It's a good list, but "alignment" is much more targetted. I attended a workshop with researchers from OpenAI and Anthropic also present, where the objective was to hash out what the problems in alignment even are. This, it turned out, was extraordinarily difficult.
The problems with alignment are to do with how we define and search for this vague notion when it is mathematically ill-posed at present.
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.
Those don't have the property of being easily verified, which the problems proposed here do. I think that's a smart idea because it's a way to capture quick PR seeking AI-lab dollars for quite useful outcomes.
Being easily verifiable does not elevate something to the level of being a grand challenge. It really drives home the point that biology is not math or coding.
I guess to me the grandiosity here feels fake and unearned - like they vibe slopped it together without much input in the way of deep thought or expertise.
For example, synthesize arbitrary dna sequences > 3000 nt in length with error rate < 0.001 at > 95% purity. Easily verifiable, beyond the frontier, and generally useful.
I agree with you there are other much grander challenges, but apart from that I don't think the list is horrible, because as I said it's incentive-aligned with the current moment we are in. Your suggestion would definitely be a good addition to the list for sure.
I think some of the items on the list are also way less likely to be worked on (like cryogenics) than others, because they really require some heavy infrastructure to iterate. My money for which of these gets cracked with help of an AI would be rubisco, that can be quite effectively worked on in a closed loop lab fashion with a standard lab or CRO.
Biology is a really really big field. Many problems in biology are that of math and coding. Just as a simple example look at the golden ratio in living organisms. Biology follows a lot of different algorithms because they are energy efficient and come with massive secondary benefits.
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.
Everyone interested in biology and intelligence should look up Michaels work, it is amazing because he's ignored a lot of assumptions that are held by the community and come up with new and interesting tests.
Also his work on algorithmic intelligence in cells and the mathematical foundation of intelligence will change many fields, including AI, if it can be empirically tested.
> 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…
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.
> The petri dish differs from the rat differs from the human and that is a part of what makes biology harder to progress.
They all use DNA.
But I agree that nobody has shown in the lab how any of this leads to a genetic system that can self-reproduce reliably and assemble biomolecules/metabolites. This is a missing link. Just showing how RNA or amino acids arise, says nothing about any genetic system. They can not even answer whether RNA or DNA viruses existed first; and whether these existed before organisms/cells did.
I really really recommend looking up Michael Levins bio work on intelligence at the cellular and organ level.
His most recent work is starting to touch on some pretty far out concepts. And I should note, that he does not state they are true or not, but they are attempting to make empirical methods on testing them.
One of the concepts they are looking at is "math as an actual thing" and that some simple algorithms have new deeper behaviors that we're just finding now. The hypothesis is that over the eons life has probed mathematics at scales humanity cannot even begin to imagine and is exploiting this deep algorithmic efficiency in accomplishing any number of tasks. These algorithms could help explain the missing links.
I'd suggest starting with some of his older work to see they are a credentialed research scientist and not making up 'woo' whole cloth.
The goal of the suggested "origins of life" problem, as written, isn't to guess at history - it's to create some similar plausible self-emergent system in the lab.
Seems a bit of an ambitious goal for a language model though! There are presumably dozens of steps before you get to an RNA-based full-blown cell, and it's only been very recently that humans have managed to make an artificial self-replicating "cell" (container) of any type in the lab.
> 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
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.
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
"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
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.
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.
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.
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.
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.
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?
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.
There are certainly non engineering problems out there... For one example, in biomedicine it's known cancer in different organs can have preference of having immune hot (in skin and lung cancer, e.g.) and cold tumors (in pancreatic and prostate cancer, e.g.), and current immunotherapy work much less well on the latter. Why this pattern exists is still an open question very important for treating patients and it's not a how did nature engineer question as it's a unintended byproduct from several tiers of complex biology involving understanding mutational burden in tumor cells, immune surveillance surrounding the tumors, and mechanical structure of the tissue, etc. The engineering payoff comes later, i.e., immunotherapy works better on a particular subset of patients, after explaining and understanding the biological phenomenon first.
It seems that physics -> chemistry -> biology is a layering of abstractions and/or emergent phenomena, and any explanations of mechanics at these higher levels is more along the lines of "how was this built from these lego blocks" rather than being some more fundamental discovery.
You keep on making assertions - perhaps you could back it up with some explanation of why you regard this as a more fundamental discovery (or however you would like to characterize it)?
In a sense all experimental science has an element of engineering. For instance the first problem, "the origins of life" is framed to require an experiment to show that any proposed mechanism actually works.
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."
The Millennium Problems list in math was created in 2000, hence the name. There is a $1 million prize for solving any of the problems. Creating this list is just someone's idea of listing problems of equal importance. The name doesn't fit and it's just a 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.
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.
> 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.
It's a good list, but "alignment" is much more targetted. I attended a workshop with researchers from OpenAI and Anthropic also present, where the objective was to hash out what the problems in alignment even are. This, it turned out, was extraordinarily difficult.
The problems with alignment are to do with how we define and search for this vague notion when it is mathematically ill-posed at present.
I guess to me the grandiosity here feels fake and unearned - like they vibe slopped it together without much input in the way of deep thought or expertise.
For example, synthesize arbitrary dna sequences > 3000 nt in length with error rate < 0.001 at > 95% purity. Easily verifiable, beyond the frontier, and generally useful.
I think some of the items on the list are also way less likely to be worked on (like cryogenics) than others, because they really require some heavy infrastructure to iterate. My money for which of these gets cracked with help of an AI would be rubisco, that can be quite effectively worked on in a closed loop lab fashion with a standard lab or CRO.
Biology is a really really big field. Many problems in biology are that of math and coding. Just as a simple example look at the golden ratio in living organisms. Biology follows a lot of different algorithms because they are energy efficient and come with massive secondary benefits.
SMEs please correct the record if I'm mistaken.
Also his work on algorithmic intelligence in cells and the mathematical foundation of intelligence will change many fields, including AI, if it can be empirically tested.
There’s also this study [0] I read recently, along a different path of using known growth factors and proteins to kick off regeneration.
[0] https://www.nature.com/articles/s41467-026-72066-8
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…
still not all the way to something alive-like
I recently watched this video on the topic https://www.youtube.com/watch?v=OsXGgrXwllc
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.
They all use DNA.
But I agree that nobody has shown in the lab how any of this leads to a genetic system that can self-reproduce reliably and assemble biomolecules/metabolites. This is a missing link. Just showing how RNA or amino acids arise, says nothing about any genetic system. They can not even answer whether RNA or DNA viruses existed first; and whether these existed before organisms/cells did.
I really really recommend looking up Michael Levins bio work on intelligence at the cellular and organ level.
His most recent work is starting to touch on some pretty far out concepts. And I should note, that he does not state they are true or not, but they are attempting to make empirical methods on testing them.
One of the concepts they are looking at is "math as an actual thing" and that some simple algorithms have new deeper behaviors that we're just finding now. The hypothesis is that over the eons life has probed mathematics at scales humanity cannot even begin to imagine and is exploiting this deep algorithmic efficiency in accomplishing any number of tasks. These algorithms could help explain the missing links.
I'd suggest starting with some of his older work to see they are a credentialed research scientist and not making up 'woo' whole cloth.
Seems a bit of an ambitious goal for a language model though! There are presumably dozens of steps before you get to an RNA-based full-blown cell, and it's only been very recently that humans have managed to make an artificial self-replicating "cell" (container) of any type in the lab.
> 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
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
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
At least those things cannot be solved by just burning GPT tokens.
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
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.
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.
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.
EDISON SCIENTIFIC · FUTUREHOUSE
SAM RODRIQUES · MICHAELA HINKS
https://edisonscientific.com/team
It seems that understanding biology could be characterized as trying to figure out "how did nature engineer this".
For that matter isn't all of science this way?
You keep on making assertions - perhaps you could back it up with some explanation of why you regard this as a more fundamental discovery (or however you would like to characterize it)?
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."
Now you can enjoy one man-week of rage across the remainder of your life as you won't be able to unsee it. You're welcome
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.
> 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.