All of Metacelsus's Comments + Replies

Thanks for your support! I really think you're making a great impact here.

I'm sorry to break this to you, but cloning requires live cells, not just DNA. This is one of the reasons why it's so hard to bring back the woolly mammoth. (The other reason is that it's really hard to do IVF on elephants.)

So if you want to make a clone, you'll need to do something like what I did (take cells and preserve them in liquid nitrogen).

Preserving the entire brain is much more difficult than preserving cells, and requires specialized equipment.

I don't know if targeted crossover is plausibly feasible.

It is definitely feasible. This is how artificial gene drives work.

So that's why you can't just make a human baby without knowing what you're doing: You stand a high risk of making a baby with developmental abnormalities that weren't severe enough to abort the fetus, but are severe enough that the child is suffering. If for some reason the moral consequences of that aren't enough to dissuade you, consider that other people would ban you and your children and your children's children and your artificial children and any similar research for 1000 years.

I cannot overemphasize this!

As a rough estimate, I think 3x to 5x more expensive. Marmosets are smaller (smaller than squirrels) whereas macaques (rhesus/cyno) are about 10x bigger (6 kg). And macaques take longer to develop (3 years vs. 18 months until adulthood). Finally, macaques are in high demand and low supply for pharma research.

But the benefit is that methods developed in macaques are more likely to translate to humans, due to the closer evolutionary relationship. Marmosets are a bit unusual in their embryonic development (two twin embryos share a common, fused placenta!) 
 

Unfortunately monkeys (specifically marmosets) are not cheap. To demonstrate germline transmission (the first step towards demonstrating safety in humans), Sergiy needs $4 million.

And marmosets are actually the cheapest monkey. (Also, as New World monkeys, marmosets are more distantly related to humans than rhesus or cynomolgus monkeys are.)

Ovelle, who is planning to use growth and transcription factors to replicate key parts of the environment in which eggs are produced rather than grow actual feeder cells to excrete those factors. If it works, this approach has the advantage of speed; it takes a long time to grow the feeder cells, so if you can bypass some of that you can make eggs more quickly. Based on some conversations I’ve had with one of the founders I think $50 million could probably accelerate progress by about a year.

A few comments on this:
1. The "feeder cells" you're discuss... (read more)

On the topic of SuperSOX and how it relates to making eggs from stem cells: 

The requirement for an existing embryo (to transfer the edited stem cells into) means that having an abundant source of eggs is important for this method, both for optimizing the method by screening many conditions, and for eventual use in the clinic.

So, in vitro oogenesis could play a key role here.

For both technologies, I think the main bottleneck right now is nonhuman primate facilities for testing.

Finally: we need to be sure not to cause another He Jiankui event (where an ... (read more)

I wouldn't say synthetic biology itself has been a bust. It's had lots of success in pharma (look at CAR-T, engineered antibodies, gene therapies, etc.) It's more like, "using synthetic biology to compete with low-margin petrochemicals" has been a bust.

I'm similarly pessimistic about meat produced in cell culture. It's very hard to compete on price with factory farming. (Stuff like Beyond / Impossible has better prospects though.)

Bottom line up front: with my rough DIY test setup I got 80% filtration with a long beard, 92% with a short one, and 99.7% with stubble.

As a different way of looking at it: a short beard lets 26.7x more particles past than stubble, and a long beard lets 66.7x more particles past.
 

>Mice lacking the Yap and Taz genes that control liver size have larger livers…but they also have liver cancers, and worse regeneration from liver injury.16 Similarly, mutant mice lacking Hippo signaling have unusually large livers that don’t stop growing when they hit the usual “maximal size”…but they also get lots of liver tumors not seen in wild-type mice.17

Notably, Yap and Taz are downstream mediators of Hippo signaling so these studies are looking at the same thing.

I guess the missile knows where it is

Well, actually the missile knows where it isn't.

Turns out that several of the main studies about cerebrolysin may have been fraudulent: https://www.science.org/content/article/research-misconduct-finding-neuroscientist-eliezer-masliah-papers-under-suspicion

A lot of "weird testis genes" are epigenetically silenced in somatic cells (for example, suppressed by DNA methylation), and this epigenetic control becomes defective in disease states, especially cancer. There are a whole category of "cancer/testis antigens," proteins which are usually expressed only in the testis but which are expressed in cancers like melanoma. There are currently cancer vaccine trials to target immune responses against these proteins (which might also cause male infertility but that's probably an acceptable tradeoff).

Maybe something similar is going on with LINC01609 in Alzheimer's.

Dietary vitamin A (beta carotene) is not the active form of vitamin A (retinoic acid), it needs to be converted into the active form by the body's enzymes. Once retinoic acid is formed, it can bind to the retinoic acid receptor and regulate gene expression.

Retinoid treatment bypasses these enzymes and directly activates retinoic acid receptor signaling. So, eating vitamin A in the form of beta carotene won't directly increase retinoic acid receptor signaling because the rate-limiting step is the enzymes, but retinoid treatment will. This is also why you can't overdose on vitamin A by eating carrots.

Does this meet your criteria for a good answer? If not I can explain in more detail.

Lastly, you shouldn’t use Retinoids if you’re pregnant or likely to become pregnant.

This needs more emphasis. Retinoid signaling is very important for embryonic development, so excess retinoids will really mess up your baby. 

I agree with this. There's a lot of snake oil out there and cerebrolysin is just one example. I had no idea it was so popular though.

200 mg/day is a pretty high dose (at least for me)

Not just mammals, as far as I know it only works in E. coli bacteria and not in any eukaryotes.

Source:

https://www.nature.com/articles/s41586-024-07552-4

Interestingly there was just a similar article in the news section of Science, about glacier geoengineering.

https://www.science.org/content/article/avoid-sea-level-rise-some-researchers-want-build-barriers-around-world-s-most

>I'm using Quaise Energy as an example of a much larger overall trend - of the inability of investors to effectively evaluate technologies. The ability of investors to recognize good technical evaluations is the key thing that's lacking in the economy today; there are plenty of good ideas and there's plenty of investment capital.

Yeah, just look at Varda "manufacture drugs in space," and Colossal "bring back the wooly mammoth." It just doesn't make sense for these to be profitable businesses.

Reposting a comment from the Substack:

>Recently, he solved this problem!

I'm flattered, but I actually haven't gotten all the way to haploid cells yet. As I wrote in my preprint and associated blog post, right now I can get the cells to initiate meiosis and progress about 3/4 of the way through it (specifically, to the pachytene stage). I'm still working on getting all the way to haploid cells and I have a few potentially promising approaches for this.

Very cool. I wonder which University of Missouri lab the lentiviral plasmid leaked from...

I went a few times but eventually got grossed out by all the mold. (At least they don't sell live pangolins there.)

At the time, one of the biggest problems in physics was the “Blackbody spectrum”, which describes the spectrum of electromagnetic wavelengths emitted by a Blackbody. The problem with it was that the emitted spectrum was not explainable by known physics. Einstein achieved a breakthrough by considering light not just as a wave, but also as light quanta. Although this idea sufficiently explained the Blackbody spectrum, physicists (at least almost) unanimously rejected it. The fight between the “light is corpuscles” and “light is a wave” faction had been decided a century ago, with a clear victory for the “wave” faction. 

I thought blackbody radiation was Planck, not Einstein.

Interestingly, many cancer "neoantigens" (for example, MAGEB1) are also expressed in meiotic cells in the testis. This is because they're usually epigenetically suppressed in healthy tissues, but cancer cells have messed up epigenomes. See: https://en.wikipedia.org/wiki/Cancer/testis_antigens

Also, I would disagree that synthesizing long polypeptides is easier than synthesizing long mRNAs. With polypeptides you have 20 amino acids to work with, and some require special treatment (protecting groups on sidechains). With mRNAs the chemistry is much simpler.

Testosterone will land you in more legal trouble than modafinil.

Compounding pharmacies are gray-market. (Buying on "evolutionpeptides.com" would be black-market.)

No mention of modafinil? It's quite useful for maintaining productivity on low amounts of sleep.

Semaglutide is the real-deal weight loss drug we have been praying for. It works well for 70%+ of people. Losing and keeping weight off is so difficult that prior to ozempic, it was reasonable advice to preach acceptance or extremely restricted diets. Prior to Semaglutide, I used to assume that most of my friends who wanted to lose weight would fail. Now I assume they will trivially succeed if they get on the drugs. Here is how to get on Semaglutide:

1. I purchased sema, for myself and others, on this site: https://evolutionpeptid

For biology, JoVE ("Journal of Visual Experiments") is a very good source of videos like this. https://www.jove.com/ Unfortunately it's paywalled.

I agree, I think the most likely version of the lab leak scenario does not involve an engineered virus. Personally I would say 60% chance zoonotic, 40% chance lab leak.

A commenter on my Substack got much better results using Claude 3 Opus.

>heats the water (adenosine diphosphate, ADP) to a closely related, higher-energy form (adenosine triphosphate, ATP), which is steam.

I would say protons are the steam, not the ATP/ADP. The electron transport chain "pressurizes" protons by pumping them, and then the protons flow through the ATP synthase "turbine".

I think the exact origin of SARS-CoV-2 is a largely irrelevant question. 

Given that it's plausible it could have come either from a wet market or risky biological research, we should shut down both.

(Personally I would say 60% "wet market", 40% "unintentional lab leak")

That make sense. If I were going for sarcasm I would have said Kary Mullis.

A Nobel-winning scientist like Gregg Semenza would obviously be the best possible expert

Funny you should say that . . .
https://retractionwatch.com/2023/10/02/nobel-prize-winner-gregg-semenza-tallies-tenth-retraction/
https://www.nature.com/articles/d41586-022-03032-9
 

Emmett Shear on college-level organic chemistry. His experience was that the class was composed of a mix of science track and premed track students. The science students are there to actually learn and retain the material, so even though it’s a massive amount of compounding facts you have to learn, they do fine. Whereas the premed students are happy to do the work, but are thinking of the class as a structural barrier rather than source of information, so they cram rather than retaining information, and then struggle. So it is a question of motivation. How

As a scientist I strongly agree. It seems like there's been a few steps towards this in recent years, for example with things like the Arc Institute or FROs. Hopefully this model gets the attention of government funders.

>I haven’t heard a “Polack joke” in years and I wouldn’t be surprised if the rising generation is mostly unaware that there ever was such a thing.

On the contrary, I heard one at an ACX meetup in Boston in summer 2023. I was not amused.

>I think it makes sense for some country with a high rate of alcohol flush reaction to legalize using 1-butanol or oxane as a substitute for ethanol in drinks served at bars and restaurants.

The only downside is that butanol tastes pretty awful.

I think it would be useful to examine cases where important patents for Input X expired and prices came down quickly, allowing Input X to be used to produce much more of Product Y.

That is very wrong. Diamond is hard to make with enzymes because they can't stabilize intermediates for adding carbons to diamond.

As a biochemist, I agree.

It does integrate into the genome. It's gene therapy, but not gene editing (which means editing an existing gene).

Consolidating my previous comments:

I discussed this project with GeneSmith and I think it is promising, though very challenging to implement in practice. The hardest part will be safely and efficiently delivering the editing agent to a large fraction of the cells in the brain.

Some other points:

CAR T-cell therapy, a treatment for certain types of cancer, requires the removal of white blood cells via IV, genetic modification of those cells outside the body, culturing of the modified cells, chemotherapy to kill off most of the remaining unmodified cells in th

CAR T-cell therapy, a treatment for certain types of cancer, requires the removal of white blood cells via IV, genetic modification of those cells outside the body, culturing of the modified cells, chemotherapy to kill off most of the remaining unmodified cells in the body, and reinjection of the genetically engineered ones. The price is  $500,000 to $1,000,000.

And it only modifies a single gene.

This makes it sound like CAR-T is gene editing, but it isn't. Instead of editing a gene, it introduces a new one (a chimeric T-cell receptor). Although some c... (read more)

There's also a lot of statistics that go into designing experiments (rather than analyzing them afterwards). For example, fractional factorial designs, or adaptive clinical trials