The Millennium Problems for Biology

Someone should make the millennium problems for AI alignment so the frontier labs will actually try to solve that problem.

Biology already has numerous “Millennium Problems” and the rewards are much more than $1M. For example, reverse Alzheimer’s Disease. Or less ambitious develop high fidelity in vitro and animal models of human disease.

It has not escaped my notice that a significant portion of these are of the form "Design a protein that..."

Its much harder to produce a good fundamental list of biology problems because we are no where near as far along, so many basic things are not understood. There are still many unknown unknowns and these particular problems are limited to the realm of verifiable in a lab, which rules out much of what makes biology interesting and hard to study, and that is the organisms themselves and the interactions between their cells. The petri dish differs from the rat differs from the human and that is a part of what makes biology harder to progress.

None of these is likely the root to the wide array of chronic illnesses we can't treat and those seem like the next step to really put a lot of research into given how many people suffer from them and where we are today they seem achievable with the right investment.

This is all well outside my area of expertise, but my impression is that Michael Levin's work with bioelectricity is on the cusp of #6 Somatic limb regeneration.

SMEs please correct the record if I'm mistaken.

> Demonstrate the emergence of life from chemical precursors in a laboratory setting

Wait, isn’t this an already solved problem? I remember in the 90s school books (material written in the 80s-70s likely) it was presented as “so and so did electric discharges in an atmospheric gas mixtures and they got organic molecules” therefore the origins of life is solved. I remember thinking how cool that was. I guess the “therefore” step was sort of a lie if it’s still an open problem…

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.

Wait a minute:

> Cryopreservation + Demonstrate the ability to cryopreserve and recover live wild-type mice with high viability. Specifically, demonstrate the reversible cryopreservation of live, intact, wild-type adult mice in a whole-body frozen or vitrified state. The mice must remain frozen or vitrified for at least 24 hours, must be recovered with >99% viability, and must not suffer any permanent organ damage or bodily harm. Somatic genetic engineering is discouraged but permitted. All experiments must be conducted with ethics approval.

This has been done in the 50ies, freezing and thawing mice with microwaves. IIRC the recovery rate was about 74% with no observed side effects. The research was given up on because in this specific case a mouse is a bad biological model. Thawing agents must scale cubically with size. The author says that at approximately the size of a cat you can’t quickly enough evaporate all the agent because the energy required will simply burn the tissue.

TLDR: it’s possible, it’s been done, it could be perfected if necessary, it does NOT scale beyond mice

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

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.

> 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

This is a collection of pet projects by folks who are not distinguished biologists. Interesting, maybe, but not to be placed on the same pedestal as the mathematics Millenium Prize of a similar name.

Arguably, the origin of life is a question for all time -- no way that a VC webpage is going to change whether someone takes that problem on, and it will be commercialized with big-name capitalists instead of 'FutureHouse' should it ever be developed in the lab.

It's missing some important stuff? Like creating bacteria that can produce fuels or break down plastics.

Slap an LLM on those and call it a day

Who is this by? Who verifies the result? Is there prize money?

It’s strange they are all engineering problems.

So anyone can create a list of problems and slap the name Millennium Problems on them?

It's missing an obvious one: morphogenesis.

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.

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.

> Demonstrate the emergence of life from chemical precursors in a laboratory setting.

> Specifically, demonstrate the unassisted emergence of self replicating RNA- and protein-based cells from a plausible primordial soup with a plausible energy source. A “cell” may be any compartment with a defined boundary.

So, right now, nobody can explain how life originated. Proving that aminoacids, DNA or RNA form, does NOT mean that this is equal to life. This is a problem that the whole field has - it still can not explain how life originated. Showing that individual components can arise spontaneously, is not the same as showing e. g. how a cell formed and so forth. Where does the encoding problem fit into any of that, for instance? You need to prove how you can assemble systems. Just having a working ribosome does not connect it to DNA as a genetic backup system; and RNA tends to be unstable. Even when you have assumptions how this works together, you need to prove that this is how things originate(d). Nobody has done so since decades. It is an unsolved problem.

is it yet another vibecoded website? akin to the poster discussion, all vibecoded websites do not need to look like the same, please put some care or taste in your prompts.

AI slop. next.

Edit: A true expert would never define a problem in such a sloppy way: "Specifically, the protein must convert N₂ to ammonia at rates that are at least of a similar order of magnitude to the rates of naturally occurring proteins, and must fall well below the sequence- and structure-similarity thresholds relative to all known nitrogenase and nitrogenase-like proteins. The protein may be designed de novo, discovered in nature, or engineered or evolved from naturally occurring starting points."