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Comment by j6m8 | Hacker News Reader

A few years ago my team mounted what I think was the largest-(to-date) scale search for this in electron microscopy brain tissue volumes [1].

I STRONGLY believe there is a substantial central nervous system microbiome, but (spoiler alert) no evidence found in that search :)

If you're excited about this work, the datasets are all freely available from BossDB [2] — well over a dozen petavoxels of it! I'd be so curious if models these days could pick up on something we missed!

[1]: https://www.biorxiv.org/content/10.1101/2022.07.12.499807v1 [2]: https://bossdb.org

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> I STRONGLY believe there is a substantial central nervous system microbiome, but (spoiler alert) no evidence found in that search :)

What gave you reason to believe this if you found no evidence of it in your own search?

Microbes are CRAZY. They're everywhere. Thermal vent-friendly microbes. Space-friendly microbes. Vacuum-resilient, heat-resilient, acid-resilient. Microbe-free-environment-friendly microbes [1]. It seems hard to imagine that a blood-brain barrier could really keep the brain sterile.

We're lucky to live in a scientific era during which a "gut microbiome" is taken for granted (heck, even FDA-approved treatments depend on it! Google FMT, but don't click "images" from your work laptop), but it wasn't so long ago that we felt microbes were unlikely to live endogenously and harmlessly anywhere in the body.

There were also some hypotheses (untested, if memory serves) that COVID-19 influenced olfactory neurons through direct infection. Don't tell the blood-brain barrier, but if I were a bacterium, the nasal palate would be my ingress strategy. Or maybe the gums or gut — one of the cranial nerves, certainly. [edit] I should clarify — covid is viral, not bacterial, but it does show that this is a potential entry vector.

The central nervous system is incredibly complicated, and our symbiotic relationship with microbes is extraordinary. I think it does a disservice to bacteria to suppose they DON'T get involved in an organ :)

[1] https://www.space.com/ryugu-asteroid-sample-earth-life-colon...

Our defenses are also crazy. For example, the inner mucus layer of the colon is able to keep trillions of bacteria at bay the vast majority of the time (unless there is inflammation or takeover by specific mucus-eating bacteria). Many of the proteins in the secreted mucus layers are still unknown in function, like FCGBP which comprises up to 40% of the protein content of mucus.

The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria https://pubmed.ncbi.nlm.nih.gov/18806221/

Bacteria penetrate the normally impenetrable inner colon mucus layer in both murine colitis models and patients with ulcerative colitis https://gut.bmj.com/content/63/2/281

So I think without trillions of bacteria to exclude, in the absence of any other issues excluding bacteria from the brain seems pretty doable.

Many viruses infect neurons, but they are way smaller than bacteria.

Absence of proof is not proof of absence. I would imagine that it would take a lot of negative searches by many people trying different approaches to rule it out. The searches are likely to be carried out by people who believe in the idea rather than those that are skeptical they will find something (the skeptics will work on reproducing any positive results).

It should be noted that absence of proof is evidence for absence. And since in the physical sciences, unlike mathematics, actual proof of absence is impossible, absence of evidence (after thorough searches) is the best we've got to form a belief for absence of the phenomenon.

That is, we believe, very strongly, that it's impossible for two masses to repel each other gravitationally, for example, but we will never have actual proof it's impossible.

None of this to say that it's irrational to believe in a brain microbiome despite this search seeming fruitless, as there are good a priori arguments for expecting one to exist.

> It should be noted that absence of proof is evidence for absence.

Exactly. Like the apocryphal small chocolate teapot orbiting the Earth

But evidence of absence is, and in this case we have a lot.

For the last 400 years, pathologists on every country had filleted and put, lets say tens thousands of human brains and human guts under the microscope. One of them has systematically a microbiome, easy to see. The other don't, except when is diseased or rotten. The sample token here is huge, maybe millions.

If we would had searched 400 years for this chocolate teapot without finding it, we could conclude with a solid suspicion that there is not such thing.

This is very different than just saying "I don't think that there is bacteria in the brain but I never searched for it". All pathology science is based in searching for it. We created gram staining dyes, scanners, tags, gold coated plates for electronic microscopes, DNA analysis... exactly for that.

If there really is a microbiome living in each healthy brain, we should have found it 150 years ago.

> For the last 400 years, pathologists on every country had filleted and put, lets say tens thousands of human brains and human guts under the microscope. One of them has systematically a microbiome, easy to see. The other don't, except when is diseased or rotten. The sample token here is huge, maybe millions.

Is that really the case? By my understanding of the article, we find plenty of bacteria whenever we look at human brain samples. The problem is that it's very hard to tell if that bacteria was already present in the brain, or if it got in through the process of cutting the brain open (especially by contamination with other tissues), or if it was indeed present before the procedure, but only because the individual was very old or had a disease.

Yeah exactly. It’s not an unreasonable search and we don’t have confidence our search methods work. Hell, the Ryugu sample was contaminated while in a hermetically sealed clean room filled with nitrogen gas. Either the blood brain barrier is even more effective or maybe the story isn’t quite so clear. This is not an unreasonable hypothesis nor do have we exhausted search. Hell, we’re literally talking about it in response to a related find in another species. So it’s definitely not a wild theory or one that conflicts with known theories.

The chocolate teapot example is a non sequiter as it fails both Occam’s razor and the principle that extraordinary claims require extraordinary evidence not to mention that it wouldn’t follow any laws of known science and it’s existence very well would upend quite a few of those. The scientific method isn’t something you get to apply piecemeal.

Unfortunately many people claim an absence of evidence _without_a_thorough_search_ is evidence of absence. As in "I have haven't seen it so it must not exist". Many people who are experts do this. There needs to be some new terminology here, just saying "there is no evidence" is meaningless, people need to start saying "there is no evidence after <these> kinds of searches" to qualify their statements. Like "I haven't seen any evidence, but I haven't really looked", or "I asked some of my collegues and none had seen any relevant papers", or "I did a PubMed search and found no papers on that topic", or "I did a PubMed search and found 10 low quality studies that showed no evidence of that". Otherwise it is completely reasonable to interpret "there is no evidence" as "I don't know".

This might be too nitpicky, but isn't believe exactly what one has in absence of evidence?

They're is no evidence that Russell's Teapot is floating out in space in orbit around the sun, AND I don't believe that it's there.

If I said "I STRONGLY believe that a teapot is out there," it would be reasonable to ask me why.

Also (and this is a pet peeve of mine), we're talking about evidence not proof. They're not the same thing. Just because there's evidence that something happened, it doesn't mean that it happened.

Evidence is a thing that you claim could be part of an valid argument that something happened ("is consistent with"). This isn't a universal definition, but there's got to be some separation between proof and evidence. When there's evidence admitted into a court case, it doesn't necessarily mean that someone is guilty. When there's a lot of evidence and still no proof, you can and should (and will) still make a probabilistic case that something did happen.

So I'd agree with and disagree with you. There's no evidence (that you know of) that Russell's Teapot is there, which is why you do not believe it is there. If somebody does believe it is there, but admits that they have no proof that it is there, it would be reasonable to ask what evidence makes them believe that it is there.

Where I obviously agree with is that "belief" can't mean just something you want to think for no particular reason. Or if it does, it's certainly not worth talking about.

What makes a hypothetical brain microbiome so hard to find? I would think that once you’re doing microscopy on brain slices that a biome would show you quite fast. But if you’re still optimistic after a negative search I assume there must be many reasons why a brain microbiome could exist but still be hard to detect.

I once saw a video about using a scanning tunneling microscope. I wanted to get a handle on how hard it was, so I scanned an area the size of 4 football fields and found a single dime. It takes a long time just to figure out what you are looking for. We have literally not even scratched the surface.

I would bet that your search was interesting, and that eventually you will find something.

Mikelson-Morely went looking for ether, and Einstein found relitivity.

Thank you for your work.

> I scanned an area the size of 4 football fields and found a single dime.

Despite only finding a single dime, that sounds fascinating. Can you say more?

Cool! Has anything similar been attempted in tumor tissue, given the many claims of microbes in tumors? Especially tumors not in contact with the exterior.

As far as I know, most of the tumor microbiome claims haven't held up very well. For example, the 2020 Nature paper "Microbiome analyses of blood and tissues suggest cancer diagnostic approach" was retracted this past year [1].

Given the ease of contamination of tissues (and databases), I tend to be pretty skeptical of tumor microbiome claims -- especially the wide-ranging claims of microbes being present in all tumors.

[1] https://www.nature.com/articles/s41586-024-07656-x

I know nothing about this, so I guess I'm asking "why can't we do this?": take some brain, throw it in a blender, and look for DNA the same way the ancient environmental DNA people do?

You can't find out this way. Removing brains exposes it to an outside environment where there are microbes. You can't tell if they arrived before or after you removed the material.

Related recent story about earth microbes colonizing what was hoped to be a pristine sample of astroid captured in space: https://www.space.com/ryugu-asteroid-sample-earth-life-colon...

Maybe the first point you make is also the argument for why our brain might have a microbiome, as our body is not in any way hermetically enclosed, and e.g. amoebas are able to infect our brains just by going through our nose.

Very hard to clean a blender!

More nitpickfully, one of the big things we care about is if the bacteria are living _harmlessly_ in the brain. i.e., site of microbes, and a lack of inflammation, will answer more than just "are there microbes around".

You’d have to get that brain cleanly from the creature to the blender.

Place body in sterile isolator, expose dura mater, DNase treatment of the area, insert sterile syringe into brain? Repeat experiment several times, and also process negative controls.

Not my area. I guess the fact that it hasn't been done proves it's way harder than I'm assuming it is.

From what I understand Joe DeRisi's approach[0] comes relatively close to your "blender" idea!

[0]: I already mentioned Adam Savage's excellent podcast with him elsewhere in this dicussion but here's a direct link: https://m.youtube.com/watch?v=MzzD2F73iGU&t=2s&pp=2AECkAIB

Since I don't have enough information on the topic... how would one distinguish a microbiome that was present while the organism was alive, from contamination after death?

That's a question more suited to a microbiologist or bacteriologist than to me, but my educated guess, at least in the electron microscopy case, is that you'll see the bacteria inside the depth of the slices, rather than sitting "atop" the slices. i.e., if you cut open an apple and find half a worm, the worm was in the apple. If you cut open an apple and then see a worm on top of the slice, it's possible it arrived post-cut.

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