Now, as we’re getting more comfortable with chaos and complex inscrutable systems (such as neural nets and the like), we view the mess of proteins less like a lock-key and more like a dynamic complex system. Not being critical... but, it’s worth noting the source of these analogies.
- TeMPOraL 5y ago
  I never liked this hypothesis. The way I see it, we're returning to a "dynamic complex system" view from a brief infatuation with computing, and I'm not even really convinced the naive computing analogies were present anywhere else than in popular science and K-12 education. I'm having trouble imagining serious scientists believing there's a discrete, digital logic present in what's clearly an analog system built out of feedback loops - a conceptual framework that dates to the beginning of the 20th century if not earlier.
  - XorNot 5y ago
    HackerNews comments tend to build a contrarian narrative where the "young dynamic outsiders" are right and the "establishment" is crusty and old will be quickly superceded. This dominates in fields where the specialists tend not to post here (molecular biology) and gets shot down rapidly in areas where there's more people with domain expertise present (semiconductor manufacturing). It's a tech startup forum: the whole concept is based on this theory and the appeal depends heavily on ignoring the exceptionally high failure rate of start ups.
    - LargoLasskhyfv 5y ago
      OTOH citing Max Planck from there: [1] https://en.wikiquote.org/wiki/Max_Planck https://en.wikiquote.org/wiki/Max_Planck A new scientific truth does not generally triumph by persuading its opponents and getting them to admit their errors, but rather by its opponents gradually dying out and giving way to a new generation that is raised on it. … An important scientific innovation rarely makes its way by gradually winning over and converting its opponents: it rarely happens that Saul becomes Paul. What does happen is that its opponents gradually die out, and that the growing generation is familiarized with the ideas from the beginning: another instance of the fact that the future lies with the youth.
      - ncmncm 5y ago
        Originators of new ideas are finally vindicated, and win awards, only after almost all of their opponents have died. The satisfaction is muted.
  - lurquer 5y ago
    > I never liked this hypothesis. The way I see it, we're returning to a "dynamic complex system" view from a brief infatuation with computing, I don’t know if there was much of the “dynamic complex system” stuff in the 1800s. (What a terrible way to describe it... but, I think you know what I was saying.) The theme seemed to be striving towards simplification. That is, as Newton transformed the convoluted epicycles and platonic spheres and all the other bizarro theories explaining astronomical movements down to F=MA with a nice simple inverse-squared law tossed in, I think scientists writ large believes a similar simplification would occur in other fields. This was justified to some degree; chemistry was beautifully simplified in a short time. As was, to some degree, medicine with the advent of germ theory. But, biology seems immune. I really don’t think many biologists were thinking in terms of complex dynamic systems. (Ironically, Turing — a computer guy — was with his paper on reaction/diffusion equations.)

popcube 5y ago

if this base on one research article, may I find in the beginning of article and hilight it? beautiful found! we can spend more time on try model subsystem of some molecular, fortunately, most of molecular biologist's work still do not need to change

VSerge 5y ago

I think (hope) that the deterministic model known as lock and key has been known to be a flawed view for quite some time. Books published in the early 00s (notably "Ni Dieu ni gène", by Kupiec and Sonigo) were already making this point in a popular science format, and explaining that even the concept of cells exchanging signals was flawed. A cell has no evolutionary reason to transmit signals. It will however eat molecules it can use, and excrete molecules that are no longer needed, because this allows the cell to survive and reproduce. A white blood cell eating a bacteria doesn't do so with an intention to protect some organ somewhere in the body, it does so like predator eats prey. Leukocytes who eat well, ie face a bacteria they can eat, then multiply, and end up eating all the bacteria, before dying off when there's nothing more to eat. So they protect the body and then remove themselves, not because they have the intention to do it for the greater good, or because they received a signal, but because they have evolved to prey on bacteria within the ecosystem of the body. Thinking of the body as a well ordered mechanism is a flawed view, there are no locks and keys, and most likely very few signals if any. Thinking of the body as a dynamically balanced ecosystem seems much closer to how cells behave and to the fantastically complex feedback systems that have evolved over eons and are now balancing the populations of cells in our bodies. We may be ecosystems of individually oblivious and dumb little cells, but isn't it wondrous that from this emerges a complexity that can say "I" and has consciousness of self?

tines 5y ago
But reproduction is a fundamental aspect of evolution, and (most?) cells in the body don't reproduce on their own, but rather they are manufactured. T cells for example are manufactured by bone marrow and the thymus multiplies them if I'm understanding correctly. So I'm not sure how that fits in with the view you explained in your post. In other words the T cell doesn't get feedback on its own fitness. The fitness feedback is at the level of the reproductive success of a human being (healthy humans can have more kids than sick ones), not the reproductive success of a T cell (because it has no reproductive capabilities and therefore cannot be subject to selection pressures). Correct me if I'm wrong.
- UnFleshedOne 5y ago

thanatosmin 5y ago

This is the paper the article is covering: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5612783/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5612783/ It is beautiful work, but this breathless coverage really ignores that these properties have been previously characterized in other receptor signaling families like FcRs, cytokines, FGFR, TGFb, etc.

zosima 5y ago

The main problem is the old idea, that the message is the messenger. In a way that is still true, but its not one message per messenger molecule. The message is intimately connected to what other messenger molecules are around, what are they bound too, what composition of receptors are on the cell surface, what are those receptors connected to, what secondary messages are being sent intracellularly and what messages have the cells received previously. As we have understood the hormones passing loud, clear and overruling messages (like e.g insulin and thyroid hormone) we start discovering the much more specific and context-dependent hormones. And those are going to have effects that are much more dependent on the cellular state, and so are much more difficult to understand. It's extremely complex, because the state of the cellular machinery is huge, and quite a lot of things we can't really observe directly.

mensetmanusman 5y ago

In case you missed the photo competition, here is an amazing image of neurons: https://www.nikonsmallworld.com/galleries/2021-photomicrography-competition/microfluidic-device-containing-300k-networking-neurons-in-2-isolated-populations https://www.nikonsmallworld.com/galleries/2021-photomicrogra...

asdfman123 5y ago

Nature is messy and organic because no one needs to understand how it works in order for it to work.

rdlecler1 5y ago

if ( (BMPa & BMPB) & (Ra & Rb & Rc & Rd)){ //Do Something } ^This is the algorithm they describe. They make it sound like there is some mystic computation going on. This is how biological computation networks work. A lot of the complexity is just what’s needed to get an analog system to perform digital computation.

hikerclimber1 5y ago

hopefully millions of people die because biologists screwed up.

dilawar 5y ago

Probably nature doesn't care about the way we classify the mechanisms. There are lock-and-key mechanisms (receptors), weak interactions, combinatorial interactions, signals (neural signals), boolean networks (gene switching) etc. As an electrical engineer, who did Ph.D. in system biology, I wa s fascinated by the different routes biology takes to do seemingly same computation. As someone said, "Nothing in Biology Makes Sense Except in the Light of Evolution". If there is a way to select a mechanism that gives a real advantage to the organism, then it doesn't matter which bucket it falls into. PS: I was also amused by the lack of sinusoids and an abundance of sigmoids in biochemistry.

ncmncm 5y ago

Endocrinology recognizes whole other modes of action, where is it not just the presence or absence of this or that molecule or complex of molecules, but the rate of increase of concentration. Or, the rate relative to another rate, so which is rising faster is what matters. Maybe the effect of who wins depends on the immediate concentration of some other molecule. There is no upper limit to the complexity that biological systems are willing to use. They only have to work just well enough not to interfere with reproduction. Also: That endocrinology is even meaningfully possible to do is astonishing.

kazinator 5y ago

> But this lucid vision of circuit-like logic, which worked so elegantly in bacteria, too often fails in more complex cells. “In bacteria, single proteins regulate things,” said Angela DePace, a systems biologist at Harvard Medical School. “But in more complex organisms, you get many proteins involved in a more analog fashion.” How does "analog" rule out "circuit".