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Close-Up View of DNA Replication (ucdavis.edu)
304 points by mgalka on June 20, 2017 | hide | past | favorite | 113 comments



For anyone interested in the molecular process of DNA replication, here's a pretty cool video that explains what happens at the protein level. It's always amazing to watch what is in practice a molecular-sized machine:

https://www.youtube.com/watch?v=OjPcT1uUZiE


If you liked this video, also check out this one:

Inner Life of the Cell https://www.youtube.com/watch?v=FzcTgrxMzZk

And here's a nice TED talk by Drew Berry:

Animations of unseeable biology https://www.youtube.com/watch?v=WFCvkkDSfIU

These kind of visualizations are of course an idealized view on how it works. As others have already mentioned, the processes are hugely chaotic and much more probabilistic than deterministic. On this scale everything is just one huge wobbling soup of things crashing into each other, which makes it even more fascinating that it works as well as it does.


maybe that's why we need a lot of sleep to grow or recover, then it's not all that wobbly


I can also recommend an undergrad text book called "The Molecular Biology of the Cell". New editions are expensive, but second hand or older editions can be had relatively cheaply.

https://www.amazon.co.uk/gp/product/0815341067


Probably fine for the basics, but you will find some details outdated if you buy a 20-year old copy.


It's very nice to grab 2nd hand books for cheap. Saved me in linear algebra 2 years ago.


I think it's safe to say more has changed in our understanding of biology (compared to linear algebra) in the last twenty years, though.


Sure, I realized that old editions were very very cheap but very outdated, the 5th (2012?) is about 20$ that's probably the best compromise


That was amazing! Especially the machinery of the second part where the DNA strand is replicated backwards!


Have a look at this lecture. It's really well explained, at a undergrad level, how the cell keeps the error rate low. Quite impressive, imo. https://youtu.be/DRBREvFL19g


That looks more error-prone, wonder if that copy has more mutations...


yes, e.g. [1], but there are specialized repair mechanisms that operate at the same time, so the 'final' error rate is much lower than the 'initial' rate.

[1]: http://www.nature.com/nature/journal/v518/n7540/abs/nature14...


yeah I am wondering if there is any research on that particular matter.


Am I the only one to see lists and map/reduce here ?


So how would you solve e.g. a number factorization problem using these machines and a divide-and-conquer strategy?



I'm always wondering how long the machine just sits there waiting for the building blocks to arive, before it detects them, and uses them. Is the soup of building blocks just swirling so fast that the machine can continue working without interruptions? Or is waiting just part of the game?


The substrates aren't just floating free, in many cases they're collected by binding proteins, which form parts of protein complexes, and these protein complexes are guided around the cell by it's cytoskeleton. In most cases when substrates are unavailable the protein complexes maintain the enzymes in an inactive state.

Don't think of cells as disordered bags of water. They're more like highly ordered liquid crystals.


Talking about dna and machines, Schabanel-Rondelez-Woods of Paris Diderot Univ. did design DNA tiles as building block for turing capable machines. They have demoes of gliders, and even a nanoscopic dna hello world in lab.

"program" size limited to 500 tiles IIRC, because the design will break when things get larger. Still amazing, happy googling.


Yes. Oh my god yes.

So there is this HUGE part of biophysics that we completely isolate all of the undergraduate students from, with these pretty videos where one machine magically swims out to exactly where it's supposed to go and then the next machine magically swims in to do the next thing and then the next machine, and so on, until you've got this perfect assembly line chugging away at this stuff. That is NOT what happens.

The reason that we make those "schematic" videos is that if we drew the real video, you could get overwhelmed by detail and miss the actual mechanism that we're talking about. What's actually happening is that this whole activity is happening in one big churning sea of all of these things knocking into each other bouncing around chaotically. That one machine that went to the right place is symbolic of hundreds of machines that happened to bounce off into the wrong one; that straight line is symbolic of an average of a million possible bouncy trajectories which went in all sorts of different directions before getting there. Everything is at a high enough concentration and pulsating and buzzing so much that in short order the "right stuff" happens to bounce together to do whatever is happening. Sometimes, even, the cell makes the "local concentration" of some machine or part even higher, via either containing some structure within a bag or else by producing proteins which attract "the right sort of thing" to them, so that more nucleotides or whatever happen to be nearby.

Just to give a more concrete example, in the fertilization of an ovum, we showed you a nice picture of one single solitary spermatozoon which shakes hands nicely with one ovum, and they became best friends. We also tried to scare you with "just one sperm is all it takes!" reasoning, which is technically true but misleading. If we were showing you the absolute truth, you'd see that the ovum is getting beaten down by a bunch of spermatozoa pelting it like a pack of wolves, trying to break down a chink in its shell, called the "corona radiata", until one of them burrows into a thin tear. Then the eggs of most mammals have to chemically shift composition of their borders to actively prevent "polyspermy", getting penetrated by multiple spermatozoa, through that tear. What's really fascinating here is that we're not completely sure how this happens because usually this process is happening during meiosis, another of those things where we separate the story for the textbooks ("meiosis happens, then you store the resulting cells, finally some of them bubble up for fertilization" -- no, meiosis actually has these two long pauses in it; long-term storage happens during the first one (the "dictyate") and fertilization happens during the second one before meiosis is complete). So it's hard to say "this prevention of polyspermy is due to meiosis" vs. "it's due to fertilization."

Suddenly it's not so much of a surprise that some of your friends were trying for years to conceive while some teenagers you know of got pregnant too soon -- that "it only takes one" rhetoric makes people very worried very rapidly, "what if I waited too long, what if I'm infertile" and the "there is literally a wall there and it's a matter of luck whether something breaks through it or not" story reveals the real emotional truth: "oh, we have like no real control over this; whatever will be, will be."

It's just that at the lowest levels there's a ton of bouncing chaotic pulsating activity, things smashing into each other routinely, and heck, the only reason that your proteins even keep their characteristic lumpy shapes is that they're designed by evolution to take on this shape when water molecules are bouncing against them chaotically enough that they happen to curl up into it. The machines to replicate DNA similarly are sitting in a sea of nucleotides smacking against them, which is why the helicase can't unzip too far ahead of the polymerase; that polymerase might be able to handle the stray nucleotide that binds prematurely to the DNA, but it might have real trouble if an extended sequence gets accidentally bound that way.


I'd like to see an updated version of that second part including the new findings from the parent.


I'm looking at this video and can't stop thinking: "Who created this process?" With all advances in technology and know-how we are not able to put such sophisticated process together... And it is present in EVERY living creature and happens millions of times in every body... So how this process came into existance?


My understanding is that this process didn't really come into existance but stayed in existance. Countless other arrangements failed to replicate and endure.


And that seems to require quite a bit of faith.


We both agree the process exists. The overwhelming evidence is that species evolve over time. We can conclude that this is the process that won out evolutionarily or that God did it.

I suggest God did it requires the most faith and incidentally more likely leads to a stifling of curiosity. God did it might possibly be true but it is the refuge of the incurious. It can be used at every turn. It can be used to answer all 'why?' questions. And thus it is singularly the most incorrect answer in history. That's why God did it requires the most faith. It has been wrong so often that I wonder why it hasn't been discarded for the intellectual crutch that it is.


(I apologize for the long post. I hope it is thought provoking nonetheless.)

I think it is useful to consider the difference between "Who made this?" and "How was this made?"

As a coder, when I see a program that achieves something I didn't know was possible, it makes me very interested in how it was accomplished. I say, "Great job, that is awesome. How did you do that? Where is the source code?"

In the same way, I see the complexity of life: the required components and all the intricate processes (Search for ""Inner Life of a Cell" on Youtube, it's really amazing).

I try to comprehend the level of complexity and I quickly realize that even Scientific Notation cannot express it appropriately.

So, when I appreciate the Creator and say, "Well done, that is insanely awesome!" I also say, "How did you do that?" "How was that made?" "How does this work?" "What can I do with it?" "Can I hack it to do something else?"

---

As far as complexity of faith, the difference is a matter of simple set theory:

Define 2 Sets:

- All things that are made (the Universe) (U)

- All things that are not made (the Eternal) (E)

You have stated that it requires more faith to believe that there are 2 sets (U,E). However, it could be argued that absolutely denying the possibility of the existence of one set (E) requires a stronger choice of faith.

Also, the 2 sets (U,E) makes sense to me, but I see a contradiction in the single set (U only).

It's simple logic:

If (U only) is the set of all things that are made, then the question begs to be answered: "Where did it come from?"

If (U,E), then the answer is obvious: The set of all things that was made (U), came from the set of things that were never made (E).

I often hear: "Ok, where did E come from then?" Well, by definition E was not made. E is not U.

Also, beyond basic logic, if we consider the theory of the big bang which fits with out measurements of an infinitely accelerating expanding universe: The big bang itself points to a specific point in time where the Universe began (or at least was transformed from a singleton to an accelerating expansion).

So if you limit the choice to only (U), again you are faced with a question, "What prompted the initial bang?"

One possibility is that (U=E). Another words, the universe itself must be eternal.

In that case, we would expect an eternal cycle to be observed (something like the Bang-Bang Theory). However, our best measurements indicate an expanding universe that will never collapse and bang again. There is no support for a Bang-Bang theory which would indicate an eternally cyclic universe.

Everything we can measure indicates the universe had a beginning and that it will continue to accelerate it's expansion infinitely.

So the most logical explanation I see is (U,E): that the universe was created (by something that was not created i.e. The Eternal One - aka God).

And that makes me even more curious: I want to explore all the beauty inside the box because now I have someone to direct my appreciation to say, "Well done! That's amazing!".


> I often hear: "Ok, where did E come from then?" Well, by definition E was not made. E is not U.

Your logic boils down to the fallacy of special pleading and thus fails. You can't define God into existence by calling him eternal and avoiding the question of where he came from.

> One possibility is that (U=E). Another words, the universe itself must be eternal.

That is the only logical choice.

> In that case, we would expect an eternal cycle to be observed

No we would not, that an eternal cycle might exist does not imply it can be observed or detected.

> However, our best measurements indicate an expanding universe that will never collapse and bang again. There is no support for a Bang-Bang theory which would indicate an eternally cyclic universe.

Untrue, if it expands out to nothingness, nothingness itself is prime to create a big bang as nothing is not a quantum stable state. The real answer is we don't know.

> So the most logical explanation I see is (U,E): that the universe was created (by something that was not created i.e. The Eternal One - aka God).

There's nothing remotely logical about that, you've just invoked special pleading and presumed creation by something is necessary when we in fact know it is not. The universe just is, that's the only logical conclusion we can make from the available evidence. You've dressed up a logical fallacy in set math to perhaps try and make it seem reasonable, but it isn't, it's just bad logic.


A good example of special pleading would be saying:

- Nothing can exist that wasn't made - Except the universe: it wasn't made

---

If one says "the universe just is" one cannot claim logical superiority to the statement "(E) just is".


Yes, but no one but you is saying nothing can exist that wasn't made; that's a statement of faith, not one based on evidence. We already know it's factually wrong, quantum mechanics has already shown particles spring into and out of existence randomly.

Beyond that, you can't claim special pleading on my part and still argue it's OK for God to exist without being made, that's special pleading. All special pleading is fallacious. None of my statements are special pleading, I haven't claimed nothing can exist without being made. That's one of your premises, not one from the science argument.

> If one says "the universe just is" one cannot claim logical superiority to the statement "(E) just is".

Yes one can for one simple reason, the universe's existence is not in question, therefore stating that it just is is logically superior to stating that E just is as E, i.e. God, is not known to exist and thus that statement is begging the question.

More simply put, you can't prove God exists with math, math doesn't always map to reality. Existence requires evidence in science, math never serves as proof of physics absent physical evidence, it can only serve as a guide in looking for corroborating evidence.

Ultimately however, the main point I'm making is that your logical analysis is fallacious, it boils down to nothing more than special pleading and the baseless presumption that things require a creator.


First, you have to define "made". Does fire make ash? What was the fire thinking when it was making ash?

Also, why define the "eternal one" as God. That eternal one may be so simple, and dumb, like that DNA replicating machine.

Usually "God" implies conscience. Are you okay with brainless God? And if you are okay with brainless God, then the word God has become meaningless, because now God can't even think, it surely then isn't God of any religion.


Thank you for your response. I do not deny that god could possibly exist. I don't currently believe that god does exist but I recognize that it is possible. I do deny the logic given in the post I responded to. If someone believes that god exists and said god is vastly more complex and intelligent than we are then they can not logically argue that god exists because we are sufficiently complicated and therefore must have been created whilst believing that god is not created.

i think that all reasonable people believe something has to have existed that wasn't created. It is a bad argument to say we have to have been created because of our complexity.

It appears you choose or have been led to conclude that god exists and it the uncreated thing. I have been led to conclude that matter/energy is the uncreated thing. I do not wish to persuade someone that god doesn't exist. I wish to persuade someone from making a very bad logical argument.


Ah, yeah I see what you mean.

If one argues that the level of observed complexity cannot come from randomness alone and therefore must have been created by an external actor, then how does the external actor have sufficient complexity to create the complex universe.

So going back to my notation of (U - things made) and (E - things not made).

If (E) made (U) then where did (E) get enough complexity?

The only conclusion is the complexity in (E) is eternal also.

In plain words, that would imply that if God exists, then He would be eternally complex of complexity >= universal complexity.

Thank you for pointing that out, that's cool to think about.


You believe that god exists or has existed. You believe god is complex. You believe that god did not have a creator and did not come from something. Therefore you believe it is possible for complicated things to exist without being created. We are in agreement on this. Namely, complexity does not imply creation.

In the same my statement, "god's existence begs the question, who made him?" is not valid to you your question who made matter is not valid to me. The question implies creation and both of us believes that something wasn't created. We just differ on what thing is.


Yes, I agree.

Both systems are logically consistent so there would need to be other reasons to choose one or the other.

If there is an (E) the only possible way we would have of knowing - would be if (E) communicated somehow and provided evidence.

Even if one considered complexity as evidence it would not be sufficient or specific about (E).

In my case, the evidence that leads me to conclude that (E) does exist has little to do with the complexity of life.

Anyway, thanks for your time and thoughts. I especially appreciate your insight about the requirement of eternal complexity in my point of view. That will give me something to think about for quite a while to ponder it's implications.


What are elements in this Eternal set? I would posit that the Eternal set is composed of things we don't yet understand or are unnecessary entities.

If you're wanting to look at this as a set problem, let's take the set U as the Universe of everything that we see evidence for and the Occam's razor understanding of things required to precede U.

Now take G as the set that is God - capable of not only creating U, but loving us each individually through some telephathic means, and creating an everlasting existence for each believer in some sort of eternal afterlife.

Belief in U + G requires much more accommodation than just belief in U.


Well, I didn't say anything about the quality of set (E), only that it makes sense to consider the possibility of it, especially when there is an apparent contradiction in the (U only) set.

I agree that specific beliefs about the Eternal=God would require much faith since (E) is by definition outside the box (U), and therefore beyond our reach of scientific experimentation.

There might be avenues where (E) could communicate with members of (U), but that is a different discussion. I would recommend as much evidence as possible should be pursued in verifying any specific claims about (E).

---

Going back to your first point, I understand that you are saying that there could exist a set (U+O) = all things that are made and all things that preceded it (Occam's Razor).

So that would make it equivalent to the (U=E) set which I mentioned.

Another words, if something exists in the set of things that are made, it was also made, which was made, recursively.

However, when we consider the Big Bang, then something spontaneously prompted the singleton to transform into an infinite expansion.

From this observation, the only possibilities I see are that either the universe was affected by an external actor (E) or the universe itself is eternal and cyclical and the singleton was a temporary state (Bang-Bang theory).

Logically, I don't see a contradiction in either possibility.

However, I do see an extreme difference in quality:

If (E):

Things in (U) have the possibility of eternal significance and stuff actually matters:

- Love - Relationships - Death - Work - Exploration - Joy - Suffering - Eternal Life is a Possibility

If no (E):

On the other hand, if we are simply existing in a cyclically eternal universe, then absolutely nothing matters. We are simply a dot on an infinite timeline. Our atoms will be scattered across empty dark space in an infinitely expanding universe. All is entropy and darkness. Meaning is an illusion.

If the second is true, we don't act like it and we lock away the people who do.


On the other hand, if we are simply existing in a cyclically eternal universe, then absolutely nothing matters

So the only way that anything matters is if you personally live forever?


No, I meant that something I do only matters if it has permanent consequence.

If, no matter what I do, every atom I have ever encountered is doomed to be scattered across empty space, then any effort of my part is without long-term effect.

For example after the sun goes supernova and burns out as the universe accelerates its expansion to nothingness. In that picture, we are nothing but a dot on a quickly passing timeline. (In this case, all meaning is an illusion and purely subjective. Objective meaning doesn't exist.)

On the other hand, if what I do does affect eternity, then my actions matter whether I live forever or not.

(Of course, if living forever is an option, that's even better.)


It really depends on how you define "meaning". Is there meaning to treating a dog with love and respect even though it has no eternal future? How about the kindnesses we do for others - even though they may not notice and they certainly won't recognize us for doing them?

I think we make our own meaning in our every actions - regardless of whether or not those effects last for an eternity... which even with belief in a creator of the universe, there's no reason to believe that physics doesn't rule the universe and that it's not headed for heat death.

One way that I like to think of my permanence in the universe is that there's no reason to believe that every thing we do isn't recorded in time. Sure, our consciousness seems to exist only in the present - but perhaps the existence of our lives isn't totally lost in some form. Perhaps this moment of my typing these thoughts will exist as long as our universe does. Could they be accessed at least in read-only form one day by a future civilization? Maybe.


Right, that makes sense.

So that definition of "meaning" would be purely subjective meaning. It's meaning that is self-determined.

In your example, maybe an extra-universal future being might be able to read an echo of our impression on the timeline.

That's dreaming of an idea that might make a hint at a sense of purpose.

But that is what I don't find that fulfilling at all.

What I deeply desire is evidence-based objective meaning, and knowing that you and I and everyone else is truly important and valuable and that the choices we make shape eternal reality.

So that is what I see as the qualititative difference between subjective meaning (meaning purely determined by the subject) and existential meaning (one's existence having an eternal value).

Also, yes the dog would have existential value because it would contribute to the eternal effect. In fact, if there is an Eternal One then love and respect for everything he has designed becomes very important and things made from atoms would carry existential value beyond the physics alone.

As a side note, if there is an Eternal One who cares to be known, then he would have to communicate himself and provide evidence for his existence. (And Yes, I do believe that evidence actually exists and I believe it is very good: it fills my heart with hope and deep meaning as I face the problems of this temporary life.)

Anyway, I appreciate the dialog and I hope it is somehow useful for you.

Thank you for taking the time to think through it with me.


Actually, this was a "how" question.


How does "natural selection of sufficiently reliable reproductive methods" not describe the most likely pathway?


I think this is more around the mechanisms of abiogenesis rather than how a single celled organism became Brock Lesnar.

The process detailed here (https://www.youtube.com/watch?v=OjPcT1uUZiE) no doubt has been refined through evolutionary pressures, but even the earliest of organisms must have had something similar take place in order for the traits encoded into DNA to be passed from generation to generation. This mechanism is something we can barely observe with the most advanced technology available to us, let alone reproduce or synthesize on our own. I think this is what the original question was about, where did that first process come from?


I was under the impression that RNA replication was simpler and therefore likely to be the predecessor of DNA-copying organisms.

As for how: chance.

Given a bubbling stew of organic compounds with chemical energy gradients available, eventually a random reaction created something with the ability to self-replication.

Almost irrelevant of how simple / ineffective / unreliable that method was, it represented a huge advantage (in the numerical offspring sense) over sheer random reactions. This life therefore dominated and exploited the available energy to reproduce.

Then mutation begat mutation, as selection picked favorable traits and more and more complex systems of encoding and reproducing traits developed.

I'm not saying it's been proven (to my knowledge), but it seems reasonable given what we know. And moreover I don't see any "the beginning must have been fundamentally different than business as usual" requirement for whatever happened. As Ian Malcolm says, "Life finds a way."


What do you think of the point made in this video about the mathematical improbability of making a single protein by chance?

https://youtu.be/W1_KEVaCyaA

I've always heard people just assume it would happen given enough time, but I haven't seen anybody actually calculate the probabilities and deal with the real numbers.

Also, beyond the video, the simplest bacteria we have been able to discover/modify requires around 200 different types of proteins to function (numbering in the 100,000s all together in their specific arrangement inside a cell membrane.)

This is the minimal viable life form we know, yet just to randomly construct a single protein from amino acids would take a practically infinite amount of time given all the resources of the known universe.

Then 100,000s of those proteins have to randomly find themselves inside a cell membrane...

People are quick to dismiss complexity philosophically, but it just avoids the reality of it.

The numbers are so far beyond astronomical they make astronomical numbers look like basic arithmetic.

Anyway, I was hoping you could provide some feedback on whether you think the math is accurate and why it should or should not be considered.


Flip a coin 100,000 times. Make a list of the results. Now go to someone and say, "what's the probability of me ever flipping this sequence?" It's quite close to zero. But you did flip it. Calculating probabilities for things that have happened by asking what's the probability of it ever occurring again can be misleading.


Good point.

So this would only apply when a specific sequence is required.

In analogy, if making a puzzle the first piece could be cut randomly. However, the following pieces would have to fit with the proceeding pieces. And each additional piece would grow in specification.

So for a cell, it is true that there could potentially be a large number of proteins that could prove useful. However when that one protein requires 99 other protein types that "fit" with it in the puzzle of a single cell, then you have a specific sequence required which would be more and more precise for each additional protein.

In addition, since there is a need for 1,000s of copies of each protein type, there is also a need for factory proteins of even greater complexity.

In the case of every life form on earth, they all have these protein factories built-in which read the rna to create specific proteins.

Although, there might potentially exist other possible protein combinations that could create an alternative functional protein factory, any protein factory would have many interacting parts that each require increased specification as each part is included in the design.

In addition, it would be hard for a protein factory to function without a healthy cell holding all the necessary parts close together.

---

Another analogy would be like sodoku.

With a blank board, it Is possible to put any number anywhere.

However, as the game gets closer to completion, it requires a specific answer for each square.

If randomly putting a single digit in each square, the likelihood of getting a correct solution would be:

- 9^27 ~ 6e25 (possible random configurations of 1-9 in each square)

Divided by

- ~ 6e21 Number of correct solutions

So it would be like this for a random single cell:

- Number of possible amino acid combinations for ~100,000 proteins of average length ~50.

Divided by

- Number of protein combinations that would function as a living cell


That doesn't describe the pathway; it describes the result.


No, not really. Quite the contrary actually. It would be very unlikely that a volatile and nonreplicating molecule would be the carrier of biological information through billions of years.


And thus, the argument from incredulity was born, with a dash of personification.



Huh? That's one self-described "thought experiment" by two scientists that attempts to fit Moore's law (you know, governing CPU speeds) to evolution. It doesn't fit, surprise. This is after they arbitrarily define "genetic complexity".

That's not the argument from Phys.org which is just a online news organization, anyway.


Haha, true, but that's kind of an unsatisfactory rebuttal, as it comes from the conscious mind of a being (or blob of matter, less mystically) that was ultimately synthesized from that process.


> I'm looking at this video and can't stop thinking: "Who created this process?"

Then your thinking is flawed, there is not "who", the process was not "created", it evolved. Nature is not a "who".


ID movement uses information theory to correlate the complexity of such mechanisms (each part having specific components and being in the right place at the right time) with their probability of realization. The amount of information present in a system is inversely proportional with the probability of that mechanism realization. The more information there is, the less the probability. If no intelligent agent is at work, that is.


It's that second statement that is wrong. If that is one of the foundations of the ID movement then it is on quite shaken grounds.

Let's suppose god exists and is extremely powerful and intelligent. The amount of information contained in the system god is vastly greater than on Earth. Thus by the statements you've made the probability of the god system being natural, that is not created by an intelligent agent, is orders of magnitude closer to zero than the system on Earth.

OK, so ID people will claim that god is the sole uncreated intelligence, or uncaused event. But they are at the same point no -ID people are at. Namely, that very complex systems can exist without being created.


> with their probability of realization

But they, and this is expressed very well in the NOVA documentary about the Dover trial, always assume the components have to work as is in the end result. The bacterial flagellum, for example, is one of the examples they keep trotting out despite counter-examples of it used as an injection mechanism in bacteria, and other things.

To re-use the analogy from the documentary. They see organisms like mousetraps. And if any part is removed it no longer functions. That's true to an extent. It no longer functions as a mousetrap, but it could function for a variety of other things. The mousetrap is a flawed analogy because it does not pursue self-preservation, so it's easy to say "well it's useless now" from our perspective, but not so much when it comes to actual living things that we know little about.


I'd like to see this in a simulator.


Something I've never understood is how the nucleotides arrive to be included in the DNA strand. These animations always just show them appearing in perfect sequential order when they're needed, which is of course not what happens.

How are they delivered to the polymerase in the first place? How do they "know" where to be?

Are there just so many of them in the cytosol that through sheer numbers, there's enough random chance they'll just shuttle into place when the polymerase needs them?


I wrote a blog post a few years ago explaining how molecules get to the right place at the right time. The short answer is that cells are nothing like the nice, peaceful animations. Cells are extremely crowded and things move extremely fast. Glucose molecules, for instance, move around cells at 250 miles per hour and collides with something billions of times a second. An enzyme might collide with a reactant 500,000 times a second. And proteins can spin a million times per second. So as you suspect, by random chance molecules are in the right spot very frequently.

http://www.righto.com/2011/07/cells-are-very-fast-and-crowde...


Thank you for writing this. I used to wonder how flies have such terrific reaction times and whip around the air with insane agility. And then I wondered if we are just seeing them in fast forward, due to the relatively slow clock in our heads. I imagined it was why they had such a short lifespan of just several days. And I imagined them seeing us as glacially moving statues—"man this guy hasn't moved in years!"

Reading your description of cells as moving imperceptibly fast only fills me more with this sense—that we are very slow moving giants, waiting on the billions of "years" of inner machinery time to tick us forward ever so slowly.


Time for you to read "Dragon's Egg", a hard sci-fi book about a civilization that evolves on a time scale far shorter than humans ultimately leading up to interaction with humans and this civilization. Awesome book which explores different time scales.

https://en.m.wikipedia.org/wiki/Dragon%27s_Egg


Dude, that was awesome. Thanks a lot!

I haven't had a book this good in some weeks. Cheers!


There is supporting evidence for your intuition. See for example:

http://www.sciencedirect.com/science/article/pii/S0003347213...


thanks for the citation! I converted Table 1 to show timescales using the CFF column:

    European eel                    0.23x
    Leatherback sea turtle          0.25x
    Blacknose shark                 0.30x
    Tokay gecko                     0.33x
    Rainbow trout                   0.45x
    Scalloped hammerhead            0.45x
    Little skate                    0.50x
    Tiger salamander                0.50x
    Harp seal                       0.53x
    Japanese rice fish              0.62x
    Lemon shark                     0.62x
    Brown rat                       0.65x
    Green sea turtle                0.67x
    Loggerhead sea turtle           0.67x
    Great horned owl                0.75x
    Tuatara                         0.75x
    Guinea pig                      0.83x
    Cat                             0.92x
    American red squirrel           1.00x
    Homo sapiens                    1.00x
    Goldfish                        1.12x
    Anolis cristatellus             1.17x
    Short-eared owl                 1.17x
    Budgerigar                      1.23x
    Dog                             1.33x
    Green iguana                    1.33x
    Yellowfin tuna                  1.33x
    Chicken                         1.45x
    Common treeshrew                1.50x
    Rhesus macaque                  1.58x
    Common starling                 1.67x
    Rock dove                       1.67x
    Yellow-pine chipmunk            1.67x
    Golden-mantled ground squirrel  2.00x


I've been having this same thought lately, about the scales of time that exist below/inside what we perceive. I agree that smaller/simpler brains probably run on a higher clock speed than those that are larger or more complex, and that impacts perception. But even within the fastest little minds, the rate at which chemical reactions take place or electrical signals propagate make them seem glacially slow in comparison.

I was actually thinking about putting a little video together about these scales of time, with the video containing nothing more than a person's blink reaction slowed down 5,000x.


I wonder if we allow enough for this in our search for alien life? Are their other life-forms out there somewhere whose timescales are radically different from ours? How would we find or communicate with them if there were?


like forests? I cannot forget the statement in 'Avatar' describing the 'tree of life'. How is it that memories have not been encoded in massively networked aspen forests? Or may they're there and we just havent looked. And with large encoded memory stores, manipulation of that data is what we call conciousness.



Just to clear up a minor (yet undying and continually propagated) fallacy, the lifespan of house flies is actually around 28 days.


>Cells are extremely crowded

Thanks for the excellent blog post. This is something more people need to appreciate.

I never realized just how crowded until I saw David Goodsell's molecular illustrations[1] in Drew Barry's TED talk.[2] Goodsell's drawings show the actual density and diversity of molecules inside the cell.

[1] http://mgl.scripps.edu/people/goodsell/illustration/public

[2] https://www.youtube.com/watch?v=dMPXu6GF18M


Those are nice.

People get confused because they read that cells are ~99% water by molecule count. By weight they're only ~65-70% water. One out of three atoms being part of a non-water molecule means cells are tightly packed.


Thanks for posting. That was fascinating.


Thank you for this. I have always figured something like this must be the case but it's never really explained very well in school.


> So as you suspect, by random chance molecules are in the right spot very frequently.

With that in mind I'd guess the bigger issue is how cells avoid having to deal with molecules being in the wrong spot.


there are both active and passive transport mechanisms in the cell.


> Are there just so many of them in the cytosol that through sheer numbers, there's enough random chance they'll just shuttle into place when the polymerase needs them?

Yes. Everything at that scale is very small, very close together and moving very, very fast.

This kind of thing is very common at the cellular level: have a receptor/channel/process/thing that only one precise 3d molecule can fit into - and then just wait.

As long as there's a process somewhere to make/acquire that molecule, then one will be along in a few nanoseconds or so, depending on the concentration. In the meantime the recipient will just wait.

In this way otherwise independent processes can regulate each other, and respond in a concentration dependant way to changing conditions without any central control.


I always thought of it as a probability field of molecules.


> have a receptor/channel/process/thing that only one precise 3d molecule can fit into

But what if the molecule has an unexpected "tail" attached to it? How to prevent the process from getting stuck?


I imagine there are not many things with unexpected shapes at that level that aren't accounted for somehow. Anything that doesn't slot into it perfectly will get knocked away by collisions. Bad shapes do exist however (prions) and are a cause of diseases.


Generally bulky substrates are inefficient and require additional catalysts for binding. (Typically kinases.)

So something with an unexpected tail won't react. It will not occlude the receptor either because it won't bind with it reliably...

These things are very, very precise.


https://www.youtube.com/watch?v=VdmbpAo9JR4#t=0m51s [warning, the view is jittery, due to being bumped around like a protein]

Also interesting things, just for scale: see a bacterium and a cell nucleus: https://www.youtube.com/watch?v=mdhk_-o8_n8

And an actual protein diffusion measurement from inside a nucleus (via light emitting proteins): https://www.youtube.com/watch?v=cDxUmCPxP_E

So, we're still some time from getting a "real" picture of the nucleus. Mostly because it's so dense.

(Here's a video about single particle tracking on the plasma membrane https://www.youtube.com/watch?v=dlq3kkbskaA and the nucleus is at least a magnitude more dense/busy.)

Life is very much about density gradients. Ion channels, osmotic pressure, and so on.

40% of the cytoplasm is proteins (by volume), which is remarkably high, considering a naive lattice packing is just 34% (the tetrahedral lattice with a density of).


As you said there are a lot of them, and they move randomly at crazy speeds (see Brownian Movement), accidentally coming together.


Yes, and indeed, this is why life as we know it only works in a narrow temperature range: high enough for Brownian motion to drive reactions, low enough not to unravel the results too quickly.


I can feel there is something really interesting here but the writing, title and explanation here seems to be poor. The surprise here is the random starts and stops as well as 10X speed difference in the DNA replication process. Wouldn't it be more surprising that these processes run at the same speed?

"...started watching individual DNA strands..." I'm wondering how important the visualization and nature of "filming" helped to form the idea or prove the hypothesis that replication is a async process. I didn't quite gather which is more impressive, the filming or the discovery.

“Sometimes the traffic in the next lane is moving faster and passing you, and then you pass it. But if you travel far enough you get to the same place at the same time.” also doesn't quite make sense to me as the video clearly shows no queuing structure as seen in real life traffic, and there is no real hypothesis to explain the sudden stops and starts.


> “It’s a real paradigm shift, and undermines a great deal of what’s in the textbooks,” he said.

Sorry, but is this really that new? I've never been taught that the DNA strands coordinate with each other while replicating, so it seems quite possible that synthesis of each strand can be independent of each other.


When I did my Phd in bioinformatics about 10 years ago, most of the molecular biologists and biochemists I talked with expected that something similar to what these researchers found was what happened, but the details was of cause not known. Thus this is maybe the least surprising result they could get. In Kuhnian terms, this is puzzle-solving rather than a paradigm shift.


The "paradigm shift" is referring to the "stochastic" nature of replication, which apparently was not known before.


i was taught all the things they're saying in this press release ~20 years ago in biochem class.


It's a university press release. They're all written that way, unfortunately.


> “We’ve shown that there is no coordination between synthesis of the two strands. They are completely autonomous,” Kowalczykowski said.

Couldn't that be the unintended effect of doing things in a flow chamber?


This is amazing. I can't wrap my head around the fact that some brilliant people discovered this long back. Scientists and Physicists are so talented! And I can't center a <div> without googling. Sigh...


But hey, these scientists only figured out what was already there, whereas your <div> is completely novel :)


text-align: center

align: center


only works horizontally :/


This says more about the talent of the designers of the CSS spec.


Thanks. You get the metaphor.


Hmm…possibly there's some other process going on during those "slowdowns" that we haven't observed yet?


I agree, that's part of the import here.


My mind always boggles at the sophistication of this little machinery, and what forces drove random chemicals into the first primitive forms of encoding and reproducing heritable traits subject to selective pressure. The bootstrapping of evolution.


- "Almost all life on earth is based on DNA being copied, or replicated" - Can anyone tell me what they are referring to here? (life on earth that isn't based on DNA)


RNA I believe. ( Which I only existed at one time, in theory? Or some people think viruses count as life )


i did spend an embarrassing amount of time trying to find an example of RNA life after reading your initial reply lol.

I suppose viruses do count as 'life' in some sense, so fair enough, thanks for clearing that up.


viruses don't count as life. they have no metabolism (but satisfy the other requirements).


I really appreciate science journalists who can explain accurately and clearly in this manner. Good job.


As someone who works in the DNA analysis software industry...

#neat


Not sure if the apparent stop start observation, and also one strand sometimes getting synthesized while the other isn't would actually occur in-vivo. This is a pretty cool technology but a heavily artificial in-vitro system at the end of the day.


Most explicit porn ever!


I have no idea what I'm seeing here.

I don't doubt what they are saying, but that looks nothing like the models of DNA that are used as eye candy in movies and such.


I assume the eye candy was an ultra sharp zoom into a single strand showing the double helix?

This is zoomed out and fuzzy, such that you see a bunch of growing strands...not the detail of just one.

And just as fuzzy white lines, given the relative size and techniques used to make it visible.



It doesn't look like DNA models you are used to because a microscope that would give you that level of resolution does not exist.

Even in the best images that exist, all you are going to see are little bits that look like string.


I guess I'm just struggling to see how the animation maps to the DNA or how the scattering of dots becomes a double helix.




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