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Building A House, Building a Cell

I’ve been thinking (for a long time now!) about how to explain to people outside of the field how odd drug discovery really is. And that comes down to explaining how odd things are inside a living cell.

They’re very odd indeed. This has been brought home to me, yet again, by a recent deep dive into the literature on a particular cellular pathway – a complex one, to be sure, but one that illustrates just how multileveled these things have gotten over the last few billion years of tinkering. Here, then, is an attempt at describing the construction of a house, as if it were being done by the processes that take place inside the cell.

First, the tools. There are hammers and saws and power tools of all kinds, of course, but they behave differently than you’re used to. As they do inside the cell, they float and wander around to find their places and to do their jobs. Some of the hammers have screwdrivers or saw blades poking out of the back of their handles – if the hammer end senses a nail within range, it will start pounding away, and likewise the saw blade spins up to full activity if it sees a piece of wood with the appropriate “Cut here” mark on it. There are dozens of such marks, maybe hundreds (nobody knows for sure), and some saws respond to several of them, while others only seem to care about one. What makes these marks? Various colored pencils wandering about the construction site – they seem to sense patterns in the wood grain, or particular arrangements of boards, that make them leave their individual marks. Looking closely, some of these are also marking each other, if they happen to come within range.

The hammers are odd in other ways. Some hammers whack onto other types of hammer if they see them, and this can lead to the second hammer suddenly changing into a different variety – claw, roofing, tack. Or it might hit another hammer and have it then break into two smaller hammers, or a shower of nails, or a hammer and a handful of colored pencils. Sometimes you’ll see two or three of these smaller tools get screwed back together by various sorts of wandering screwdrivers or wood-glue dispensers, a group of apparently unrelated tools fitting together into something new whose functions can only be guessed at.

But the house is getting built by these weird things. Off in the middle of the construction site there’s a blueprint room, with little page-flipping devices whipping the various plan documents back and forth in complicated patterns. Pages somehow copy themselves when they get into the right orientation, and these pages float up, crumple themselves, and harden into templates that can interact with all the tools around them. There’s some sort of odd plastic around the blueprint room – some of the tools and plan documents seem to be able to shimmy through it, and some can’t. In fact, there are several kinds of these plastic dividers, you realize, oddly shaped and moving around, and they seem to be part of what sorts the various tools into the right places on the site. The entire house site has a big covering around it as well, with deliveries coming up to it from outside and somehow squirting, wiggling, and hopping through in various places.

Back closer to the blueprint room, there are all sorts of little tool foundries that pick up on the crumpled plan-document things, spitting out new screwdriver-saws, hammer-screws, sander-sprayers, and other oddities. The only reason that the place isn’t nostril-deep in such things is that the more worn examples of the various tools are themselves getting marked on by colored pencil-bearing tools in turn, ones that somehow sense the scuff marks, dulled saw blades, or rattling noises, and once such tools get marked, they get red ribbons stuck onto them in various places and get pulled, ribbon-first, into grinding waste disposal machines.

These, on close inspection, are made up of lots of saws, hammers, and so on, arranged in circles, and various small tool pieces come flying out the back ends of these things, aimed at the tool foundries that are cranking out new versions. In fact, everything seems to be made out of something else. Combinations of screwdrivers, planes, grinding wheels, nail guns, glue dispensers and all sorts of other devices are constantly assembling and coming apart again, and somehow they encounter piles of boards, connectors and nails, whirl around in dizzying patterns, and move on, leaving behind complete joists and assemblies. The scent of freshly cut wood attracts drywall-installing assemblies and shingle-attachers, themselves made up out of bizarre arrays of smaller tools strung together, and they in turn leave completed work behind them. Wood frames that have had drywall show up on one side of them seem to be attractive to brick and siding devices, more tools made out of tools, which come along to them and crawl up and sideways, laying down finished materials as they go.

When you look closely at the bricks, you find that they’re made up of tiny latticework of nails and screws, stuck together. The siding is assembled from smaller parts, too – pieces of it that were left over from the installation devices are getting red-ribboned and hauled off to be recycled. Everything’s getting repurposed all the time. Tools are materials; materials are tools. It’s hard to tell what’s being built and what’s being torn down, or what’s being worked on versus what’s doing the work, but a house is being built, remodeled, and maintained somehow in this buzzing cloud.

Looking down the street, you realize that there are hundreds, thousands, millions of similar construction sites and buildings, of all different shapes and sizes, stretching off into the distant hills. It’s where you live. It’s where we all live. It’s living, itself.

44 comments on “Building A House, Building a Cell”

  1. Kling says:

    It is amazing that all this came about by iterative random chance, that given infinite time, was destined to occur.

  2. DrOcto says:

    And then for no apparent reason the entire house splits in half….

    1. Vampyricon says:

      We aren’t even there yet!

  3. BigO says:

    Great post! I’m sharing this one with my children and anyone else who asks about what I do (drug discovery). Very creative.

    This simple analogy begs a couple questions: What is energy/force behind the beautifully orchestrated order and precise machinery within our cells? How does it work? After all, we live in a universe that naturally tends toward disorder, and our intracellular milieu is anything but! Is it possible that there is creative and sustaining designer behind this order? In my mind, it’s an explanation that is not so easily dismissed.

    Thanks for the invigorating and entertaining read. I now have an extra measure of excitement as I head back to the lab to creatively design some new tools for cells to wrestle with, modify, reject or perhaps permit entry into an uncharted path.

    1. Erik says:

      Agree with all your questions, but on the point about the possible creative and sustaining designer: I don’t think its an issue of whether that’s an easily dismissed possibility. Without specific evidence, its no more or less likely than any other possible explanation that doesn’t have specific evidence. We shouldn’t leap to any particular explanation just because we don’t understand what’s going on. That’s all — and, agreed, this was a very nice analogy and a good read.

    2. Pennpenn says:

      “After all, we live in a universe that naturally tends toward disorder, and our intracellular milieu is anything but!”

      I dunno, from what was written here it sounds pretty chaotic and disordered, but functioning well enough to keep going (since the more egregiously non-functional ones would have crapped out earlier). Then again, “disorder” is kind of a woobly, hard to nail down term when talking about the universe.

      “Is it possible that there is creative and sustaining designer behind this order?”

      I would hope that if there was they would have made the cell a little bit more organized, easier to parse out and understand, rather than some kind of constantly shifting jumble of parts shifting around, forming, reforming, constantly flowing and moving like some psychedelic early cartoon (you know, the ones where everything is always moving?).

      Honestly, the more complex the universe turns out to be the less it makes me think something deliberate made it.

    3. Chris Phoenix says:

      So you think there’s a literal miracle going on in all of our cells, all the time, to keep them ordered in the face of entropy?

      That is a completely unscientific position to take. While it can’t be falsified, it also explains nothing.

      On the other hand, in a non-closed system (such as we are, every time we eat food) energy can be used to overcome entropy locally. This is a completely non-miraculous explanation for how cells can continue to work.

      Please don’t spread Intelligent Design BS on a science website.

    4. Charles M. Hamm says:

      “Is it possible that there is creative and sustaining designer behind this order?”

      No intelligent designer would design such a system. On the contrary, this is exactly the type of system you’d expect to get after many thousands of “good enough” hacks had been applied, one after another. Exactly.

      1. Hap says:

        It’s possible that this is the optimal way to do things (that a designer used these methods because they are better than the ones we would use). It’s also possible that (as Dr. Lowe has noted before, but I can’t find) an omnipotent being doesn’t have to act smart – they have omnipotence, and time, on their side. It’s also possible that there isn’t a designer at all. Science doesn’t seem to be telling us – other than that what we think of one doing likely isn’t correct, or isn’t complete.

        Science seems to be telling us that our ideas of design don’t fit the way that life works, which doesn’t preclude or mandate a deity or deities. It just says that life doesn’t fit our understanding of design (or we don’t know enough to tell). Life that did would probably be uninteresting.

        1. Gareth Wilson says:

          Robin Hanson complained on his blog once that having most of the body’s metabolism duplicated in each cell was terribly inefficient. I think he was proposing that should be specialised organs for every macromolecule, which would be transported throughout the body and assembled in the cells. I can see his point, but it’s hard to see how that would evolve.

          1. CD says:

            Exactly! If you look at, say, the humanoid robots from Boston Dynamics, which *are* intelligently designed, you can see how entirely differently they are conceived and put together. Why would you ever design a machine with trillions of simultaneously-running copies of its operating system? (A few backups, sure…) I’m an abject layman, but for me, once I got a vague handle on how single-celled eukaryotes worked, it became obvious that the multicellular ones are complete kludges.

    5. tim Rowledge says:

      “After all, we live in a universe that naturally tends toward disorder, and our intracellular milieu is anything but!”
      Hmm, if only there was a convenient supply of high quality energy to power this and compensate for the whole entropy thing. We could gather it up into a big ball and I guess we’d need to keep it well away because of the intensity… say .. quick calculation, a few engineering approximations… ooh, call it 150 million kilometres.
      We could call it something simple, like “the Sun”.

      1. Pennpenn says:

        In a few arguments I’ve had with Creationists they’ve complained that evolution would require a massive and constant inflow of energy to keep going (something something laws of thermodynamics wurble flurble) but when I bring up the Sun they seem to think that doesn’t count. Because… I dunno. Reasons.

    6. Wallace Grommet says:

      Where is the behind that your designer is located? Or the front? Or the side? Let us say that the designer is within. Now. Creation is now. Nothing is solid or permanent or material. Those are merely aspects of a reality that is eternal, changing constantly, and one that we are an intrinsic part of. We are both inhabitants and habitat.

    7. Yusra says:

      Beautifully said. There is no question that the designer is a smart, beautiful, intelligent and loving. I am a scientist and I would not believe any less than that.
      It would be foolish to think otherwise. Just because someone doesn’t want to believe in a creative designer, it simply permit the rest of us to be ungrateful. Actually the more we know about how the living cell is orchestrated the more one should be humbled by the intelligent being behind it.

      1. Pennpenn says:

        There are plenty of unanswered questions about the supposed “Designer”, starting with “Does it even exist?”. And just because you believe it, doesn’t mean anyone else has to buy it.

        And honestly, the more I’ve learned about how cells work the more it seems like if there was a designer then it was a wildly incompotent being hammering scrips and scraps together until something worked.

      2. Barry says:

        You can believe what you want, of course. But if you want to discuss Intelligent Design with scientists, you’d do well to first read “Blind Watchmaker”. Your arguments are old, and less solid than you may realize.

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

  4. Doug says:

    Well done! Normally when I’m trying to build an analogy about some complicated process, I’ll go to either sex or cars. Your use of a house is inspired.

    1. Wallace Grommet says:

      And don’t forget about sex in cars!

  5. SeekingZprime says:

    Wow this is pretty darn awesome. I will share this with my son who is a high schooler and majoring in Biology.

    I have to confess that it would help me greatly if someone could annotate this writeup with actual biological processes. And I’m hoping someone reads this and is inspired enough to make an animation out of it. Wouldn’t that be cool.

    1. UKPI says:

      Based on a recent, excellent talk by Judy Hirst: a good example is mammalian complex I…it looks someone dropped the bacterial one and stuck it back together with bits of string and sticky tape.

  6. Ted says:

    Wonderful work. That is an excellent picture in words: I’d love to see a Richard Scarry or David Goodsell rendering to accompany it!

    However, I really think you missed the chance to make it a lane-swerving Winnebago under construction during a transcontinental trip…

    -t

  7. Wavefunction says:

    Some excellent metaphors in there. The only thing I would add is a running thread that connects the tools to their evolutionary origins and sheds some light on how all this machinery was sculpted imperfectly by natural selection. Much of what we do as drug designers is try to both harness and fight against the constraints of evolution.

    1. Hap says:

      The plans get misread and the resultant hammers can be used to pry nails from the wall or push out stray pieces of drywall? The analogy doesn’t sound good at our scale, because we don’t have generally adaptive items.

      1. NJBiologist says:

        Hap, I was thinking about plan misreading when I read the post….

        Misread plans lead to the production of tools that cause the house to catch fire, although not immediately. Some of the tools that catch fire are safely ground up into pieces that don’t burn. However, if enough tools are on fire, things can get ugly. The house can implode, leaving a neat pile of rubbish. It can explode in a mess that the neighbors have to clean up. And every once in a while, the burning house produces multiple copies of itself–all on fire–which start by crowding the neighbors, but which eventually become their own house movers and hit the road to settle in other towns.

      2. Wavefunction says:

        Slaying of a pretty picture by an ugly fact?

  8. Uncle Al says:

    Viscosity at scale! Is the secret of life…Brownian motion?

  9. luysii says:

    Great post. Don’t forget the lumber from an earlier building is still around, and is still being used — microRNA, competitive endogenous RNA (ceRNA), circular RNA, nonCoding RNA, transcribed pseudogenes etc. etc.

  10. Chris Phoenix says:

    This beautiful and accurate* animation shows the hammers, screws, monorails**, and blueprint pages interacting as a leukocyte transforms its shape to exit a blood vessel in response to signaling:
    https://www.youtube.com/watch?v=wJyUtbn0O5Y (with music)
    https://www.youtube.com/watch?v=FzcTgrxMzZk (with narration)

    * They had to downplay the Brownian motion randomness, and they only show a tiny fraction of the molecular soup. But they tried to make the shapes and functions as accurate as possible.

    ** There are monorail tracks running throughout the construction site. On close inspection, they’re made of nails and screws too. Some of the hammers will grab tools or house parts, latch onto a nearby track, and scoot along for a ways before letting go. The tracks can fall apart and reassemble themselves in response to dancing tools that respond to (among other things) something pushing on the outer envelope, or particular tools wiggling through it.

  11. Rob says:

    As someone from outside the industry who reads your column fairly regularly (TIWWW got me here 🙂 ), I want to thank you for posting a description that got the absolute enormity of what goes on inside a cell and brought it home to me.

    Thank you!!

  12. anon the II says:

    And, unlike Coleridge, you claim not to use mind altering substances. Well done.

    1. Derek Lowe says:

      Yep, still don’t. My wife’s theory is that I apparently don’t need them.

      1. John Wayne says:

        Fantastic.

  13. flem says:

    Fantastic analogy. gives a sense of mind numbing complexity of cells.
    I’m curious of scale: how big is the house if the nails are say 2″ long?

  14. Tomas says:

    I’m reminded of the science fiction book “Mote in God’s Eye”, describing a civilization that has been around for far too long without room to expand. Everything is hyper-evolved and connected together to foster efficiency. Once in a while the whole society accumulates too much damage and, basically, dies apoptically, to be rebuilt from protected caches of cultural information.

    A lot of software becomes a “legacy horror” through being adapted one too many times to the immediate need. Pressures to be small and efficient gave us non-repairable electronics. Airplanes cost $150m+ because no part is “stock” – all are customized in drive for lower weight.

    That evolved systems are fundamentally non-decomposable may be the greatest cognitive barrier technological progress is facing.

  15. GutDecipher says:

    And the blueprints keep getting modified and edited as if in a power struggle over the ultimate vision.

    And certain projects are getting scrapped to reroute supplies to a more urgent need that could derail the whole construction.

    And some of the houses become McMansions that are taking over the landscape and crowding out the more efficient, subtle dwellings. And then they get hit by a meteor or suffer an earthquake.

  16. Vampyricon says:

    Reminds me of an analogy of particle physics by Sean M Carroll, that when you smash two cars together two skateboards fly out in addition to the cars going through each other unscathed.

  17. Ken says:

    There are also smaller houses inside the big house. They have their own blueprints, which don’t have plans for everything in the small house – in fact they just have plans for a dozen or so hammersawdrills, and for the tool foundries. Everything else they get from the big house.

    But the small houses use their hammersawdrills to glue board A onto board B, and turn the result into board C, which is then bent into board D, which is cut into board E, and so on – until suddenly it’s back to board B, which can then be combined with another board A from the big house and run through the cycle again. That somehow produces a steady stream of power for the tools in the big house, plus (when needed) supplies of B, C, D, etc.

  18. Kaleberg says:

    It sounds like something from Ikea. Seriously though, thanks for the great metaphor.

    I should point out that entropy is overrated. Even physicists don’t have a good handle on it. Without gravity, the state of maximum entropy would be a very thin cold gas. With gravity, no one really knows.

  19. Anon says:

    This sounds like a drunk non-scientist blabbing in a bar. Which is probably exactly what drunk non-scientists need to get the idea! 🙂

  20. anon says:

    Alpha Go Zero

  21. Wallace Grommet says:

    And yet everything is a physical manifestation arising within a time/space field of immense energy, eternal and ephemeral.

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