
Researchers have identified a new DNA structure called the i-motif inside cells - braythwayt
https://www.scimex.org/newsfeed/found-a-new-form-of-dna-in-our-cells
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klmr
Original paper:
[https://www.nature.com/articles/s41557-018-0046-3](https://www.nature.com/articles/s41557-018-0046-3)

Full text PDF:
[https://paperpile.com/app/p/ce9c364d-416a-0ede-9233-adf31910...](https://paperpile.com/app/p/ce9c364d-416a-0ede-9233-adf319101f59)

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chiefalchemist
The was an article in The Atlantic a couple+ months back - which after 10 mins
I still can't find - about some scientist and his alt view / theory on DNA.
The gist, if I recall correctly, was (and forgive me if I fall short of
capturing the significance of his idea):

How DNA functions is far more complicated than how current accepted science
pictures it.

1 - Certainly seems like he might be onto something.

2 - If so, could the use of CRISPR be premature, if not dangerous?

~~~
klmr
> 2 - If so, could the use of CRISPR be premature, if not dangerous?

This is really an ill-posed question. First off, CRISPR is a tool. Its novelty
is the fact that it makes an experiment vastly simpler and more reliable —
but, fundamentally, the experiment was already possible beforehand. So CRISPR
itself isn’t dangerous. At most, modifying genetic material could be.

Secondly, genetic modification — whether by CRISPR or other methods — is an
_extremely generic_ process. Sure, it could be dangerous, if you use it to
perform dangerous experiments. Can it have unintended side-effects? Sure, we
already know about those. In fact, one of the great things about CRISPR is
that it drastically decreases side-effects.

But is CRISPR dangerous specifically because we underestimate the complexity
of DNA? No. Nothing about CRISPR assumes that we know all biological processes
that involve DNA. In fact, _we know_ that we don’t know them all.

Lastly, somebody with an “alt view on DNA” immediately sounds like a crackpot
with a poor handle on modern biology. That may sound harsh but biology is a
science, not a pseudoscience or protoscience (or magic): we’re moving within
some relatively fixed boundaries imposed by experimentation and evidence.
Uncertainty or lack of knowledge isn’t a free-for-all to insert wild
speculations that usually amount to “everything we know is wrong”. It’s _very
rare_ that “everything we know turns out to be wrong”. In reality, subsequent
findings refine existing ones, or disprove specific hypotheses. They don’t
disprove an established field. Even something as revolutionary as Einstein’s
theory of relativity didn’t do that: gravity continued to function just fine
afterwards. Newton continues to be taught in school, because Newton’s laws
continue to be relevant.

~~~
chiefalchemist
> "already possible beforehand"

How so? And if so, why is CRISPR such a big deal?

Not being a jerk. I'm truly interested in filling the blindspot in my
"software."

That said, the gist of the guy / article was (and I'm spitballing) CRISPR is
an over-simplistic view of DNA. Sure, it might work for a couple of things,
but to presume that pov / lens is OSFA is likely not correct.

> "Lastly, somebody with an “alt view on DNA” immediately sounds like a
> crackpot with a poor handle on modern biology."

Right. Because the world was and still is flat? SMH

If I had $20 for every crackpot in the history of science I'm be FU money
wealthy :) __The whole point of my comment_ was to say this new tread/artice,
along with the mentioned article in The Atlantic seems to be saying it's
__possible__ our understanding of our current understanding of science is off-
base.

That's not crackpot. That's science.

~~~
klmr
> How so?

With other gene editing techniques, such as TALENs (and others before that).

> And if so, why is CRISPR such a big deal?

CRISPR/Cas9 is a big deal because it makes gene editing a lot easier and less
error-prone (and hence cheaper, etc.). But (and not to diminish the tremendous
scientific achievement behind the technique) the hype in the press around this
technique is only partially warranted, and a lot is getting lost in
translation. Part of the reason why CRISPR specifically is a big deal in the
popular press is due to the extremely dirty fight for its exclusive patent
(and the Nobel prize for its discovery): To gear up support for their side,
both institutes involved created substantial media coverage that far exceeds
what new discoveries normally get.

> CRISPR is an over-simplistic view of DNA

I would really like to read that original article because stated like this,
the claim is simply incorrect.

> Right. Because the world was and still is flat? SMH

I honestly don’t know what you mean by the rest of your comment. But it’s
worth noting that, in the modern history of science (i.e. since doing
something that actually deserves that name), crackpots have virtually never
been right. Progress (even paradigm shifts) came always from experts inside
the field. The only near-counter-examples I can think of are Semmelweis (but
that was _before_ modern biology existed, and even he was an expert in his
field), and Wegener (likewise, for continental drift). It’s easy to assert
that science doesn’t have all the answers, and that theories are a temporary
view of the world that’s going to be proved wrong in the future. But this has
never been accomplished by people who doubt the veracity of extremely well
established facts.

Our knowledge of DNA is _far_ from complete. But the things we know about it
today will stick around: they have been tested by millions of experiments,
performed around the globe each day. Paradigm shifts will come because we will
discover new things about it, not because we’ll disprove established facts.

------
epistasis
Some previous HN discussion of this:

[https://news.ycombinator.com/item?id=16909328](https://news.ycombinator.com/item?id=16909328)

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foxhop
I wonder if the formation of an i-motif could change the behavior of the
"normal" DNA code. Like a flag on a function to slightly change how it works.

Could make certain parts of reading normal double helix DNA a no-op, for
example by accumulating parts before they can be read.

Another idea is maybe this is just a structure for temporary memory for use in
a more complex "algorithm".

We used to think DNA was just mostly static data but now it seems there is
some computation going on.

If not computation to change behavior, maybe the i-motif act like a check sum
to make sure a complex or essential part of DNA isn't corrupted (by a storage
failure or a virus)

~~~
subroutine
I dont think this motif brings anything spooky/special to the fore. DNA is
swarmed by proteins, ribocomplexes, acetyl/methyl histone mods, etc. all of
its own making. Whatever special computation one might speculate this motif
could perform- that computation or fidelity check or whatever else is probably
a known and well-documented function of some DNA-associating complex. While
it's fun to speculate how this might 'change the game', in all likelihood,
this finding is a very small drop in a very large bucket.

But if we are speculating... That a motif forms by a single strand of DNA or
RNA is expected (given certain properties or symmetries). What the image in
the article depicts and given the quote that this is often seen at start
codons, to me, suggests this motif forms whenever transcription machinery has
opened the helix creating two single strands. And instead of hanging out as
single strands (a very vulnerable state, to DNase degradation, etc) they coil
unto themselves. This might also suggest this segment of DNA is relatively
easy to unzip, and has built-in degredation protection, making for ideal
consensus sequences as start codons.

------
subroutine
Seems like these "i-motifs" form transiently during transcription.

If they are making the argument these motifs exist much longer than the course
of transcription I'd like to how DNA could remain stable in such a
conformation. There are molecular machines inside nuclei that really dont like
single stranded DNA, and will chomp it up on sight. If the complementary
strand to the i-motif isn't itself moonlighting as some double stranded motif,
how is it protected from these dnases.

If they are only saying the conformation exists while DNA is undergoing
transcription... this isnt exactly on par with a A-,B-,Z-DNA conformations.

The primary source is behind a paywal for me (while off campus), but I'll be
interested to read more about this later:

[https://www.nature.com/articles/s41557-018-0046-3](https://www.nature.com/articles/s41557-018-0046-3)

(also, how do you confirm the existence of transient structures using fluoro
antibodies? 'fret'? 'fish'?)

~~~
alexholehouse
So it seems like there are two timescales for what 'transient' means in the
paper.

1) There are different levels/numbers of i-motifs identified depending on the
cell cycle position (highest at G1/S boundary, although this is only comparing
cells synchronized to G1, G1/S and early S so maybe more at different
points?), suggesting these structures don't just stably form and then just sit
happily around for the entire lifetime of the cell.

2) _In vitro_ these motifs are less stable than (say) G-quadruplexes so
presumably there is a suggestion they may be transient over short timescales,
but this is not actually examined in the paper. No idea how you'd actually
test this without inherently perturbing the equilibrium being examined _in
vivo_. Even if you could avoid fixing the cells antibodies would be out of the
question because of the inherent linkage (if you bind the i-motif with a 500
pM Kd [high affinity] you're gonna HUGELY stabilize that conformation).

~~~
subroutine
I'm curious about this...

"What excited us most is that we could see the green spots – the i-motifs –
appearing and disappearing over time, so we know that they are forming,
dissolving and forming again,”

anyone know what technique they used during this observation? It sounds.. not
fixed?

what matters most in my opinion is whether this is a spontaneous DNA
conformation or whether this is a transient conformation DNA assumes while
transcription machinery is preparing to read nearby bases. (if the former,
kinda interesting; if the latter, much less interesting)

~~~
alexholehouse
Right - yeah; I don't know, I had the same thought when I read the commentary
(I read the paper first). Nothing in the papers suggests the ability to
monitor formation/loss in realtime I don't think? My guess is this is an
interpretation of the data from the fact that you see lower levels in G1,
higher levels in G1/S and lower levels in early S - i.e. they must be
'transient' because the levels go up and down again.

Seeing this happen in real cells in realtime would be – I would have thought –
technically almost impossible. We're at the cusp of viewing the formation/loss
of clusters of RNA POL or mediator clusters with the most advanced super-res
(see Ibrahim Cissé's work) but these are comparatively massive protein
clusters, so the idea of being able to view DNA structural transitions at
[effectively] single-molecule resolution where that transition involves a few
nucleotides in a non-perturbative way seems like a reach.

Seems like the obvious next step is to break 'em with synonymous mutations and
ask if there's any detectable phenotype.

~~~
subroutine
Apparently they used ELISA.

~~~
subroutine
But like you said...

"No idea how you'd actually test this without inherently perturbing the
equilibrium being examined in vivo. Even if you could avoid fixing the cells
antibodies would be out of the question because of the inherent linkage (if
you bind the i-motif with a 500 pM Kd [high affinity] you're gonna HUGELY
stabilize that conformation)."

I mean, I trust the reviewers/editors of Nature but I don't understand how
this is not a serious confound!

------
dekhn
Those of you who are CS people who are trying to stretch this paper into more
significant than it is: please go and read all the first-year biology
textbooks before speculating.

~~~
laythea
I am a CS person. If the article is not readily consumable for a CS person why
is it on a website called "Hacker News"? Seems like a bad submission if you
ask me...

~~~
Jedd
> I am a CS person. If the article is not readily consumable for a CS person
> why is it on a website called "Hacker News"? Seems like a bad submission if
> you ask me...

Like many before you, you appear to assume Hacker equates to the C in CS.

~~~
laythea
Like the many that will, after me, assume Hacker to mean the C in CS.
Technically, you are correct, and I agree. But I must point out, that
actually, you are wrong - the general use of the word belongs to computers.

~~~
laken
The word hacker isn't about computers. [https://stallman.org/articles/on-
hacking.html](https://stallman.org/articles/on-hacking.html)

~~~
laythea
Most people would have no idea about Richard Stallman, and I maintain that due
to popular media the general public associate the word with computer
technology.

~~~
Ascendency
This is Hacker News, not the general public. If we don’t know who Richard
Stallman or what a hacker is, who should?

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quark33
I'm curious what sort of implications this will have for hereditary disease
gene research (Cancer, Alzheimers, etc).

~~~
jeppz
The problem right now is that "has only been witnessed in vitro – that is,
under artificial conditions in the laboratory, and not inside cells." which
means it may not even exist in our bodies.

~~~
alexholehouse
But this is _literally_ the entire point of the this paper. The sentence you
just pasted was the the previous state of the art, this paper makes the point
that they have now imaged them in cells (using i-motif specific antibodies).

~~~
subroutine
'in vitro' can mean 'in cells in a dish'. I think the previous state of the
art was 'unsure if these exist in living cells' (could be wrong, but id be
surprised if they did this exp in vivo). edit based on your comment above you
probably have the paper and are in a better position to comment on this. I
defer to op.

~~~
alexholehouse
Yeah agreed (what _in vitro_ means to different people is a whole other
conversation :-P), but that sentence makes it pretty clear that by _in vitro_
they mean _not in cells_ (because it says, "and not inside cells"). Agreed, of
course, that this doesn't _necessarily_ mean it happens in cells in an
organism (though in the authors' defense they do examine three different cell
lines).

Edit: For clarity - all the in cell work is cultured cell lines and not cells
taken from an animal model or _in situ_ imaging.

Literally my only point was that 'this might not matter for biology because
we've not even seen it in cells' is no longer true. It still might not matter
for biology though!

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nukeop
Will Apple sue the researchers for trademark infringement?

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twodave
Wait, they identified it AND managed to get it to tell them its name? Wow!

------
isthatart
Computation: “What excited us most is that we could see the green spots – the
i-motifs – appearing and disappearing over time, so we know that they are
forming, dissolving and forming again,” says Dr Mahdi Zeraati, whose research
underpins the study’s findings.

~~~
bitL
Hooray! Finally the inevitable happened! I guess this will turn biology upside
down, everybody assumed DNA/RNA were static (with the exception of some
primitive viruses).

Now how to reverse engineer "machine code"?

~~~
dekhn
this doesn't turn biology upside down in any way.

~~~
ryanwaggoner
This amuses me. When was the last time any major finding turned an entire
mature field of study on its head?

~~~
dekhn
I don't understand. Are you implying this paper is a "major finding"?

Many things that happen in biology occur without any real meaning or utility.

~~~
ryanwaggoner
No, I'm agreeing with you. I think it rare that any mature field these days is
"turned on its head". I doubt most of the examples given by other comments
would qualify if you dig into them.

