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It’s Weird Down There

It’s not easy – especially when you’re a mere chemist – to picture what’s really going on inside a cell. The sorts of pictures that most of us tend to use (two blobs to represent a ribosome, little snakey line curving out from it to represent a new protein) are helpful memory devices, but have very little to do with reality.

Just to pick one example, I’ve had to update my thinking the last few years as the importance of condensates has become more apparent, for example: the inside of the cell is constantly experiencing the formation (and dissolution) of all sorts of tiny nonmixing liquid droplets of concentrated proteins and RNA species, like a bottle of salad dressing a few seconds after you shake it up, but without the further separation into two bulk phases. Here’s another: that mental picture of a ribosome I just mentioned doesn’t get across the way that proteins that are destined for a home in a membrane (the cell’s plasma membrane itself, or the ER or what have you) generally get recognized by their N-terminal sequences while the protein is still coming out of the ribosome. The whole shebang gets hauled over to its new home with the ribosome paused until it gets situated and protein synthesis starts up again.

There are plenty of other co-translational events going on as well. Many proteins that have an important partner actually have regions that bind to some part of the translation machinery (such as the mRNA of their partner-protein-to-be), so that they’re waiting right there while said partner emerges from the ribosome. And don’t get the idea that all of this is happening perfectly all the time, either – all of these mechanisms are constantly throwing errors, and that ribosomal complex is surrounded by other proteins whose job is to constantly look for trouble and try to correct it. I am reminded of a college classmate of mine who had a summer job – briefly – at a bottling plant in Alabama. There was a part of the line where the bottles narrowed down to a single file for some step (capping or labeling, I suppose) and this would occasionally jam up when two of them did the perfectly timed slapstick jammed-in-the-door maneuver on their way into the single file part. My friend’s job, as he described it, was to watch for these events and to reach in and straighten them out, which had to be done with speed and precision and which could happen as often as two or three times per eight-hour shift. He made it through two or three days of that before deciding to seek other employment, but the quality control proteins have no other options.

How about transcription? You might have a model of a few ovals and circles (the RNA polymerase complex) smoothly ratcheting along a strand of DNA. But in reality, many of those complexes take off in the wrong direction and stall. And they will rachet backwards on purpose if a base polymerization error is detected, although that process sometimes stalls out, too. This “backtracking” has a whole suite of correction mechanisms on top of it. At any rate, the time a Pol II complex spends actually transcribing DNA and the speed at which it does so seem to be pretty variable.

But we don’t have to get into such details in order to see how “off” our perceptions are. I, and probably many others, have a mental picture of an mRNA sequence being read out and transcribed into a larger protein, but that can’t be right. And it isn’t! In reality, the mRNAs are, on average, about ten times the size of proteins themselves. This feels wrong to us, because we’re used to our own preferences for algorithmic compression: blueprints are smaller than houses, but not inside the cell. Of course, when we’re talking about RNAs, we have to remember that those blueprints themselves are folded up to make small houses of their own – and if you’d like more metaphors of that kind, I have plenty of ’em.

So we should stay humble when we start talking about what’s going on inside the cell. It’s weird in there, and it’s important not to confuse our diagrams and shorthand with reality. Under the current coronavirus conditions, that means that when someone starts lecturing you confidently about exactly what’s going on (you see, the zinc opens the channels and then the hydroxychloroquine goes in and. . .), keep in mind how little we actually understand. . .

51 comments on “It’s Weird Down There”

  1. Fraud Guy says:

    Cue defenses of zinc in three…two…one…

    1. Sc says:

      Derek should think twice before wishing to live in a world without zinc.

      1. Dre says:

        Classic Simpsons quote

    2. Carl says:

      Get your shot of Zinc today, and burn that virus away!

      1. Thoryke says:

        “If it wasn’t for Zinc Oxide….” — Kentucky Fried Movie

  2. steve says:

    Dewpoint Therapeutics was recently formed to look at this. The main issue is that cells aren’t bags of aqueous solutions they’re gels with locally different properties that change constantly. Not my area of expertise but enzymes in test tubes don’t represent physiology anymore than cells glued down flat on to plastic plates do.

    1. LEB says:

      It speaks to me of how over-heated the current financing environment is, that companies are formed around general concepts in cell biology that are probably 10 years + from being developed enough to yield tractable hypotheses about diseases. The surprise is that VCs don’t want the NIH to fund this research for a while longer before putting their IRRs at risk

  3. David Eugene Young says:

    (amusing how Derek got the “alleged” mechanism backwards. “zinc opens the channels and the Hydroxychloroquine goes in”. Very funny!!!)

    1. Derek Lowe says:

      You take your humor where you can find it these days!

    2. sgcox says:

      “BTW, what do you know about Zn ?

      I mean much Zn should we add per person ?
      I do not know, may be one mole ?
      Yeap, sounds about right… ”

      Or something like that.

  4. Barry says:

    Without knowing the details, we do know some of the outputs. Interferon expression is suppressed. Is MHC expression suppressed, too? That would be a big difference between what we’d expect in response to a vaccine vs. infection.

  5. B says:

    Perhaps motivated by this tweet I saw circulating the other day?

    https://twitter.com/MarkDePristo/status/1299761329851396096

    http://book.bionumbers.org/

    Has anyone read through this? Any good?

  6. Politically Neutral says:

    It was almost perfect. A great, non-Covid focused post that beautifully describes that no matter how hard your Cell Biology class was, the real world is even more complicated. But at the end he had to take a shot at “the rubes,” and of course the commenters had to pile on. Does this really make you happy, pointing out how stupid everyone other than you is? And for every average Joe talking out of his depth about HCQ, one of you in the comments feels free to pontificate about gun control without even knowing the first thing about firearms, or any other political or technical issue that you don’t know the first thing about.

    But more important than that, can we really not carve out a single space, for a single moment, in society that is non-political? I can’t turn on a sporting event, or just about any entertainment venue, without getting lectured to. And Derek cannot seem to finish a blog these days without taking a shot at Trump or his fans. Why have we not realized that unless we have some politically neutral spaces in society that we will fracture as a country?

    And honestly Derek, the fact that you said in 2016 that you usually vote GOP but this is too much is revealing of either how little politics you know or care about. You seemed to have no trouble voting for Bush, Mccain, or Romney, even though the former killed half a million Iraqis on the basis of outright lies and ran a covert torture program, and the latter 2 seemed to have little problem with the War in Iraq. But somehow Trumps boorish behavior is too much for you. Because as we all know, killing untold innocents is precisely the definition of Presidential.

    1. JD says:

      >>”Does this really make you happy, pointing out how stupid everyone other than you is?”

      As a Ph.D graduate in chemical biology who cannot stand Ph.D graduates in the sciences for this very reason, I will venture that yes, yes it does. In fact, I’d argue that that is the low-key primary driver of job satisfaction in academia. The equivalent of a touchdown/home run/contract closing/car sale etc.

      This is because those in academia measure themselves by their mental acuity; knowledge projection is the currency of value so by declaring others wrong, one gains value in the currency of “rightness.”

      It’s a rather interesting psychological phenomenon that is related to our inherent desire to compete and be slightly better than others, no matter the setting. Historically, this manifests in actual currency (“richer” = “better”). But in academia, it manifests as knowledge-projection, in more or less exactly the same way the church values “holiness.” By declaring others stupid, whether they are or not, one gains value, in the same way that in ye olde days the religious could simply gain value in their society by declaring opposition as unbelievers or sinners.

      Different settings, exact same psychology. Fascinating.

      https://www.theatlantic.com/magazine/archive/2015/10/why-we-compete/403201/

    2. Alex says:

      >>”But more important than that, can we really not carve out a single space, for a single moment, in society that is non-political? ”

      Something you can think long and hard on: you could make it all go away by voting for a moderate like Joe Biden.

      Under any other administration, drug efficacy would not be a faux political debate. The FDA and CDC would not be making politicized decisions. Conspiracy theories about vaccination would be barely worth talking about. Athletes wouldn’t be protesting en masse.

      **You have a strong opportunity to make all of these social trends that frustrate you so dearly start to go away this November**. But as long as a mad man with no care for the truth is the President, they are just going to get worse.

      1. Jake says:

        “The FDA and CDC would not be making politicized decisions”

        They would absolutely continue to make politicized decisions, the difference is it’d be a return to the political decisions of the previous era.

        “Conspiracy theories about vaccination would be barely worth talking about”

        Those people aren’t going back in the bottle, and they were bad enough under Obama.

      2. Charles H. says:

        You are grossly overly optimistic. There has always been lots of politicization of the FDA and the CDC. But it has usually been expressed in ways that benefit some company over some other company. This has been true all the way back to T. Roosevelt.

        Neutral evaluation of scientific merits isn’t something that people are good at, and politicians are worse than average. Which doesn’t imply that the current state of affairs isn’t the worst I’ve seen.

      3. x says:

        “Something you can think long and hard on: you could make it all go away by voting for a moderate like Joe Biden.”

        By “moderate”, we must suppose you mean “corrupt, racist, right-wing sex criminal with advancing dementia whose campaign has rejected or walked back every progressive proposal on the table”.

        If the Devil’s biggest trick was convincing the world he didn’t exist, what must we say about the Democratic Party’s trick of convincing voters that they were fighting the right instead of moving toward it?

    3. Semichemist says:

      750 words, and one extremely brief closing sentence about being wary of medical misinformation. If you think this post is about politics or elitism you’re seeing ghosts, friend

    4. navarro says:

      forget the iraq war references, this relates to a “golden age” myth when the republican party was filled with kindly folks who understood how to think scientifically. unfortunately cruelty has been the point since reagan or nixon.

      1. Charles H. says:

        Eisenhower was the president of “Brinkmanship”. My memory doesn’t go back further than that, but I don’t recall a Republican party that was full of good wishes. Regan emulated that, but he certainly didn’t manifest it. He had good wishes for a certain small segment of the population, and expressed the intention in terms vague enough that people could think they were part of it. And he had a genial manner most of the time…but that’s a very different thing. When I raised chickens I always adopted a non-threatening manner as I approached one with a butcher knife in my hand.

    5. johnnyboy says:

      lawl. Derek makes a tiny little joke to end a post, then a few commenters add on tiny little jokes of their own. And then ‘Politically Neutral’ (so ironic) comes in like a bull in china shop, whines about putting politics into a scientific post, and then proceeds to…pile on the politics himself, completely unprompted. If one brief mention of zinc makes you froth at the mouth with gun control, GOP, Iraq, Trump and god knows what else, you need to readjust your medication. Or maybe, just consider stepping away from the computer, for just a little bit ?
      Also, if you don’t like what Derek writes, then maybe write your own damn blog ? I’m sure it’ll be great.

      1. Hap says:

        It’ll be the greatest, absolutely the greatest blog in the history of blogs. You’ll see.

        2020 is what happens when Dunning-Kruger and rabies spawn.

    6. Shazbot says:

      Hmm, three paragraph format.

      Paragraph 1: Claim that the post isn’t full of interesting useful information, which is somehow ruined.

      Paragraph 2: It’s Derek’s fault that everything is political these days. So.. victim blaming?

      Paragraph 3: Half a million dead Iraquis!

      Always the same. Deny everything, blame the victim, and change the subject. And never ask questions.

    7. x says:

      Normalizing a culture where ignorance and stupidity is recognized as such and rejected is a positive thing. Anytime you disagree, feel free to go back to demons and poultices. And rather than asking whether it pleases Derek to mock the rubes, ask whether he’d like fewer rubes; I suspect I know the answer.

  7. Anon says:

    Monkeys dancing across typewriters producing the works of Shakespeare. How does life even…life?

    It’s all a simulation.

  8. Anon says:

    By the way, this HCQ-Zinc-Covid theme is passe now. The new hot kid on the block is low-dose Colchicine and its mortality reduction in coronary disease. Something that could actually save lives. Perhaps Derek can address that emerging story in his next non-Covid post.

  9. LeeH says:

    Not to defend Bush or the Iraq war, neither of which I supported. But the Iraq war was ratified by a majority of both parties in congress.

    Not to defend Derek, who is perfectly capable of defending himself…

    Describing Trump’s behavior just as “boorish” is, simply put, extremely bizarre. Certainly at odds with the name “Politically Neutral”.

    And you ignore the American deaths that could have been avoided during this pandemic. Had we had the same death rate as most other industrialized countries, we could have easily avoided half of the current count, perhaps a lot more. When all is said and done, the excess deaths could approach the Iraqi losses (even if I accept your figure of a half a million). I think that’s what is eating at the sensibilities of this crowd, and prompting the politically-derived jokes. Bad science is the cause here, not a tendency to drift to politics (of which this forum has been guilty of).

  10. Dr. Manhattan says:

    One item to help visualize what is happening in the cell is David Goodsell’s book “The Machinery of Life”. He is a renowned medical illustrator, and the drawings in the book do a wonderful job of helping to give some perspective on how components and organelles interact. And, just how crowded things are “Down There”

  11. Rhenium says:

    It is clear from the above post that Derek is in the pocket of big ribosome!!!

    Silly humour I know, but I’ll take whatever lightheartedness I can muster these days…

    1. Derek Lowe says:

      Big Ribosome keeps telling me that the payment is about to transfer, but then they back up again. . .

      1. Leak says:

        It could have been worse; it could have been Big Towel… (see link for comic)

      2. Hap says:

        Doesn’t Big Ribosome only pay out in protein? Unless you’re Sigma, that doesn’t help you much.

      3. JulieNotPhD says:

        Those little turkeys…

  12. TallDave says:

    yes, our modelling ability is still fairly primitive

    many exciting lessons to be learned from nature!

  13. Greg says:

    Cells, especially Neurons, remain beautiful black boxes. A case in point was the identification earlier this year of Ribosome associated vesicle, RAVs (https://advances.sciencemag.org/content/6/14/eaay9572), not to mention Ribophagy, which all add a whole new dimension and dynamic to the humble role outside of the Ribosome in the central dogma.

  14. loupgarous says:

    Material for a whole new book there – It’s Weird Down There, sort of a companion to Richard Feynman’s famous article on nanotech, “There’s Plenty of Room at the Bottom!” (a few days in hospital getting transfusions gave me time to reacquaint myself with Feynman’s popular-audience anthology volumeThe Pleasure of Finding Things Out)..
    .
    Seriously, though, a whole book on how we fill in the blanks of our knowledge on physical processes with useful metaphors, illustrated with descriptions of translational events in the cell such as your second paragraph above:

    “Just to pick one example, I’ve had to update my thinking the last few years as the importance of condensates has become more apparent, for example: the inside of the cell is constantly experiencing the formation (and dissolution) of all sorts of tiny nonmixing liquid droplets of concentrated proteins and RNA species, like a bottle of salad dressing a few seconds after you shake it up, but without the further separation into two bulk phases. Here’s another: that mental picture of a ribosome I just mentioned doesn’t get across the way that proteins that are destined for a home in a membrane (the cell’s plasma membrane itself, or the ER or what have you) generally get recognized by their N-terminal sequences while the protein is still coming out of the ribosome. The whole shebang gets hauled over to its new home with the ribosome paused until it gets situated and protein synthesis starts up again”.

    would have been really useful to 1980s me in biomedical engineering school, trying to get my head around coursework and robotics club (where our motto was imbibo, ergo sum). A hypertext structure would have been very nice in going from metaphor to metaphor.

    Linus Pauling once was quoted as saying

    “ideas are the shit of human brains, constantly being produced by creative thinkers“

    I think that your metaphors are worth much more than that to those who are interested in understanding the function and mechanics of the cell, a place many of us just place in the margins of an illuminated map of our thinking on such matters, beyond a dragon belching fire and shouting

    “here there be translational events!”

  15. Simon Auclair the Great and Terrible says:

    Big Ribosome! That would be 80s not 70.

    Also, colchicine?!

  16. 11 fingerssss says:

    Ha ha, literal Big Ribosome.

  17. Sunyilo says:

    The biological consequences of in-cell liquid-liquid phase separation (LLPS in the literature) could be intriguing if these play indeed such a crucial role in protein-nucleic acid interactions. Hydrodynamics, thermohydrodynamics, and electrohydrodynamics have already developed a broad set of tools (theoretical and experimental) to predict the behavior of such systems.
    Somehow, what has always fascinated me in living organisms: we keep discovering novel and novel mechanisms that can be inherently unstable (reaction networks, LLPS, that can get out of control through small perturbations – far more out of control than a cancer cell, for instance) yet cells reproduce and function with remarkable stability.
    Which suggest that the most insightful discovery into living systems is … yet to be made.

  18. Cb says:

    It’s weird that we can find drugs that really work down there; amazing isn’t

  19. Weird is a great word to describe the situation . This brief blog post hints at why biomedicine is so challenging ( and this applies to most science ) . Our models are only so good . We have to use models . To paraphrase Aristotle , man is the map making animal .

    Thanks for your work Derek.

    1. loupgarous says:

      First, thanks, Simon for catching my conflating 1980s and 1970s biology.

      And thanks, Michael, for catching the crux of what I meant – models of how cellular mechanism, even sketchy ones that contradict other models (under other conditions) are necessary to actually proceed from a lower state of knowledge to a a higher state of knowledge.

      There are two seminal concepts in most fields of hard science – one must be willing to express a degree of doubt about what is happening when the data are incomplete. That came from the late Richard Feynman.

      And from Freeman Dyson, who we just lost in February of this year, we learned it is better to be wrong than vague (sort of a corollary thought to Feynman’s thought on the value of doubt – oddly fitting when one considers that at one point it was Dyson’s job to explain Feynman”s quantum electrodynamics to others within the US’s nuclear weapons establishment such as J. Robert Oppenheimer, whom Dyson reports was (at first) “vituperative” about QED).

      One can only proceed to greater knowledge if we know what our starting point is as precisely as possible.

      Thanks, Derek, for reminding us that in some fields of science we have to work with incomplete data, and with concepts which don’t entirely mesh with others – yet.

  20. loupgarous says:

    “First, thanks, Simon for catching my conflating 1980s and 1970s biology.”

    Oops – that wasn’t me.

    Pain medication isn’t a “smart” drug.

  21. Piabet says:

    Piabet Bahis, Bahisin adrersi!

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