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Sequencing is the new microscope (ldeming.posthaven.com)
74 points by sethbannon 70 days ago | hide | past | web | favorite | 16 comments

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

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.

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


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.


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.

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!

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

In the grand scheme of things I think the superres Nobel was extremely immature.

My PhD was mainly focused on microscopy. I'd say yes and no - we are definitely heading towards the realm of dimnishing results with most microscopy techniques (cryo electron microscopy is an exception which is being used to understand protein structure, though id argue it's only important because we still don't have the computational ability to solve a protein structure given its sequence even though it's pure chemistry).

The field of connectomics is also exciting in this regard.

However, I'm more hopeful for future versions of microscopes which are not even in the realm of imagination of current researchers (an MRI microscope with micron resolution? Yes please!)

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.

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.

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.

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).

> 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.

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.

> 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?

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.

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

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