
Sequencing is the new microscope - sethbannon
http://ldeming.posthaven.com/sequencing-is-the-new-microscope
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epistasis
Yes, looking at the vast array of techniques for sequencing that have been
advancing in the past 5-10 years, and I'm truly amazed at what we can see and
what we are discovering--it seems far far above the potential of any
microscope. Various sequencing preparations allow determination of 3D
organization of the genome, and association with proteins, RNA, and other
small molecules with those 3D structures, among much more that I haven't been
able to keep up with.

As Feynman said nearly 60 years ago:

> We have friends in other fields – in biology, for instance. We physicists
> often look at them and say, "You know the reason you fellows are making so
> little progress?" (Actually I don't know any field where they are making
> more rapid progress than they are in biology today.) "You should use more
> mathematics, like we do." They could answer us – but they're polite, so I'll
> answer for them: "What you should do in order for us to make more rapid
> progress is to make the electron microscope 100 times better."
> [https://www.zyvex.com/nanotech/feynman.html](https://www.zyvex.com/nanotech/feynman.html)

Turns out that biologists (and chemists and some physicists working on bio)
ended up hacking together a bunch of techniques that work far far better than
wildest dreams of current microscopy. It requires tons of informatics
afterwards, but it gets answers and information of such magnificent scale that
even an electron microscope 100x better couldn't dream of.

It turns out you don't just need the resolution, you also need a massive field
of view, and a massive _volume_ of field of view not just a plane, to get
close to the discoveries that go into a state of the art paper these days. I'm
not sure if microscopy can catch up, it if it ever does it will be through
massive deep learning on teravoxels or maybe a few orders of magnitude more.
That's not in the cards anytime soon, as far as I know.

~~~
kurthr
Actually similar to the electron microscope Feynman describes for pharma-
biochemistry is the new microED (micro Electron Diffraction) for biological
structure determination.

[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5656569/](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5656569/)

The ability to see the actual atomic organization of a molecule (and its
various confirmations) of previously "uncrystalizable" compounds is also
amazing. There is money to made building these lab systems! It needs to be
automated ,but everyone will need to upgrade.

[http://blogs.sciencemag.org/pipeline/archives/2018/10/18/sma...](http://blogs.sciencemag.org/pipeline/archives/2018/10/18/small-
molecule-structures-a-new-world)

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dekhn
Microscopes are the new microscopes. They tell you a lot more about
phenotypes. And genotypes- some recent papers can identify specific cancer
mutations simply from images of tumors. Also, recent work has shown that you
can do sequencing _with_ a microscope.

~~~
tmearnest
Seriously. Progress in microscopy hasn't slowed down at all. There was an
Nobel prize given for optical super-resolution imaging recently. Cryoelectron
tomography is insane: near Angstrom level resolution of 3D segments of cells.
People are measuring the entire transcriptome of single cells using
microscopy. Optical tweezers are allowing researchers to measure forces inside
cells by literally grabbing intracellular structures with a laser and yanking
them around.

Progress in sequencing is also exciting, but don't discount microscopy!

~~~
adrianrocamora
There's even 2-photon laser microscopy. I worked on such projects before and
the field of optogenetics is amazing!

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biophysboy
As somebody whos been working in this field for a bit, both sequencing and
microscopy are advancing in very exciting ways. So Its weird to see an article
pitting one against the other.

I do wonder how easy/costly it is to compare differences in single cells via
sequencing. I realize there are methods for cell isolation using stuff like
microfluidics. But a lot of these methods use elements of microscopy.

My sense has always been that next-gen sequencing coupled with superres
microscopy is the way forward.

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schizoidboy
It's a short(ish) and somewhat thought-provoking read, although it has the
questionable value of most analogies, and is light on details; however, I
enjoyed this line:

> One of my biggest personal fears is working in the wrong field to achieve
> the goal I care about.

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jkh1
There is no opposition between microscopy and sequencing. To the contrary,
technologies are converging on the microscope as "omics" data (sequences are
one type) are now moving to the microscope because of the need for additional
information such as cellular states or spatial information. For example, in
mass-spectrometry imaging, mass-spectra are associated with regions of an
image or single molecule fluorescence hybridization (smFISH) techniques are
used to produce transcriptome data at the single cell level on a microscope.

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j7ake
How do you deal with spatial resolution? Whether a part of a tumor is nearby
blood vessels seems important information that sequencing is difficult to
address.

Other things that come to mind:

\- Size of cells \- Texture / shape of cells \- Local microenvironment \-
Morphology of tissue

Combining both seems like a promising step forward (as commenters here have
already mentioned).

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mmt
> the outperforming endurance of DNA compared to any modern hardware

This struck me as a strange analogy, considering DNA's inherent fragility, but
it would make more sense compared to modern software than hardware.

Alternatively, it also makes sense if "hardware" means a particular
model/architecture, with DNA corresponding to an HDL, rather than an instance
of hardware (e.g. single CPU, server, or smartphone). A frequent enough topic
on HN is the challenge archivists have with archaic software and data formats,
even if all the original collections-of-bits are faithfully preserved.

~~~
Real_S
DNA is not fragile, and can act as a very stable long-term storage medium.

DNA in living cells has some fragility because it is in an aqueous solution
and also actively used to generate RNA. DNA out side of cells is even more
fragile, it will inevitably be eaten by bacteria. But put DNA in the right
sterile environment, it can last for thousands of years and has great
resistance to electromagnetic interference.

~~~
mmt
> the right sterile environment

This has echos of No True Scotsman. Computer storage media also have ideal
conditions that can be used to extend their lifetimes (though, granted, not
indefinitely, AFAIK).

What about in real conditions, subject to things like temperature variations
(including "extreme" heat that non-operating computer hardware can do just
fine in), exposure to light, humidity from the air (to put it back into
aqueous solution occasionally), and common oxiders found floating around in
the air?

Could one rely on an arbitrary single strand to last even 5 years in an office
environment, or are numerous, RAID1-style, copies required to maintain
fidelity?

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jiggunjer
I don't think one can perfectly replace the other. In many experiments where
both technologies could be used, sequencing data is more valuable (currently).
But for some questions, you must have microscope data.

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kleopullin
Nah, programming and computer power are still the new sequencing and
microscopy.

