
Living cells are very fast and crowded places (2012) - manigandham
http://www.righto.com/2011/07/cells-are-very-fast-and-crowded-places.html
======
tasty_freeze
I highly recommend the book "The Machinery of Life" by David S. Goodsell. It
isn't too long, the text is interesting with out getting too bogged down in
the details (there simply would be too much to cover in detail), but the
highlight is he a professor of molecular biology, he is an excellent
illustrator, and the book is packed with detailed illustrations that alone
make the book worth it. $18 on amazon. (get the 2nd edition, not the 1st
edition)

Just do a google search for images on the book title and author name to see
what is inside.

~~~
javajosh
Sounds great! Along these lines, I've really enjoyed some of the iBiology[0]
videos, especially the ones about molecular machinery. It's the 3blue1brown[1]
of molecular biology.

0\.
[https://www.youtube.com/user/ibioseminars](https://www.youtube.com/user/ibioseminars)

1\.
[https://www.youtube.com/channel/UCYO_jab_esuFRV4b17AJtAw](https://www.youtube.com/channel/UCYO_jab_esuFRV4b17AJtAw)

------
nsxwolf
I wish I understood where all this stuff came from. When we talk about
evolution we talk about random gene mutations and natural selection, but it
doesn’t seem like the machinery of the cell itself is described by DNA. How do
cells themselves and all their internal machinery evolve?

If all you had was a genome, could you really use it to engineer the cell
required for it to go inside of?

~~~
100ideas
If all you had was unix kernel machine code, could you really use it to
engineer the hardware required for it to go inside of?

~~~
haihaibye
This is a bad analogy - the instructions for making everything in the cell is
in the dna, so you also have the blueprints for the hardware fabrication
plant.

~~~
rleigh
No, it's a pretty reasonable analogy. For the original point, if all we had
was machine code, and that code had a complete description of the machine
which could run it and how to create it, it would still be useless without a
machine to process it. The code on its own would not be sufficient to create
the machine.

You can't make use of DNA without all the complex machinery required to
transcribe it, translate RNA and replicate it. There's a chicken and egg
problem. The DNA does indeed encode the instructions to make and assemble all
the rRNA, tRNA and protein sequences to do this, but you have to already have
the machinery in place to do so. Kind of like compiling a compiler. You need
an initial manual bootstrap, which in the case of life as we know it, took
place many millions of years in the past. Just as the code for a compiler is
just so much meaningless ones and zeroes without a working compiler to process
it, so is DNA in the absence of the translation machinery. Without any context
for how to process it, it's just a meaningless jumble of bases.

One thing to think about. If we discovered intact dinosaur remains with non-
degraded DNA, could we resurrect it? We don't have the machinery since it was
lost with the death of the organism. But we could potentially bootstrap it by
placing it in the cell of a related species, e.g. a reptile. But if it was a
completely different form of life, we wouldn't even know where to begin.

~~~
haihaibye
>> if all we had was machine code, and that code had a complete description of
the machine which could run it and how to create it

That's a reasonable analogy but it's not what the original poster said.

------
hyperpallium
The information processing capability of cells, and the fact that single-
celled creatures have behaviour, makes it hard for me to believe that neurons
(not just in humans, in all animals with neurons) _don 't_ use any of this
information processing capability.

I understand researchers have claimed to replicate the brains of some very
simple animals (having something like 306 neurons)... but have they replicated
the behaviour, i.e. for the same initial and ongoing inputs, you get the same
outputs as the modeled brain? That should show the accuracy of the neuron
model.

~~~
_Wintermute
They've tried, but there's definitely a lot more work to do. If you're
interested check out the Open Worm project

[http://docs.openworm.org/en/latest/faq/](http://docs.openworm.org/en/latest/faq/)

------
mncharity
> cells are extremely crowded and busy places

Cells are extremely crowded and busy... _and random and violent_ places.

Molecular biology dances in a nano moshpit from hell.

 _The Inner Life of a Cell_ is badly misleading. It reinforces many
educationally toxic misconceptions. Yes, the graphics technology was limiting.
But the video doesn't attempt to mitigate the negative impact. For instance,
adding a couple of frames of Goodsell's crowded proteins, fading to
sparseness, could have reduced its reinforcement of the "big empty cell"
misconception.

And it doesn't just hide almost everything (crowded), or slow everything way
down (busy), or show completely aphysical rendezvous and docking (random), but
it also strings together carefully selected snapshots to tell a misleadingly
peaceful narrative (violent).

That kinesin walking along, towing a vesicle? Its "feet" are actually madly
flapping around. It is randomly "stepping" back and forth - only its _net_
motion is biased. And between one net step and the next, that big vesicle has
been slammed around to every position within reach of that tether. It's a
random walk on a leash. Reality isn't a donkey quietly towing a slowly-moving
barge. It's a balloon flapping madly in a hurricane, tethered to an
intoxicated panicked mouse clinging to a rope.

Biology rides a ragged energetic edge, between things being too strong, too
expensive to dis/assemble, and being smashed to pieces too quickly.

More generally, the video illustrates a pervasive problem with science
education media. Even when done "well", some aspects are done with great skill
and care, while other aspects are silently left utterly bogus. Pity the
students, who lack the knowledge to sort out _which is which_. So rich
ecologies of misconceptions are established. And are intractably expensive to
displace. It's so easy to create content that leaves students worse off than
if they had seen nothing at all. So that's, in general, what we create.

The violence of nanoscale is a critical, defining characteristic. That so many
biology undergrads are unclear on it, let alone high-school and primary
students, shows just how very far we have to go before teaching deep
understanding, transferable knowledge, and cross-cutting principles, finally
becomes a reality. Or more upbeat, how breathtakingly awesome science
education might eventually become.

(FWIW, the top section of my very crufty
[http://www.clarifyscience.info/part/Atoms](http://www.clarifyscience.info/part/Atoms)
might help some with getting a handle on at least the size aspect of small
things.)

~~~
koliber
Thank you for this writeup that peels away a layer of simplification and more
vividly and accurately explains what is going on. you have a way with words.
The intoxicated panicked mouse will stay with me forever.

That being said, I don't agree that it is a pervasive problem that
simplification and abstraction is used in teaching. New concepts have to be
introduced piecemeal. If a new topic was explained to an audience of neophytes
in all its gory details, the effectiveness of the knowledge transfer would be
low. Some may grasp the complicated details and form a valid mental model.
However, many will be put off, as it is too much stuff at once.

Teaching is about introducing a simpler model first. Such a model is a rough
abstraction with tons of simplifications and inaccuracies. Once understood by
the student, it is about introducing a more intricate and realistic model,
while demolishing parts of the simpler one that no longer fit. Once this more
intricate model is internalized, another even more detailed one can be taught.
This goes on until you get to the limits of understanding of a certain system
or process. At that point, the student has the option of becoming a researcher
and forging new models that have not been created before.

You can not dump the most detailed and intricate model on new students. At the
same time, a good teacher is cognizant of the fact when their students have a
solid enough grasp of a given model to start introducing the more intricate
one, while dismantling the old one. It's a tough balancing act.

~~~
erasmuse
Yes, our understanding gets more refined the more we learn. It remains messy,
error-prone and incomplete. So the solution can never be to learn things
'well' or get things right first time or produce perfect teachers/videos or
something like that. The solution is to go on correcting misconceptions where
we are interested. Ken Shirriff's blog, mncharity's website, comments here and
so on simply _are_ part of the ongoing spontaneous correction process. Like
the contents of a cell, they may look crazy and disorganised but they get the
job done.

~~~
bumbledraven
Hi erasmuse, the Fallible Ideas mailing list
([http://fallibleideas.com/discussion](http://fallibleideas.com/discussion))
would be a more fruitful place to discuss your ideas. There, openness to new
ideas is valued, as is being willing to discuss disagreements persistently
until resolution.

[http://fallibleideas.com/paths-forward](http://fallibleideas.com/paths-
forward)

~~~
erasmuse
I doubt it. New ideas develop slowly and can't be communicated or explained
until they are ready. If you look at creative intellectuals they work alone
or, rarely, in pairs. Discussion to the point of resolution would be more like
politics or opinion-leading; perhaps necessary for defence or for sorting out
existing ideas but otherwise harmful to progress.

~~~
bumbledraven
Work has multiple parts. Some work is done alone, some in pairs, and some in a
public group. The public group part has value and importance: for example,
getting more variety of criticism and other feedback such as what people don't
understand. Work done in a public group also helps others learn, so that's
good.

If, hypothetically, you should join the group, in what way could you find that
out? What would change your mind?

Example of Fallible Ideas thinking: [http://fallibleideas.com/taking-children-
seriously](http://fallibleideas.com/taking-children-seriously)

~~~
erasmuse
_> What would change your mind?_

Something like historical examples of fundamental breakthroughs in science or
great works of art produced by committee.

Criticism is for stuff one _doesn 't_ like, which is why it belongs firmly in
the public realm of news, politics, etc. A group isn't public. When it comes
to your private work, ignore criticism and trust your intuition. Ideas need
room to grow just like children do.

------
ggm
I spoke to a colleague who had done some work in his PhD in the physical
chemistry of cells. Concepts like 'liquid' do not translate well at the intra-
cellular level. 'holes' or 'channels' in a membrane, again are mostly about
metaphors rather than mechanistic statements of completeness. he said for some
things, an Escher infinite-space filling grid was as good a metaphor, for the
cellular structure that the various organelles negotiate. (this btw, is
asinine, and would deserve a "physical chemist here: this is bullshit"
response)

~~~
msie
To clarify: your colleague's comment is asinine?

~~~
ggm
Ah grammar, where would we be without you.

------
dkural
Although there is truth in the post, this is not entirely correct. Many
chemical and biological processes take place in a much slower timescale than
hundreds of thousands per second, many miles per hour etc.

These processes include DNA synthesis/cell division, transcription, the
transmission of electricity / ions between neurons, and many other basic
processes.

Also, Many proteins don't simply float every around the cell at these massive
speeds - they form stable, localized protein complexes that keep on doing what
they're doing at the same location for quite a while. That's why we can image
them and make real-time movies at human scales of perception (seconds, minutes
etc.).

Even more so for more complex processes - this is also why cellular motion
takes quite a while - go on youtube and watch dictyostelium cells move towards
folic acid. It takes quite a while, many hours in fact despite the presence of
a very clear folic acid gradient as the signal.

~~~
abecedarius
Also, speeds like "100 times per second" should be scaled down with the size
scaling, if you want a feel for mechanics. Times Square is about 1km long, and
a eukaryotic cell around 10 microns, so scale by 100 million. (A pretty
typical protein, 5nm across, becomes 0.5 meters across in Times Square.) From
this perspective even the rapid purposeful actions the article talks about go
extremely slowly: 100Hz becomes a million seconds per action -- a couple
weeks. The biomolecules do whip around at random very fast -- but net progress
happens only after a _lot_ of wriggling.

~~~
100ideas
> Also, speeds like "100 times per second" should be scaled down with the size
> scaling, if you want a feel for mechanics.

I'm a little confused, are you saying that the _real_ speeds and rates in the
article/this thread are all too fast by a factor of 100 million, or are you
saying that its useful to perform this scaling mentally when imagining these
systems to get a better intuition of their mechanics...?

~~~
abecedarius
The latter. Maybe I should reread the post, but it invites you to visualize a
cell as Times Square -- scaling the sizes -- and then the unscaled speeds give
the wrong impression within that visualization. (Mechanical properties like
stiffness don't vary when you scale space and time together.) Outside of it,
of course the absolute speeds are what you want to know.

~~~
100ideas
Thanks for the clarification, I see what you’re getting at.

------
pdm55
I found Goodsell's images of the crowded intracellular environment in E. coli,
useful visualisations in developing a model of a living cellular process,
namely, transcription control. Transcription is the first step in gene
expression: in E. coli, RNA polymerase transcribes a complementary copy of a
gene, namely, messenger RNA, for further processing to protein. The
transcription process is controlled by proteins that either compete with RNA
polymerase for the start site of transcription (turn off the gene) or bind
adjacently and promote transcription (turn on the gene). The difficulty I had
in constructing a mathematical model of transcription control was that I
wanted to include nonspecific binding, where RNA polymerase binds with low
affinity to random stretches of DNA. While such binding occurs with low
affinity, the sheer length of the DNA meant that a significant proportion of
the RNA polymerase was bound in that form. Fortunately, I became aware of the
work of people like Allen Minton (NIH) and Tom Record (U Madison-Wisconsin)
who studied molecular crowding. To borrow a sentence from Wikipedia, "[H]igh
concentrations of macromolecules reduce the volume of solvent available for
other molecules in the solution, which has the result of increasing their
effective concentrations."
[https://en.wikipedia.org/wiki/Macromolecular_crowding](https://en.wikipedia.org/wiki/Macromolecular_crowding)
I found (I hope correctly) that Tom Record's quantification of crowding, as
affecting a 100-fold increase in concentration, "exactly" compensated for the
reduction due to nonspecific binding.
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5425810/](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5425810/)

------
danaliv
I am suddenly very uncomfortable, imagining myself as a roiling blob of goo.

~~~
Terr_
If it helps, consider that you are the descendant of the original "grey goo"
which since pervaded the surface of an entire planet. The inheritor of a
billion years of techniques in construction, alliance, deception, and warfare.
A uniquely coordinated swarm of assimilating nanotechnology, poised to leap
into the cosmos.

... No pressure.

~~~
Asooka
Or you can sit here and wait to become a star again.

------
Ultimatt
This article mentions two things as if they are unrelated. That the cellular
environment is crowded is exactly why you need transport proteins and
vesicles. All the really fast proteins are mostly going nowhere, they're just
wobbling on the spot bumping into everything crammed next to them. Sandwiched
most of the time between membranes they cant diffuse through freely. Its like
angry jelly not hot soup.

------
vbuwivbiu
"As a result of all this random motion, a typical enzyme can collide with
something to react with 500,000 times every second. Watching the video, you
might wonder how the different pieces just happen to move to the right place.
In reality, they are covering so much ground in the cell so fast that they
will be in the "right place" very frequently just by chance."

That's the problem with those visualizations - they aim to give one an
intuition of what's happening, but in fact they mislead. I wonder how it's
possible to give an intuition of the reality, when in addition to the crazy
statistical noisyness of the scene, those molecules are also in quantum
superpositions.

------
jlebrech
God is a using 4 dimensional Autocad, unaware that his gears and cogs have
created life. that's my guess.

------
ngsekar
Interesting.... Its very difficult to think about works of cells... if god is
there... he is so great of creating lifes...

~~~
Ultimatt
If god was so great (or at least smarter than humans) most of it would work a
lot better than it does!

~~~
elboru
Care to explain? What could be improved?

~~~
D-Coder
Knees. What half-competent engineer would hold a weight-bearing joint together
with soft tissues?

Teeth. Replacing these with a new set every 10 or 20 years would be pretty
nice.

