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Posted by artninja1988 2 days ago

The Millennium Problems for Biology(millenniumproblems.bio)
160 points | 119 commentspage 2
freebsd_lovefes 2 days ago|
It's missing some important stuff? Like creating bacteria that can produce fuels or break down plastics.
flexagoon 2 days ago||
Bacteria that break down plastic already exist, both naturally and synthetically. Optimizing those is one of the most popular student projects in my university. Hardly a millennium problem.
HarHarVeryFunny 2 days ago|||
What seems ridiculous to me is putting together any such lists, even in math, and expecting/hoping the AI companies to solve them. The people working for the AI companies are not scientists or experts in anything outside of building LLMs. The best chance of making progress on genuinely tough (not just computationally challenging) tasks is to put advanced tools in the hands of actual scientists.
pickleRick243 2 days ago|||
Actual scientists are not interested in using these tools to their full capability because of a fundamental psychological block where they have the need to feel superior to the LLM. The point is that AI labs have a thesis that AI will supersede humans in all cognitive work, and since few scientists have this view (or have the temperament to even contemplate this view), they have to do it themselves. In any case, they are attracting strong/talented biologists (Dario himself has a biology background) to work on this and provide their expertise, but presumably they filtered for scientists who are in fact "AI-pilled".

Look at what's happening in the math community- rather than excitedly embracing the power of AI's ability to generate new proofs, they are screaming for it to slow down (and quite a few want it simply stopped). Many scientists, even in ostensibly more real-world fields are broadly cut from the same cloth.

HarHarVeryFunny 2 days ago||
There may be a few scientists rejecting use of AI for that reason, but I would expect them to be a tiny minority, just as I would expect the number of developers who accept that AI is a powerful coding tool, but refuse to use it just because they want to feel superior, is very small!

A much more practical reason we're not yet seeing a lot of headline scientific mathematical breakthroughs is just that it is ungodly expensive! e.g. The Navier-Stokes result cost around $20M at API prices, and academics just don't have that kind of money to spend. You'll see more mathematical and scientific results from practitioners when either the cost of compute needed for these sort of brute force results is more in line with the size of academic grants, and/or the AI companies donate more compute to the scientific community.

There are different reactions from different mathematicians of course - Terrance Tao vs Cedric Villani, and no doubt a lot of shock at the speed of advance, but it seems the reasoned complaint why they don't want the AI companies themselves working on these problems is because the outcome is not the same - you get a result that in of itself may have been suspected or useless (Navier Stokes), but no write up of any new math or insights that were developed along the way, which is the real reason mathematics and people like Erdos pushed these famous problems in the first place - because they were expected to yield interesting mathematics, just as years of work on FLT had done. Imagine if instead of Wiles's work, and all that had gone before him, all we had was a $20M compute bill, hundreds of pages of impenetrable math, and a billion lines of Lean proving it was true?!

zhaoziyuan2000 2 days ago|||
It seems that in a frantic pace to prove general usefulness of these LLMs the AI companies are also picking up the role of traditional scientific researchers without really have enough proper communication with the scientific community at large... I agree putting tools in the actual scientists will be very helpful but do they have the patience waiting or even parsing their feedback?
HarHarVeryFunny 2 days ago||
Sure - the AI companies want some quick trophy kills to feature in their IPO prospectus, but they are not going to themselves be cracking the genuinely tough problems.

There is a difference between what's easy/hard for a human vs computer, and LLMs haven't changed that. You might expect a computer to be good at tasks requiring prodigious memory and compute, and it turns out that some of these long-standing math problems are of that nature - not requiring new breakthroughs but rather just massive exploration of what is already known and what they were trained on.

There will no doubt be more math results like this, but presumably also ones that are "hard for a human, easy for a computer", requiring massive search (e.g. find an example/counter-example cf Navier-Stokes & Jacobian conjecture) rather than creativity.

bonsai_spool 2 days ago||
It's inane, actually - I thought this might be something put on by an Allen Institute or some actually well-respected organization.
ak_111 2 days ago||
Not an expert, but as I understand from my colleagues you can make a case for lots of really important problems related to protein folding to be included in the list. As protein folding hasn't been nearly "solved" by alphafold as has been reported in many places.
thehamkercat 2 days ago||
> 02 - Cryopreservation

Demonstrate the ability to cryopreserve and recover live wild-type mice with high viability.

> 06 - Somatic limb regeneration

Demonstrate the ability to regenerate lost limbs in adult wild-type mice.

Interesting, but looks like these problems are proposed in September 2026, unlike original 7 Millennium Prize Problems of Maths

ginko 2 days ago||
> Demonstrate the ability to cryopreserve and recover live wild-type mice with high viability.

I thought we already managed to successfully cryopreserve and recover small rodents like hamsters in the 50s.

Edit: See https://en.wikipedia.org/wiki/Cryopreservation#History

Sharlin 2 days ago|||
Of course. This is just a list of someone's ideas for equivalently difficult (and transformative) unsolved problems in biology. Many of these would of course have obvious and immediately impactful practical applications, unlike the math problems.
DoctorOetker 2 days ago||
> ... This is just a list of someone's ideas for equivalently difficult (and transformative) unsolved problems in biology. ...

I think GP was saying the proof of the pudding is in the tasting: the longer a problem has provably resisted resolution the more difficult it is considered...

bombastically decorating a problem as equivalently difficult does not make it so.

Sharlin 2 days ago||
Well, if LLMs actually turn out to solve some of the Millennium problems, at least some of these biology problems are almost certainly at least as difficult. Certainly solving any of them would be Nobel-worthy if biology nobels existed (and solving some of them would likely easily be worthy of a medicine Nobel). It's not like these are new problems whose difficulty is unknown!
DoctorOetker 2 days ago||
The Millenium Prize problems didn't only withstand decades/century of resolution, they also withstood the same test of time in ridicule of the challenge statement.

This list of "Millenium Problems for Biology" contains such brainfart level "analogies" that there the list will be ridiculed, for the question / challenge itself displays a lack of understanding of the subject in question. Science is also asking the right questions.

Consider for example:

> 10. Protein Amplification Chain Reaction:

> Demonstrate exponential amplification of arbitrary peptide substrates.

> Specifically, demonstrate input-protein-dependent synthesis of new, full-length, sequence-faithful covalent polypeptide copies from amino-acid monomers without a nucleic-acid template or preformed cognate scaffold, in a single pot reaction. For the challenge to be considered complete, at least 100 random peptide sequences of at least 50 amino acids each must be preregistered, synthesized, and pooled. It must then be shown that the abundance of these peptides in solution can be amplified at least 1000x with at least 90% sequence accuracy on a per-residue basis. Reasonable modifications may be added to the peptide sequences to facilitate post-amplification analysis if necessary, provided they are not active in the amplification. Methods that rely on explicit sequencing of the peptide are not permitted. Methods that rely on reverse translation to generate a nucleic acid intermediate are not permitted, because they are duplicative with a separate Millennium Problem.

The analogy is very clear: to amplify DNA or RNA one uses PCR, basically throw the desired product in a cauldron with monomer building blocks, then by repeated heating and cooling the lone monomers find their permitted locations on a complementary pre-existing strand, and form the new polymer strand.

So it seems natural to ask for a generalization to protein polymers, except every biologist or chemist knows its nonsense: proteins don't have a complementary strand! You can't demand chemistry or physics to magically copy without a complementary template!

You may ask "but if that were true, how can we already have PCR for RNA?"

Well pretty simple: while this is done routinely, its only possible indirectly: convert the RNA to double-strand DNA, use PCR on this DNA and then convert the amplified DNA back to RNA!

The demand to not involve sequencing or the hypothetical reverse translatase from one of the other problem statements turns this one into a non-existence theorem, but the challenge doesn't describe a winner for demonstrating its impossibility!

I assure you that any chemist or biologist being asked why we dont have PCR for protein, will understand your lack of knowledge, and explain how PCR works, so that you understand that PCR was only possible because of the complementary strand!

This list will be ridiculed for being not even wrong.

gignico 2 days ago||
> 06 - Somatic limb regeneration

At least those things cannot be solved by just burning GPT tokens.

Mistletoe 2 days ago||
I’m going to be honest, I don’t know if improving Rubsico is possible. Nature has had every reason to and billions of years. It’s optimized as far as it can go and you either lose speed or specificity, I don’t think having both is possible.
dsign 2 days ago|
Your statement piked out my interest and I went searching for what Rubisco was. My prediction is that this particular one will be cracked out soon, and at around 2045, creating disgustingly efficient variants of RuBisCO along with other photosynthesis mechanisms will be AGIs’ hot hobby.

That there are no more efficient variations of it in nature just tells us that the local minimum is really deep and that natural evolution, as it is, can’t produce anything better, not even with a billion years and 10^30 organisms serving as a “brute force lab”. It’s also the kind of problem an AGI system would tackle for purely ideological reasons, i.e. to prove that it is superior to nature.

dnautics 2 days ago||
These are almost all so stupid. Written by people who clearly don't know their chemistry

Reverse translatase and protein amplification in particular.

How the fuck do you plan on selectively priming protein amplification. If you know ANY protein chemistry, you will know "the juice is not worth the squeeze" -- how would I exponentially amplify a protein? I'd do mass spec proteomics, synthesize the DNA, and express it.

Simply amazing that electrofixation is not on the list.

dnautics 2 days ago||
Which ones are not stupid?

Cryopreservation, even though I don't care much for it.

The rubisco one is sort of not dumb, but if you actually care about carbon fixation you'd just not bother using rubisco at all instead.

Programmable Proteases is fine.

Somatic regeneration is fine.

c1ccccc1 2 days ago||
I was going to comment to complain about those two as well!

Do you mean electrofixation of nitrogen? What level of biological involvement are you imagining? More like biology producing (some?) of the catalysts, or more like the entire reaction happening inside of cells?

dnautics 1 day ago||
Electrofixation of carbon. Build a bug with one of the alternate (non rubisco) pathways and pump electrons from the mains to turn CO2 into sugar
c1ccccc1 6 hours ago||
Oh, interesting, thanks. I got curious a while back about the whole "how do you attach wires to a bacteria?" thing, but didn't look into it too deeply. Do you have any takes?
hirako2000 2 days ago||
Oddly most of these challenges seem to seek to solve problems that would enable phenomenal business opportunities, that many biologists would find questionable.
hn3ufz62f7 2 days ago||
Agreeing on the model gap, the bit left out is that even human-to-human it breaks. Same drug, same dose, wildly different response depending on genotype and gut flora.
ferd 2 days ago||
Is inner-ear cell regeneration included in #06?
sajithdilshan 2 days ago||
Do we really have to solve these problems though? Why would anyone want to have an inferior bio limb when they can substitute it with a superior and easily repairable/upgradable mechanical limb? Granted that the artificial limbs we have right now are pretty basic, but wouldn’t it make sense to improve it rather than trying to grow new limbs?

Also if you think humans would ever become a space faring species, would it really make sense to stick to our carbon based biology or should we invest in transforming into silicon based beings

RamblingCTO 2 days ago|
You should really step outside more and touch some grass
alansaber 2 days ago||
"Your limb replacement technology is very good, but I believe humanity should transform into silicon-based beings, and so for that reason i'm out"- dragons den 2030
himinlomax 2 days ago|
It's missing an obvious one: morphogenesis.
kevlened 2 days ago|
That’s number 6: limb regeneration.
himinlomax 2 days ago||
No, morphogenesis is a more general problem and we know very little about it.
kevlened 2 days ago||
Agreed. Morphogenesis is more general. Limb regeneration is how morphogenesis is represented in this problem set.
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