HedonicEscal8r

One of the leading problems is that we don't know how to pick the right neoantigens (mutant cancer proteins) which can trigger the optimal immune response.

Moderna used a simple heuristic, "how likely is this antigen to show up on the cell surface?" which makes sense, since an antigen has to show up on the cell surface for the immune system to see it. But there's so much missing from this model, and we just don't have enough data. Failures in clinical trials of mRNA vaccines may well be caused by this problem. (Yes, this is a good problem for AI, if we can get enough data).

Interjecting with a fact. Moderna described the neoantigen immunogenicity prediction algorithm they used to design the vaccines as “a deterministic machine learning (ML) algorithm,” so it may be a small neural network or more traditional algorithm, probably not deep learning.

Personalized mRNA vaccines are in fact, extremely new, and only made possible by recent advances across multiple fields. This comment reveals a total lack of basic understanding on this topic.

Yes, mRNA vaccines are promising for many but not all cancer types, and there are many ongoing clinical trials. There's also a lot we yet don't know about how to design them.

Here's a great blog post on this, "How to build a cancer vaccine, and whether they will work this time": https://www.owlposting.com/p/how-to-build-a-cancer-vaccine-a...

Here's the blog post I wrote on personalized mRNA vaccines: https://hedonicescalator.substack.com/p/did-paul-conyngham-r...

The night sky isn't dark. What you're looking for is cave darkness.

If you think of your screen is a big glowy box of noise that fails to contribute to a good, meaningful life, that's a problem! Put better things on your screen.

"Multiple controlled trials" is quite different from an under-the-table, privately funded bespoke therapy for a single patient.

If the kid's old enough to be hiding their internet history from their parents, they're old enough to have some privacy.

Not that I recommend being on 3-MMC at work, but it's just a matter of dosage. People take pharmaceutical doses of Adderall at work and 10x higher recreational doses at clubs.

The only common drugs that cause deadly withdrawals are alcohol and benzodiazepines. Opioid withdrawals are famously extremely unpleasant but not typically considered life-threatening.

"In experimental studies, the incidence of headache was 50% and the incidence of clinically significant distress or functional impairment was 13%."

That is by definition not what "outlier" means.

> Mentioning that they can't actually get pregnant, or impregnate someone, is taboo.

Don't know the context, but I don't think this is a "trans" thing. It is usually considered taboo to bring up someone's fertility or sexual issues, even if said issues are common knowledge.

> Disclaimer: I don't know any trans person IRL, so my perception is likely skewed by their loud online interactions.

As an exercise, pick any other minority group, and try to imagine forming an impression of them based solely on reading about the group in culture war arguments and online controversies. I know many trans people due to working in tech, living in California, and hanging out in (bio)hacking circles, and I can promise they are sane and normal people.

I agree that you should almost never offer amputations for BIID in minors, since delaying until adulthood would only risk a couple of years of distress and would not cause additional permanent harm.

If you think that a modal person who transitions does so because they don't understand what biological changes can be achieved* and/or because society doesn't accept them "as they are" enough, you are hopelessly confused about this entire topic.

*Note that a disagreement about whether currently available medical procedures constitute a "sex change" is almost always a dispute of semantics and not of fact. A trans woman who describes herself as having "changed her sex" is almost never claiming she can give birth.

I disagree with this, puberty blockers should be used sparingly and certainly should not be taken until adulthood. Can you imagine starting puberty at 18?

Trans children deserve to mature at the same time as their peers.

If you are 11 and wait 7 years to get a tattoo, your tattoo will look just as good or better.

If you are 11 and wait 7 years to transition, you will suffer irreversible physical and psychological damage. You will have missed formative social experiences. You will have to get expensive, painful surgeries to partially correct what was done to you.

> It’s literally irreversible damage when you mess up with hormones while on puberty.

This is equally true when you don't intervene. The children being recruited for this study would otherwise be forced to undergo physical changes that cause them severe psychological distress and would need to be surgically corrected in adulthood.

I think this is a failure of empathy. "Being unable to transition before a certain age" in this context entails a child having their body modified against their will, which they can only partially correct through expensive and avoidable surgeries in adulthood. It seems much worse than merely detransitioning to me.

Which is also wrong. People living with BIID are (usually) not irrational. The small percentage that do seek amputation have usually exhausted all treatment options, and find that amputation improves their quality of life.

Yes, tanning is downstream of the activity of the p53 tumor suppressor protein in response to UVB-induced damage: https://www.lesswrong.com/posts/EFiCGc3YwadZBzvZ3/contra-byr...

Surely you would not be confused by "Place the word Madagascar in a way that makes no sense."

1. While it's difficult to put a number on exactly what % of the time this is true, depression is not always, and I would say not often, a situational problem. For almost every depressed person, there's a happy person living the same lifestyle. For literally every happy person, there's a depressed person living the same lifestyle.

2. People with depression often have careers they care about and families they need to support. Even if leaving their lives behind worked, they wouldn't want to do that for the same reason you wouldn't.

Yup, and IP theft is morally good. Are we not on HackerNews?

I agree, sounds suspicious and likely misremembered.

She had Snijders Blok-Campeau syndrome, which is caused by mutations in the CHD3 protein, which manages the structure of DNA. In her case, it was this missense variant: https://www.ncbi.nlm.nih.gov/clinvar/variation/422607/

The severity of Snijders Blok-Campeau syndrome can vary, but it sounds like Mei only suffered from mild intellectual disability.

https://en.wikipedia.org/wiki/Snijders_Blok%E2%80%93Campeau_... https://www.nature.com/articles/s41586-026-10113-6

> May be such infusion would really serve as a vaccine prepping the immune system for the main infusion later?

This is correct and exactly the problem. You don't want the immune system to react to the virus, but giving it exposure to the virus will nearly guarantee a reaction. This is why they were checking that the patient didn't have antibodies already.

Here is an article discussing this issue: https://pmc.ncbi.nlm.nih.gov/articles/PMC10673641/

Malignant hyperthermia?

There are many children with life-threatening rare diseases that would be much better candidates for risky experimental treatment like this. Very sad case.

Fidji Simo didn't disclose what condition she suffers from. In 2025, she co-founded ChronicleBio, which aims to accelerate progress on POTS, ME/CFS, Long COVID, and other neuroimmune disorders.

Lots of people suffer from unexplained chronic illnesses - hopefully Simo is right that AI will enable better treatments.