My intuition is to get less excited by single projects (a Double Crux bot) until someone has brought them all together & created momentum behind some kind of “big” agglomeration of people + resources in the “neutrality tools” space.
sarahconstantin
Karma: 7,283
I didn’t know about all the existing projects and I appreciate the resource! Concrete >> vague in my book, I just didn’t actually know much about concrete examples.
links 11/15/2024: https://roamresearch.com/#/app/srcpublic/page/11-15-2024
https://www.reddit.com/r/self/comments/1gleyhg/people_like_me_are_the_reason_trump_won/ a moderate/swing-voter (Obama, Trump, Biden) explains why he voted for Trump this time around:
he thinks Kamala Harris was an “empty shell” and unlikable and he felt the campaign was manipulative and deceptive.
he didn’t like that she seemed to be a “DEI hire”, but doesn’t have a problem with black or female candidates generally, it’s just that he resents cynical demographic box-checking.
this is a coherent POV—he did vote for Obama, after all. and plenty of people are like “I want the best person regardless of demographics, not a person chosen for their demographics.”
hm. why doesn’t it seem natural to portray Obama as a “DEI hire”? his campaign made a bigger deal about race than Harris’s, and he was criticized a lot for inexperience.
One guess: it’s laughable to think Obama was chosen by anyone besides himself. He was not the Democratic Party’s anointed—that was Hillary. He’s clearly an ambitious guy who wanted to be president on his own initiative and beat the odds to get the nomination. He can’t be a “DEI hire” because he wasn’t a hire at all.
another guess: Obama is clearly smart, speaks/writes in complete sentences, and welcomes lots of media attention and talks about his policies, while Harris has a tendency towards word salad, interviews poorly, avoids discussing issues, etc.
another guess: everyone seems to reject the idea that people prefer male to female candidates, but I’m still really not sure there isn’t a gender effect! This is very vibes-based on my part, and apparently the data goes the other way, so very uncertain here.
https://trevorklee.substack.com/p/if-langurs-can-drink-seawater-can Trevor Klee on adaptations for drinking seawater
links 9/14/2024: https://roamresearch.com/#/app/srcpublic/page/11-14-2024
https://archive.org/details/byte-magazine retro magazines
https://www.ribbonfarm.com/2019/09/17/weirding-diary-10/#more-6737 Venkatesh Rao on the fall of the MIT Media Lab
this stung a bit!
i have tended to think that the stuff with “intellectual-glamour” or “visionary” branding is actually pretty close to on-target. not always right, of course, often overhyped, but often still underinvested in even despite being highly hyped.
(a surprising number of famous scientists are starved for funding. a surprising number of inventions featured on TED, NYT, etc were never given resources to scale.)
I also am literally unconvinced that “Europe’s kindergarten” was less sophisticated than our own time! but it seems like a fine debate to have at leisure, not totally sure how it would play out.
he’s basically been proven right that energy has moved “underground” but that’s not a mode i can work very effectively in. if you have to be invited to participate, well, it’s probably not going to happen for me.
at the institutional level, he’s probably right that it’s wise to prepare for bad times and not get complacent. again, this was 2019; a lot of the bad times came later. i miss the good times; i want to believe they’ll come again.
Neutrality
links 11/13/2024: https://roamresearch.com/#/app/srcpublic/page/11-13-2024
https://amaranth.foundation/bottlenecks-of-aging the Amaranth Foundation’s bottlenecks of aging
https://www.celinehh.com/aging-field Celine Halioua on what the aging field needs—notably, more biotech companies that are prepared to run their own clinical trials specifically for aging-related endpoints.
a typical new biotech company never runs its own clinical trials—they license, partner, or get bought by pharma. but pharma’s not that into aging (yet) and nobody really has expertise in running aging-focused clinical trials, so that may need to happen first in a startup context. which means some investors have to be willing to put up more cash than usual....
https://en.wikipedia.org/wiki/Rapid_eye_movement_sleep_behavior_disorder is the rare sleep disorder that almost always progresses to Parkinson’s about 20 years later
https://pubmed.ncbi.nlm.nih.gov/12208347/ lipofuscin = cross-links.
it’s a “brown-yellow” pigmented substance (first observed under the microscope in the 19th century) that accumulates in post-mitotic cells with age.
it’s not one substance; it’s a mixture of “garbage” (mostly protein and lipid) that accumulates around the lysosome but can’t be disposed of through exocytosis.
it’s “autofluorescent”—it fluoresces in various wavelengths of light without being stained.
it accumulates more under conditions of oxidative stress like high-oxygen environments or in the presence of iron (which catalyzes oxidation reactions); it accumulates less in the presence of antioxidants and under caloric restriction.
evidence that lipofuscin accumulation causes disease or dysfunction seems a lot shakier in this paper.
https://barnacles.substack.com/p/understanding-as-an-art Laura Deming on visualization and the spiritual side of science
I was a little self-conscious about her dissatisfaction with “San Francisco courtier culture”—of course she’s much better at the hustle than I ever was, but I actually love it. If anything, I’ve more often felt hurt that so many people I know got sick of the game before I ever really figured out how to play it.
https://genomebiology.biomedcentral.com/articles/10.1186/s13059-019-1824-y some critiques of methylation clocks; the first one actually seems to have been an artifact of different distributions of cell types between old and young samples.
https://www.science.org/content/article/scientific-showdown-seeks-biological-clock-best-tracks-aging a contest for the best aging clock at predicting future mortality.
https://www.exactsciences.com/ cancer prognostic/diagnostic biomarker company
https://arxiv.org/abs/2411.04872 Epoch AI’s new math benchmark of original, very hard problems
https://arxiv.org/abs/2406.08467 a new benchmark for formal verification “hint” generation in the Dafny programming language
https://dafny.org/ ”Dafny is a verification-aware programming language that has native support for recording specifications and is equipped with a static program verifier.”
Dafny’s formal verification is based on automated SMT solvers; compared to proof assistants like Coq/Lean/etc it’s less powerful
Dafny can be compiled to familiar languages such as such as C#, Java, JavaScript, Go and Python
https://www.reddit.com/r/rust/comments/1fs12l9/what_do_you_rustaceans_think_of_dafny_language/ Rust users don’t think Dafny is practical for programming “real” things in.
https://manifund.org/projects/hire-a-dev-to-finish-and-launch-our-dating-site Shreeda Segan’s OKC-clone dating site needs $10,000 to build an MVP
https://en.m.wikipedia.org/wiki/Eubulides the guy who brought you lists of paradoxes
https://en.m.wikipedia.org/wiki/Epimenides_paradox “Epimenides the Cretan says, all Cretans are liars”
as my 6-year-old son Simon pointed out, this is not actually a paradox; to be a “liar” doesn’t mean every statement you utter is a lie.
Epimenides himself didn’t intend it to be a paradox. Apparently he disagreed with his fellow Cretans about the immortality of the god Zeus.
They fashioned a tomb for thee, O holy and high one
The Cretans, always liars, evil beasts, idle bellies!
But thou art not dead: thou livest and abidest forever,
For in thee we live and move and have our being.
— Epimenides, Cretica
Wikipedia seems to trace the idea that this is a “paradox” to Bertrand Russell.
https://en.m.wikipedia.org/wiki/Peter_the_Great
this is really badly written for a Wikipedia page. i suspect some kind of nationalist vandalism.
https://en.wikipedia.org/wiki/Russian_conquest_of_Siberia most of the conquest of Siberia actually happened before Peter the Great
https://en.wikipedia.org/wiki/Yermak_Timofeyevich the Cossack ataman who began the conquest of Siberia, under the reign of Ivan the Terrible in the 1500s.
why conquer Siberia? the fur trade.
why did it work? the khans didn’t have firearms.
he was hired by a powerful merchant family, the Stroganovs
wow. this is a very close parallel (and historically contemporaneous) with the conquistadors and privateers of England, Spain, and Portugl in the Age of Exploration...except we don’t make movies and novels about it in the West. But the swashbuckling potential is amazing.
i mean there was also genocide, to be fair.
https://daviddfriedman.substack.com/p/libertarian-poems
I’ll kind of give him Kipling and Cummings; those are genuine anti-communist, anti-monarchical-absolutism, and anti-war sentiments. Yeats is doing a different thing; I love him but he is Not Our Friend.
https://www.pewresearch.org/short-reads/2024/10/24/majority-of-americans-arent-confident-in-the-safety-and-reliability-of-cryptocurrency/ wow—a full 17% of Americans have ever owned crypto.
I agree that more people should be starting revenue-funded/bootstrapped businesses (including ones enabled by software/technology).
The meme is that if you’re starting a tech company, it’s going to be a VC-funded startup. This is, I think, a meme put out by VCs themselves, including Paul Graham/YCombinator, and it conflates new software projects and businesses generally with a specific kind of business model called the “tech startup”.
Not every project worth doing should be a business (some should be hobbies or donation-funded) and not every business worth doing should be a VC-funded startup (some should be bootstrapped and grow from sales revenue.)
The VC startup business model requires rapid growth and expects 30x returns over a roughly 5-10 year time horizon. That simply doesn’t include every project worth doing. Some businesses are viable but are simply not likely to grow that much or that fast; some projects shouldn’t be expected to be profitable at all and need philanthropic support.
I think the narrative that “tech startups are where innovation happens” is...badly incomplete, but still a hell of a lot more correct than “tech startups are net destructive”.
Think about new technologies; then think about where they were developed. That process can ever happen end-to-end within a startup, but more often I think innovative startups are founded around IP developed while the founders were in academia; or the startup found a new use for open-source tools or tools developed within big companies. There simply isn’t time to solve particularly hard technical problems if you have to get to profitability and 30x growth in 5 years. The startup format is primarily designed for finding product-market fit—i.e. putting together existing technologies, packaging them as a “product” with a narrative about what and who it’s for, and tweaking it until you find a context where people will pay for the product, and then making the whole thing bigger and bigger. You can do that in 5 years. But no, you can’t do literally all of society’s technological innovation within that narrow context!
(Part of the issue is that we still technically count very big tech companies as “startups” and they certainly qualify as “Silicon Valley”, so if you conflate all of “tech” into one big blob it includes the kind of big engineering-heavy companies that have R&D departments with long time horizons. Is OpenAI a “tech startup”? Sure, in that it’s a recently founded technology company. But it is under very different financial constraints from a YC startup.)
neutrality (notes towards a blog post): https://roamresearch.com/#/app/srcpublic/page/Ql9YwmLas
“neutrality is impossible” is sort-of-true, actually, but not a reason to give up.
even a “neutral” college class (let’s say a standard algorithms & data structures CS class) is non-neutral relative to certain beliefs
some people object to the structure of universities and their classes to begin with;
some people may object on philosophical grounds to concepts that are unquestionably “standard” within a field like computer science.
some people may think “apolitical” education is itself unacceptable.
to consider a certain set of topics “political” and not mention them in the classroom is, implicitly, to believe that it is not urgent to resolve or act on those issues (at least in a classroom context), and therefore it implies some degree of acceptance of the default state of those issues.
our “neutral” CS class is implicitly taking a stand on certain things and in conflict with certain conceivable views. but, there’s a wide range of views, including (I think) the vast majority of the actual views of relevant parties like students and faculty, that will find nothing to object to in the class.
we need to think about neutrality in more relative terms:
what rule are you using, and what things are you claiming it will be neutral between?
what is neutrality anyway and when/why do you want it?
neutrality is a type of tactic for establishing cooperation between different entities.
one way (not the only way) to get all parties to cooperate willingly is to promise they will be treated equally.
this is most important when there is actual uncertainty about the balance of power.
eg the Dutch Republic was the first European polity to establish laws of religious tolerance, because it happened to be roughly evenly divided between multiple religions and needed to unite to win its independence.
a system is neutral towards things when it treats them the same.
there lots of ways to treat things the same:
“none of these things belong here”
eg no religion in “public” or “secular” spaces
is the “public secular space” the street? no-hijab rules?
or is it the government? no 10 Commandments in the courthouse?
“each of these things should get equal treatment”
eg Fairness Doctrine
“we will take no sides between these things; how they succeed or fail is up to you”
e.g. “marketplace of ideas”, “colorblindness”
one can always ask, about any attempt at procedural neutrality:
what things does it promise to be neutral between?
are those the right or relevant things to be neutral on?
to what degree, and with what certainty, does this procedure produce neutrality?
is it robust to being intentionally subverted?
here and now, what kind of neutrality do we want?
thanks to the Internet, we can read and see all sorts of opinions from all over the world. a wider array of worldviews are plausible/relevant/worth-considering than ever before. it’s harder to get “on the same page” with people because they may have come from very different informational backgrounds.
even tribes are fragmented. even people very similar to one another can struggle to synch up and collaborate, except in lowest-common-denominator ways that aren’t very productive.
narrowing things down to US politics, no political tribe or ideology is anywhere close to a secure monopoly. nor are “tribes” united internally.
we have relied, until now, on a deep reserve of “normality”—apolitical, even apathetic, Just The Way Things Are. In the US that means, people go to work at their jobs and get paid for it and have fun in their free time. 90′s sitcom style.
there’s still more “normality” out there than culture warriors tend to believe, but it’s fragile. As soon as somebody asks “why is this the way things are?” unexamined normality vanishes.
to the extent that the “normal” of the recent past was functional, this is a troubling development...but in general the operation of the mind is a good thing!
we just have more rapid and broader idea propagation now.
why did “open borders” and “abolish the police” and “UBI” take off recently? because these are simple ideas with intuitive appeal. some % of people will think “that makes sense, that sounds good” once they hear of them. and now, way more people are hearing those kinds of ideas.
when unexamined normality declines, conscious neutrality may become more important.
conscious neutrality for the present day needs to be aware of the wide range of what people actually believe today, and avoid the naive Panglossianism of early web 2.0.
many people believe things you think are “crazy”.
“democratization” may lead to the most popular ideas being hateful, trashy, or utterly bonkers.
on the other hand, depending on what you’re trying to get done, you may very well need to collaborate with allies, or serve populations, whose views are well outside your comfort zone.
neutrality has things to offer:
a way to build trust with people very different from yourself, without compromising your own convictions;
“I don’t agree with you on A, but you and I both value B, so I promise to do my best at B and we’ll leave A out of it altogether”
a way to reconstruct some of the best things about our “unexamined normality” and place them on a firmer foundation so they won’t disappear as soon as someone asks “why?”
a “system of the world” is the framework of your neutrality: aka it’s what you’re not neutral about.
eg:
“melting pot” multiculturalism is neutral between cultures, but does believe that they should mostly be cosmetic forms of diversity (national costumes and ethnic foods) while more important things are “universal” and shared.
democratic norms are neutral about who will win, but not that majority vote should determine the winner.
scientific norms are neutral about which disputed claims will turn out to be true, but not on what sorts of processes and properties make claims credible, and not about certain well-established beliefs
right now our system-of-the-world is weak.
a lot of it is literally decided by software affordances. what the app lets you do is what there is.
there’s a lot that’s healthy and praiseworthy about software companies and their culture, especially 10-20 years ago. but they were never prepared for that responsibility!
a stronger system-of-the-world isn’t dogmatism or naivety.
were intellectuals of the 20th, the 19th, or the 18th centuries childish because they had more explicit shared assumptions than we do? I don’t think so.
we may no longer consider some of their frameworks to be true
but having a substantive framework at all clearly isn’t incompatible with thinking independently, recognizing that people are flawed, or being open to changing your mind.
“hedgehogs” or “eternalists” are just people who consider some things definitely true.
it doesn’t mean they came to those beliefs through “blind faith” or have never questioned them.
it also doesn’t mean they can’t recognize uncertainty about things that aren’t foundational beliefs.
operating within a strongly-held, assumed-shared worldview can be functional for making collaborative progress, at least when that worldview isn’t too incompatible with reality.
mathematics was “non-rigorous”, by modern standards, until the early 20th century; and much of today’s mathematics will be considered “non-rigorous” if machine-verified proofs ever become the norm. but people were still able to do mathematics in centuries past, most of which we still consider true.
the fact that you can generate a more general framework, within which the old framework was a special case; or in which the old framework was an unprincipled assumption of the world being “nicely behaved” in some sense; does not mean that the old framework was not fruitful for learning true things.
sometimes, taking for granted an assumption that’s not literally always true (but is true mostly, more-or-less, or in the practically relevant cases) can even be more fruitful than a more radically skeptical and general view.
an *intellectual* system-of-the-world is the framework we want to use for the “republic of letters”, the sub-community of people who communicate with each other in a single conversational web and value learning and truth.
that community expanded with the printing press and again with the internet.
it is radically diverse in opinion.
it is not literally universal. not everybody likes to read and write; not everybody is curious or creative. a lot of the “most interesting people in the world” influence each other.
everybody in the old “blogosphere” was, fundamentally, the same sort of person, despite our constant arguments with each other; and not a common sort of person in the broader population; and we have turned out to be more influential than we have ever been willing to admit.
but I do think of it as a pretty big and growing tent, not confined to 300 geniuses or anything like that.
“The” conversation—the world’s symbolic information and its technological infrastructure—is something anybody can contribute to, but of course some contribute more than others.
I think the right boundary to draw is around “power users”—people who participate in that network heavily rather than occasionally.
e.g. not all academics are great innovators, but pretty much all of them are “power users” and “active contributors” to the world’s informational web.
I’m definitely a power user; I expect a lot of my readers are as well.
what do we need to not be neutral about in this context? what belongs in an intellectual system-of-the-world?
another way of asking this question: about what premises are you willing to say, not just for yourself but for the whole world and for your children’s children, “if you don’t accept this premise then I don’t care to speak to you or hear from you, forever?”
clearly that’s a high standard!
I have many values differences with, say, the author of the Epic of Gilgamesh, but I still want to read it. And I want lots of other people to be able to read it! I do not want the mind that created it to be blotted out of memory.
that’s the level of minimal shared values we’re talking about here. What do we have in common with everyone who has an interest in maintaining and extending humanity’s collective record of thought?
lack of barriers to entry is not enough.
the old Web 2.0 idea was “allow everyone to communicate with everyone else, with equal affordances.” This is a kind of “neutrality”—every user account starts out exactly the same, and anybody can make an account.
I think that’s still an underrated principle. “literally anybody can speak to anybody else who wants to listen” was an invention that created a lot of valuable affordances. we forget how painfully scarce information was when that wasn’t true!
the problem is that an information system only works when a user can find the information they seek. And in many cases, what the user is seeking is true information.
mechanisms intended to make high quality information (reliable, accurate, credible, complete, etc) preferentially discoverable, are also necessary
but they shouldn’t just recapitulate potentially-biased gatekeeping.
we want evaluative systems that, at least a priori, an ancient Sumerian could look at and say “yep, sounds fair”, even if the Sumerian wouldn’t like the “truths” that come out on top in those systems.
we really can’t be parochial here. social media companies “patched” the problem of misinformation with opaque, partisan side-taking, and they suffered for it.
how “meta” do we have to get about determining what counts as reliable or valid? well, more meta than just picking a winning side in an ongoing political dispute, that’s for sure.
probably also more “meta” than handpicking certain sources as trustworthy, the way Wikipedia does.
if we want to preserve and extend knowledge, the “republic of letters” needs intentional stewardship of the world’s information, including serious attempts at neutrality.
perceived bias, of course, turns people away from information sources.
nostalgia for unexamined normality—“just be neutral, y’know, like we were when I was young”—is not a credible offer to people who have already found your nostalgic “normal” wanting.
rigorous neutrality tactics—“we have so structured this system so that it is impossible for anyone to tamper with it in a biased fashion”—are better.
this points towards protocols.
h/t Venkatesh Rao
think: zero-knowledge proofs, formal verification, prediction markets, mechanism design, crypto-flavored governance schemes, LLM-enabled argument mapping, AI mechanistic-interpretability and “showing its work”, etc
getting fancy with the technology here often seems premature when the “public” doesn’t even want neutrality; but I don’t think it actually is.
people don’t know they want the things that don’t yet exist.
the people interested in developing “provably”, “rigorously”, “demonstrably” impartial systems are exactly the people you want to attract first, because they care the most.
getting it right matters.
a poorly executed attempt either fizzles instantly; or it catches on but its underlying flaws start to make it actively harmful once it’s widely culturally influential.
OTOH, premature disputes on technology and methods are undesirable.
remember there aren’t very many of you/us. that is:
pretty much everybody who wants to build rigorous neutrality, no matter why they want it or how they want to implement it, is a potential ally here.
the simple fact of wanting to build a “better” world that doesn’t yet exist is a commonality, not to be taken for granted. most people don’t do this at all.
the “softer” side, mutual support and collegiality, are especially important to people whose dreams are very far from fruition. people in this situation are unusually prone to both burnout and schism. be warm and encouraging; it helps keep dreams alive.
also, the whole “neutrality” thing is a sham if we can’t even engage with collaborators with different views and cultural styles.
also, “there aren’t very many of us” in the sense that none of these envisioned new products/tools/institutions are really off the ground yet, and the default outcome is that none of them get there.
you are playing in a sandbox. the goal is to eventually get out of the sandbox.
you will need to accumulate talent, ideas, resources, and vibe-momentum. right now these are scarce, or scattered; they need to be assembled.
be realistic about influence.
count how many people are at the conference or whatever. how many readers. how many users. how many dollars. in absolute terms it probably isn’t much. don’t get pretentious about a “movement”, “community”, or “industry” before it’s shown appreciable results.
the “adjacent possible” people to get involved aren’t the general public, they’re the closest people in your social/communication graph who aren’t yet participating. why aren’t they part of the thing? (or why don’t you feel comfortable going to them?) what would you need to change to satisfy the people you actually know?
this is a better framing than speculating about mass appeal.
Shreeda Segan is working on building it, as a cashflow business. they need $10K to get to the MVP. https://manifund.org/projects/hire-a-dev-to-finish-and-launch-our-dating-site
Bigger Livers?
links 11/08/2024: https://roamresearch.com/#/app/srcpublic/page/11-08-2024
https://agingbiotech.info/about/ a database of aging biotech companies compiled by Karl Pfleger
https://longevitylist.com/longevity-industry-database/ a database of aging biotech companies compiled by Nathan Cheng, includes somewhat different picks
GLP-1 receptor agonist drugs reduce all-cause mortality—so what diseases or causes of death do they prevent?
https://www.nature.com/articles/s41467-024-50199-y kidney disease (in type-2 diabetes patients with kidney disease)
https://www.ajmc.com/view/glp-1s-reduce-cardiovascular-risk-equally-in-patients-with-overweight-obesity-regardless-of-diabetes cardiovascular disease (in overweight or obese patients)
https://www.science.org/doi/10.1126/science.adn4128 (sadly I couldn’t find the full article)
https://www.ingentaconnect.com/content/ben/cdr/2018/00000014/00000003/art00008 cardiovascular disease (in diabetics)
https://wonder.cdc.gov/controller/datarequest/D176;jsessionid=C53D7110417D14C262ECD70F0091 what are the leading causes of death in 2023?
heart disease, cancer, accidents, stroke, COPD, Alzheimer’s, diabetes, kidney disease, liver disease, COVID-19, suicide, influenza & pneumonia, hypertension, septicemia, Parkinson’s
surprised suicide was so high and that COVID-19 was still so deadly (I assume mostly in the elderly)
I forgot that Sam Altman invested in Retro Bio
the man has good taste. like, it’s not blindingly original to appreciate Retro, but it is eminently reasonable.
there’s a lot of moderate-Democrat post-election resignation to the effect of “this is what the country wanted; the median voter is in fact pretty OK with Trump” and “the progressive apparatus was more interested in staying in its comfort zone than winning elections”
https://substack.com/home/post/p-151278372 Jesse Singal
he was saying similar things all along: https://jessesingal.substack.com/p/democrats-should-acknowledge-reality
I’m also seeing a fair number of women going “ok, sure, there are things to criticize about feminist dogma, but actually I have experienced traditionalist religious mores and they were Not Good”, which I think is a needed corrective these days
https://substack.com/home/post/p-141175575 here’s Audrey Horne
https://backofmind.substack.com/p/incompetence-is-a-form-of-bias Dan Davies says incompetence is a form of bias—the people who have the social skills and clout to get their problems fixed, will.
Dan Davies on politics and populism...i’m not sure where he’s going here but this is intriguing.
https://esmeralda.org/ Esmerelda, Devon Zeugel’s Chautauqua-inspired village in California
links 11/07/2024: https://roamresearch.com/#/app/srcpublic/page/11-07-2024
on Donna Karan
https://du42p.r.a.d.sendibm1.com/mk/mr/sh/1f8JAEjGcfF85pENVqcuM6hh5D/tiVMw3KFimvC?fbclid=IwY2xjawGZnpRleHRuA2FlbQIxMQABHdHszEMzS3x1Xda2tTh60KMighJEJKDe30rsduQmFydSSyfTpK8mwG50vg_aem_IjjUQWdiwZf2AdgdLo9azA opinion on how hormonal contraception should be done differently—I’m intrigued but I haven’t yet checked these claims out
http://esr.ibiblio.org/?p=8720 Eric S. Raymond on “user stories” done right and wrong
https://endpts.com/biotech-industry-worries-over-potential-for-rfk-jr-ally-as-fda-pick/ Casey Means has been floated as the new pick for FDA head; apparently she’s expressed concerns about vaccines and over-medication on the Joe Rogan podcast and has written a book about how most chronic diseases can be prevented by healthy lifestyles (which probably overstates the case)
https://www.slowboring.com/p/the-tyranny-of-climate-targets Matt Yglesias on why a lot of aggressive climate targets are impossible to actually meet.
why do people try anyway? if it’s “cheap talk”, why is there so much costly, substantive follow-through? incentive misalignment, I suppose?
https://www.gordian.bio/blog/the-in-vivo-screening-revolution/ Martin Borch Jensen on in-vivo screening
links 11/6/2024: https://roamresearch.com/#/app/srcpublic/page/11-06-2024
this taught me the phrase “mishap pilot”
https://pmc.ncbi.nlm.nih.gov/articles/PMC5656536/ this is measles virus used against relapsed multiple myeloma; one complete response out of 32 patients.
https://www.nature.com/articles/s41375-020-0828-7.pdf the one patient with the CR had strong T-cell responses to measles virus proteins. suggests that when this works it’s via immune response.
https://ajronline.org/doi/pdf/10.2214/AJR.09.3672 it works on mouse pancreatic cancer
https://ascopubs.org/doi/abs/10.1200/JCO.2022.40.6_suppl.509 seems to be able to treat bladder cancer?
https://pmc.ncbi.nlm.nih.gov/articles/PMC3018921/ blocks medulloblastoma growth in mice
https://en.wikipedia.org/wiki/CD46 the receptor for measles virus is also frequently expressed by cancer cells
https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2023.1095219/full targeting CDKs in sarcomas—there are some clinical trials happening
https://ascopubs.org/doi/abs/10.1200/PO.24.00219 palcociclib: one partial response out of 42 sarcoma patients
https://aacrjournals.org/clincancerres/article/29/17/3484/728559 suggestive in-vitro/animal evidence
targeting FGFRs in advanced solid tumors with FGFR mutations/overexpression: https://dial.uclouvain.be/pr/boreal/object/boreal%3A285422/datastream/PDF_01/view
3% complete response, 25% partial response with erdafitinib
https://pmc.ncbi.nlm.nih.gov/articles/PMC8231807/ FGFR inhibitors are typically toxic
MPNSTs cluster into two distinct types of genomic alteration with different drug vulnerabilities https://www.nature.com/articles/s41467-023-38432-6.pdf
targeting MDM2 in advanced solid tumors: there’s a trial. https://clinicaltrials.gov/study/NCT03611868
https://ascopubs.org/doi/10.1200/JCO.2022.40.16_suppl.9517 2 complete responses in melanoma, 1 PR each in liposarcoma, urothelial, and NSCLC, but none in MPNST.
http://www.annclinlabsci.org/content/46/6/627.full it’s being explored as a target in cancer
https://www.sciencedirect.com/science/article/abs/pii/S0959804920313228 21% partial response in soft tissue sarcoma to a XPO1 inhibitor + chemo
review article on XPO1 inhibition https://www.nature.com/articles/s41571-020-00442-4
https://www.centauri-dreams.org/2024/11/05/vegas-puzzling-disk/ the star Vega looks like it has a disc but no planets
https://www.nature.com/articles/s41598-024-58899-7 CD74 in cancer is an indicator for M1 macrophage infiltration, across cancer types
https://bibliome.ai/ is a resource for looking up specific genome variants and their references in the literature and open-access databases.
when i click through to references they’re often inaccurate (they are claimed to reference a variant that they do not, in fact, contain) but tbh this is also true of Google Search and Google Scholar when it comes to rare variants.
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links 11/05/2024: https://roamresearch.com/#/app/srcpublic/page/11-05-2024
https://en.wikipedia.org/wiki/IMM-101 a heat-killed bacterial preparation that might actually work (with chemo) for metastatic pancreatic cancer?
https://www.annalsofoncology.org/article/S0923-7534(19)64297-3/fulltext not bad in metastatic melanoma either
https://ascopubs.org/doi/10.1200/JCO.2022.40.16_suppl.9554 melanoma: 18% CR in treatment-naive patients when combined with nivolumab. (meh, nivolumab alone is comparable)
https://pmc.ncbi.nlm.nih.gov/articles/PMC4731256/ this is one patient, but it’s metastatic pancreatic cancer, this is super hard mode
made by these guys. https://www.immodulon.com/about-us/ they don’t look crazypants
https://en.wikipedia.org/wiki/Measles_virus_encoding_the_human_thyroidal_sodium_iodide_symporter measles virus can be made oncolytic!
https://www.nature.com/articles/s41591-021-01544-x peptide vaccines have a terrible track record overall but this one (on metastatic melanoma, combined with nivolumab) looks good
https://www.nobelprize.org/prizes/medicine/2018/summary/ James Allison and Tasuku Honjo got the Nobel Prize for discovering the immune checkpoints CTLA4 and PD1 respectively
https://www.nature.com/articles/s41562-017-0055 Carl Hart argues against viewing addiction as a “brain disease”:
we have not found a physiological difference between the brains of addicts and non-addicts
people are more likely to get addicted to drugs when their lives are terrible; only focusing on biomedical angles on tackling drug addiction means that it’s not considered “real” drug-addiction work to try to improve underlying social problems like poverty or injustice
in particular drug-war policies are often part of the problem, and biomedical addiction research can’t critique laws
https://www.science.org/doi/abs/10.1126/science.abb5920 this one didn’t make the cutoff for my success-story post (only 1/10 patients had a CR) but it’s astonishing that it does anything at all; a fecal matter transplant resulted in a complete response (and two partial responses) upon reintroduction of PD1 immunotherapy, in metastatic melanoma patients who had failed it before.
i am so disillusioned with FMTs that i might still chalk this up to a fluke, but who knows
https://en.wikipedia.org/wiki/Imiquimod is a weird, weird drug, used for genital warts and cutaneous cancers.
it’s a TLR7 activator.
(more innate immune stuff!!)
sarah do you just like the innate immune system because it’s comprehensible? yes. yes i do. and you should too.
https://jamanetwork.com/journals/jamaoncology/fullarticle/2598488 works on cutaneous breast cancer metastatses.
note that it is TOPICAL.
really high complete response rates in metastatic cancers almost only occur when you have a topical/intratumoral/etc treatment physically localized to the tumor, frequently using an innate-immune mechanism.
that’s also the literal majority of all historical cases of spontaneous tumor regressions—they tend to happen when there’s an infection at the tumor site, causing a powerful (innate! fever, inflammation, sepsis!) immune reaction.
the innate immune system is potent, and it is nasty, which is why you want to confine it.
immune checkpoint inhibitors are real good for metastatic cancer:
https://www.tandfonline.com/doi/full/10.1080/2162402X.2016.1214788#abstract combined with radiotherapy, on melanoma brain metastases
https://ascopubs.org/doi/abs/10.1200/JCO.2018.36.15_suppl.9537 on Merkel cell carcinoma, a skin cancer
https://www.nature.com/articles/npjgenmed201637 on liver and lung metastases of basal cell carcinoma
https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2023.1078915/full in colon cancer
https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2020.615298/full in penile cancer
https://europepmc.org/article/med/36916116 in kidney cancer
https://pmc.ncbi.nlm.nih.gov/articles/PMC11099454/ in pancreatic ductal adenocarcinoma (whoa)
cell immunotherapies can also be amazing for metastatic cancer:
https://ar.iiarjournals.org/content/30/2/575.short this is a complete remission in metastatic renal cell carcinoma with adoptive gamma-delta T-cells (and IL-2; the innate immune system strikes again)
https://ascopubs.org/doi/full/10.1200/JCO.2014.58.9093 in cervical cancer, with tumor-infiltrating T cells
https://www.nejm.org/doi/full/10.1056/NEJMoa2028485 here’s an antibody-drug conjugate for metastatic breast cancer. not enough complete responses to make it into my post, but look at that sweet Kaplan-Meier curve.
https://link.springer.com/article/10.1245/s10434-018-07143-4 isolated limb perfusion for melanoma: get higher doses of chemo into the tumor than the patient could survive otherwise, by cutting off circulation to the limb. when this sort of thing is possible, it really, really works.
https://link.springer.com/article/10.1186/s40425-018-0337-7 this is an oncolytic virus (intratumoral!) for metastatic melanoma.
https://link.springer.com/article/10.1186/s40425-018-0337-7 more oncolytic viruses that work! (also metastatic melanoma, also intralesional).
https://link.springer.com/article/10.1007/s10549-022-06678-1 I hate on growth factor-targeted therapies a lot, but there are exceptions. Herceptin is a real drug. Look at this. 69 HER2+ patients presenting with metastatic breast cancer and treated with trastuzumab as part of their initial treatment, 54% get a complete response. 41% survived 5+ years after diagnosis. This is really, really solid.
electrochemotherapy is injecting tumors with cytotoxic drugs and electroporating the tumor so the drugs get in better.
It’s only possible when you can physically access the tumor, i.e. when it’s on the skin or when you’re operating anyway (but can’t surgically remove the tumor, because if you could, you would just do that).
it also, really, really works. https://onlinelibrary.wiley.com/doi/full/10.1002/jso.23625
if you can prove your computer program does what it’s supposed to—for almost any reasonable interpretation of “what it’s supposed to”—you will, as a side effect, also prove it doesn’t have common security flaws like buffer overflows.
people I looked up while reading Neal Stephenson’s Baroque Cycle:
Metastatic Cancer Treatment Since 2010: The Success Stories
links 11/01/2024: https://roamresearch.com/#/app/srcpublic/page/11-01-2024
https://en.m.wikipedia.org/wiki/Neats_and_scruffies a typology of AI researchers
https://notes.andymatuschak.org/About_these_notes Andy Matuschak’s working notes, mostly about educational technology (but not educational games!)
https://notes.manjarinarayan.org/ Manjari Narayan’s notes, mostly about statistics
https://www.washingtonpost.com/health/2024/05/06/ultrasound-addiction-treatment/ ultrasound being used as an addiction treatment—the full study results aren’t published yet, but the anecdotes suggest very dramatic effects.
all drugs for neuropathic pain have poor success rates.
https://pubmed.ncbi.nlm.nih.gov/24291734/ lots of people—maybe 6-10% of the world population—have neuropathic pain.
https://pmc.ncbi.nlm.nih.gov/articles/PMC3201926/ chronic pain generally affects about 20% of adults worldwide.
roughly half of opioid addicts treated with buprenorphine or methadone manage to abstain for 30 days after treatment: https://pubmed.ncbi.nlm.nih.gov/26599131/
https://www.whitehouse.gov/ondcp/briefing-room/2021/05/28/biden-harris-administration-calls-for-historic-levels-of-funding-to-prevent-and-treat-addiction-and-overdose/ the Biden-Harris administration has allocated $41B to preventing and treating drug addiction; hard to extract from that exactly how much is spent on rehab/treatment vs. anti-drug campaigns or law enforcement
https://www.forbes.com/sites/danmunro/2015/04/27/inside-the-35-billion-addiction-treatment-industry/ US addiction treatment spending was estimated at $35B/year back in 2015
Vampire Weekend’s Ezra Koenig:
their latest album Only God Was Above Us is wrenching and it’s kind of getting to me lately.
most of the commentary in interviews is about how Koening, now 40 with a 5-year-old kid, has matured and found peace (though if you listen to the lyrics it’s an extremely nihilistic sort of being “at peace” with a terrible world and giving up on trying to change it)
nobody is remarking on what I see as pretty explicit themes like:
last album’s “Harmony Hall” was about a sense of betrayal regarding Ivy-League antisemitism
this album is pretty clearly a rejection of the backlash, the Gen-X (“Gen X Cops”), ex-Eastern-Bloc (“Pravda”), or specifically Jewish (in the [[Bari Weiss]]/Tablet-mag vein) “vibe shift”.
there’s a lot of reflection on heritage and generation gaps, there’s the sense that someone (his elders? his family?) is pushing him in a direction and he doesn’t want to go that way, he thinks it doesn’t make sense in his generation, in this era, but he does care enough to be conflicted and to yearn over the pain of people still (mistakenly, he thinks) struggling (“Capricorn”).
https://people.com/vampire-weekend-ezra-koenig-finally-feels-adult-exclusive-8625179
https://www.theguardian.com/music/2024/mar/23/ezra-koenig-vampire-weekend-interview
https://www.thejc.com/life-and-culture/music/vampire-weekend-dont-call-us-white-c3xbezac
links 10/30/2024: https://roamresearch.com/#/app/srcpublic/page/10-30-2024
https://pmc.ncbi.nlm.nih.gov/articles/PMC10136898/ FRET is a biosensor modality.
“FRET is a non-radiative transfer of energy from an excited donor fluorophore molecule to a nearby acceptor fluorophore molecule...When the biomolecule of interest is present, it can cause a change in the distance between the donor and acceptor, leading to a change in the efficiency of FRET and a corresponding change in the fluorescence intensity of the acceptor. This change in fluorescence can be used to detect and quantify the biomolecule of interest.”
advantages:
real-time
non-destructive
sensitive to very low concentrations (picomolar and nanomolar)
highly specific because it detects conformational changes in biological molecules
this article is from a not-great journal and the author clearly does not have English as a first language… at some point i will need a more reputable source, this was from googling FRET quickly
https://www.astralcodexten.com/p/the-case-against-proposition-36 Clara Collier gives the narrow, evidence-based case that shorter jail sentences didn’t cause California’s property crime wave or drug overdose death epidemic, and longer jail sentences won’t fix those problems
I’m pretty convinced but I don’t follow this topic in great detail
metastatic malignant peripheral nerve sheath tumor is pretty bad—median survival is only 8 months after metastases are detected. but one M.O. that seems to help in several case studies is “sequence the tumor, find a mutation, use a drug that’s approved for other cancer types with the same mutation.”
PD-L1 overexpression? use a PD-1 inhibitor! checkpoint immunotherapy stays winning.
BRAF V600E mutation? try a BRAF inhibitor!
other Raf stuff: maybe sorafenib?
shit that doesn’t work:
chemo is...not great but better than nothing. some partial responses, no complete responses, survival extended by maybe a few months. mostly it seems best to have doxorubicin in the mix.
https://onlinelibrary.wiley.com/doi/full/10.1155/2017/8685638
https://ascopubs.org/doi/abs/10.1200/JCO.2024.42.16_suppl.11583
https://www.sciencedirect.com/science/article/pii/S0923753419377907
https://ascopubs.org/doi/abs/10.1200/jco.2010.28.15_suppl.e20512
https://onlinelibrary.wiley.com/doi/full/10.1155/2011/705345 ok here’s a complete response to chemo + surgery. it can ever happen.
https://ar.iiarjournals.org/content/40/3/1619.short case of long-term survival after keeping chemotherapy going a *really long time* at gradually decreasing dose and widening inter-treatment interval.
https://onlinelibrary.wiley.com/doi/abs/10.1002/ijc.33201 pazopanib, an angiogenesis inhibitor, similarly has a low response rate but can extend survival a bit
https://proof-scaling-meeting.vercel.app/ formal verification conference
https://chalmermagne.substack.com/p/death-by-a-thousand-roundtables what it’s actually like to work in UK policy. sounds dismal.
https://www.972mag.com/lavender-ai-israeli-army-gaza/ AI bombing. critical perspective on Israel.
https://goingon.org/ a timeline-based, “citizen journalism” news site.
https://statistics.berkeley.edu/about/news/steinhardt-announces-co-founding-transluce-non-profit-ai-research-lab AI interpretability nonprofit, Jacob Steinhardt
mech-interp seems like straightforwardly real and good work from a variety of perspectives on AI. helps with many risk scenarios including some x-risk scenarios; helps make the technology stronger & more reliable, which is good for the industry in the long run.
https://blog.benjaminreinhardt.com/young-people-technical-training this is straightforwardly true, yes, you should learn technical stuff.
https://www.washingtonpost.com/opinions/2024/10/28/jeff-bezos-washington-post-trust/ Jeff Bezos on why the Washington Post isn’t endorsing a Presidential candidate. this is a solidly written persuasive essay; it seemed legit to me, but I could be persuaded otherwise.
links 10/29/2024: https://roamresearch.com/#/app/srcpublic/page/10-29-2024
https://www.theguardian.com/news/2024/oct/29/acute-psychosis-inner-voices-avatar-therapy-psychiatry a therapist acting out the voices in your head might be an effective treatment for psychosis
https://www.futurehouse.org/research-announcements/wikicrow SOTA (?) paper summarization from FutureHouse
links 11/18/2024: https://roamresearch.com/#/app/srcpublic/page/11-18-2024
[[links]]
https://en.m.wikipedia.org/wiki/Nicholas_Roerich I like his art; he seems to have led an interesting life
https://en.m.wikipedia.org/wiki/Maurice_Quentin_de_La_Tour Rococo portraits
https://www.zach.be/p/yc-is-wrong-about-llms-for-chip-design
this doesn’t seem to be a coherent argument—author claims both that LLMs will indeed be used by chip design companies to save on human labor, and that they’re not very good and can only replace the more routine parts of a chip designer’s work. But...this isn’t “YC is wrong, there is not a startup opportunity in using LLMs for chip design!” even if it’s true it’s just a more measured and realistic picture of what LLMs will be doing in chip design!
and they even make sure to shill their own AI-for-chip-hardware startup, which they claim is working on challenges that nobody else is: https://www.normalcomputing.com/
https://www.programmablemutter.com/p/how-chaotic-is-trump-ii-going-to speculation about Donald Trump’s foreign policy
https://en.m.wikipedia.org/wiki/Daniel_Defoe i want to read his nonfiction
https://en.m.wikipedia.org/wiki/Kotex sanitary pads have been around since 1920
https://asteriskmag.com/issues/08/the-death-and-life-of-prediction-markets-at-google the tl;dr: Google’s first internal prediction market was intended to go public and stalled as the regulatory environment remained unfriendly; its successor focused on predictions about competitor activity rather than Google’s own activity (which is less subject to “office politics” considerations blocking an honest assessment of Google’s chances of success etc) and never intended to be public-facing, and is still in active use.
https://en.m.wikipedia.org/wiki/Fran%C3%A7oise_d%27Aubign%C3%A9,_Marquise_de_Maintenon
https://en.m.wikipedia.org/wiki/Madame_de_Pompadour patroness of the French Enlightenment.
“who was that woman who was an influential mistress to the King of France, politically savvy and queen in all but name”? “which one? this just keeps happening”
https://nintil.com/dont-assume this is Jose Luis Ricon life advice, which unsurprisingly tells you to be less afraid of things and talk to people more.
shan’t.
https://en.m.wikipedia.org/wiki/Bill_Monroe
https://calisphere.org/item/0bc1137c37161874ded76c71bf982409/ scary guys