I was lucky enough to witness the sea change in a relatively intellectually honest amyloid lab in the 2003-2009 regime. We were actively pursuing results in the amyloid hypothesis but just about every other lab meeting we were careful to mention that the hypothesis might be wrong. All of our papers say "suspected"... Around the end of that period we were getting word that the first attempt at a drug targeting amyloids was failing, and it was a common morbid joke among all of us that this was all a red herring.

~15 years ain't so bad for the skepticism to make its way out of insider speculation to relatively well accepted (drug trials take a long time).

I don't have a skin in the game with the hypothesis (I'm actually biased against it) but it is worth noting that most of the drugs tried are antibodies, which introduces the confounding factor that all antibodies elicit an inflammatory oxidative response by locally catalyzing the conversion of oxygen to ozone (oxidative inflammation is thought to also be causal to Alzheimer's), so before we completely shut the book on it we might want to control for that.

VCs are clueless, but at least they are results-driven in a relatively neutral way, though they are going to be biased toward initial selection of idiotic investments. (You pick to fund something because it's a friend of a friend, a referral, social validation, etc.)

> most of the drugs tried are antibodies

But not all of them right? So what exact merit does the statement hold?

I also did my PhD in a lab that rabidly believed in a hypothesis against all emerging data (it only didn’t matter that much because it was obscure). Even when my colleagues literally disproved the hypothesis my PIs undermined it while writing the paper with globs of ambiguity (just like you mentioned) and buried the result in Figure 5 instead of Figure 1, and made him never submit it to any prominent journal. All because this result made it look like they were idiots for 20 years for blindly believing a hypothesis with zero actual data. (If interested the hypothesis being IgG gets degraded in endothelial cells and that’s where the protein that salvages them works).

I’ve had front row seats for blinded belief in what you used to believe being what drives your science and focus. I am not yet prepared to forgive any lab that actually measurably put millions at misery because of it.

I don't honestly think that anyone has been put at misery. At best we will have taken slightly longer for a cure (or maybe we'll never find one). I feel like there area few too many ethical gymnastics you have to do to blame overzealous scientists for chasing down the wrong rabbit hole. But, yes the trait in general of blinded belief (versus belief used to drive effort and focus but with self-awareness that it's just a tool) among some scientists feels uncouth. I am lucky to not have had to deal with that personally. I did see it in some neighboring labs, some of those grad students got utterly fucked and when they presented consolation thesis defenses for seven years of misery, they had the dazed look like someone who had just escaped an underground cult to see the sunlight finally.

You're right not all of them are antibodies, but the ones that aren't might not be working for "other reasons". Yes, that is a cheap way out, but I still think it's worth trying (and I don't generally believe in the amyloid hypothesis)

I'm surprised IgG isn't degraded by insulin-degrading enzyme.

These are the kinds of replies that still make HN one of the best comment sections on the internet, if looking at peaks. (The average is not great, but there's huge variance.)

Thank god VC's aren't monopolistic or driven towards short terms solutions for quick profits.

Correct.

The problem with existing research is that it simply isn't that open to new ideas, particularly once funding streams are in place (because shifts in funding mean job losses, institutional impacts etc).

As you are pointing out, VC's often see monpolies as something to disrupt. So you'll take the taxi industry for example. A govt sanctioned monpoly with horrible service and low insurance limits. They'll make a play with something like uber.

Hotels -> airbnb / VRBO

And the list goes on.

You point out how VC's don't focus on short term profits. While I would agree, some however would argue that VC's should focus MORE on short term profits. I personally think too many money losing businesses are subsidized for way too long with VC money. In biotech that may be a good or necessary thing, but personally think this longer view is a bit of a negative.

My comment was extremely flippant. Let me provide an example to explain my point of view.

Cancer research can appear very stagnant. Pharma companies and researchers funnel money into existing solutions and combinations of existing solutions which increase life expectancy by a few months, and quality of life by a few degrees. Not much foundational research on cures, and why should there be when every new drug which leads to slightly better outcome will be purchased by patients who will do anything to live a bit longer?

Now, how in the hell would VC be expected to improve that landscape? The ideal solution is a cheap therapy which cures cancer. Maybe a cancer vaccine. Where's the money in a 50 (or even 1k) tailored vaccine to cure a cancer when a slightly new combination of cancer drugs can cost $50,000 a month for the rest of the life of a patient?

I'd argue VC don't think long term for the benefit of anyone except themselves. They'll invest in a moonshot if it disrupts an industry for their benefit (e.g puts all taxi drivers out of work) but not if it eliminates an industry (e.g cancer research). There's way more money in funding a slightly different cancer drug.

As you pointed out in your original comment, VC's will def fund moonshots and big growth ideas with 1 in 10 or 1 in 100 chances for payoff. These don't make short term profits, but they have the potential to do something dominating.

SpaceX against a huge established industrial base. That's going to be VC type funding, not traditional funding streams. We had govt initially doing everything they could to shut spacex out, doing block buys, trying to crush them on paperwork etc.

My complaint is simple. We know the current billions spent under current approaches have not cured a wide variety of illnesses. So what harm is there in spending some, relatively small amounts of money, on other ideas.

What's interesting is the reaction from folks like you, NIH, academics and others. It's vehement rejection. But why not instead demonstrate your approach results in a cure. The rejection is because you know you are sitting on nothing.

We see this with spaceX. Established astronomers are crying bloody murder. But this is in part because they are afraid. Their huge thirty meter telescope gravy train (decades of funding into their labs) is at risk of being totally trumped by cheaper access to space, where telescopes work great.

Established businesses tend to be risk averse. So in short, a role to play here for new ideas.

Note: Be careful about snarky comments, those are best avoided on HN, and can be a bit embarrassing in hindsight if you try to be snarky but inadvertently are correct and then have to try and walk back a point that you didn't mean to make.

What would “more foundational research on cures” look like? I do cancer research and, frankly, the work feels pretty foundational. I’m curious what you would change.

Also please note that cancer vaccines have been tried but have failed for a few reasons. First, cancer cells are quite similar to normal cells, so cross reactivity is a problem. So, a typical approach is to to target “neoantigens” which are mutated cell surface proteins that are only on cancer cells. Not all cancers have neoantigens and they can mutate to stop expressing the neoantigen. Also tumors can express proteins that suppress or evade the immune system. PD-L1 blockers target one of the ways tumors do this.

All that to say, it’s not like people aren’t trying this stuff. It’s just really, really hard.

>Where's the money in a 50 (or even 1k) tailored vaccine to cure a cancer when a slightly new combination of cancer drugs can cost $50,000 a month for the rest of the life of a patient?

Profit isn't revenue, for one thing. Does that hypothetical $50k/month treatment cost $49,999/month to manufacture? That's the story for a lot of drugs.

Hypothetically, yes. Practically, that almost never happens. The reason the treatment costs $50k/month is because there is no alternative, and that's how much insurance will pay for it.

Whether or not the unit economics are $49,999/month or $49/month has no bearing on this. Treatments aren't commodities, they aren't apples at the grocer, where if the prices are too high, you just go to a competitor across the street.

I work in pharma. Pricing in pharma for drugs like that is complicated. Usually these drugs do actually require rather expensive manufacturing processes, that have to run in extremely large facilities with extensive QA, but in fairly small batches.

More importantly, every major pharma has a compassionate use program that helps people who can't afford the drugs get them, through offsets and credits. I understand the desire to make pharma look like pure-evil profit mongers, but the reality is that this is not an easy business to be in.

Many drugs invented by US companies are available cheaper in countries that don't respect US IP law (with no differences in quality/QA process/etc). The reason for this is obvious: in the US the government gives the inventor a temporary monopoly.

It's pretty widely accepted the presence of this government-enforced monopoly significantly increases the price of many drugs.

The standard argument in favor of this is that it incentivizes R&D and we wouldn't have these drugs otherwise. I think it's debatable either way, but claiming these companies don't take advantage of this arrangement to increase prices is not true.

This is nonsense. Most Western nations fully respect IPR and patents.

There is nothing wrong with patents "promoting the Arts and Sciences".

The problem in the US is that your largest buyers (Medicare, Medicaid, VA, Tricare) aren't allowed to properly use their buying power to push pharma companies on prices.

At the same time, there's very little restriction on pharma companies advertising directly to patients (banned in most nations) which puts pressure on GPs and specialists to over/off-label prescribe unnecessary pharma.

Prices in most countries are cheaper than the US because of that buying power that the government has, along with independent assessment of the value of new drugs and treatments in terms of QALY and cost/benefit to the people.

The price of drugs in US also reflects expensive R&D and sometimes even more expensive approval process. Plus the companies has to account for the possibility of third parties manufacturing without the license which in turn requires higher unit price.

I am not aware of any large-scale alternative manufacturing facilities that explicitly avoid IP laws and market their product legally. Can you give an example?

I work for a US biotech that is wholly owned by a EU pharma, not the US.

It's the scandals on stuff like Albendazole that make y'all evil, not the cancer drugs. I mean the FDA forces us to live like we are in some Soviet style dystopia. Some ancient commodity antiparasite drugs that are cheap as salt -- so abundant that people literally use them as a drench on livestock -- can only be bought from one or two approved marketers (manufacturers), through only approved distribution channels, only at approved retailers, after unnecessary high-skilled laborers press some buttons, and only after you have the right script from the right gatekeepers.

Ok, so here's a thought: who makes money if people don't die of cancer? Let's assume they're all retirees. Agriculture, housing, the local taxation authority, and possibly their immediate kin (assuming, on average, people love their parents and want to spend time with them).

Maybe Monsanto, Toll Brothers, and local governments should be funding cancer research?

this sort of stifling is actually the story of science, which really does advance only through funerals

Well thankfully I can say I've not come across this level of narrow thinking in physics or computing.

Normally there's excitement when the research offers some weird or novel tie in or a better way of doing a thing or solving a problem.

But then again these fields don't have the same structure of paymaster.

I think this is being seen in particle physics right now, with CERN campaigning to fund a successor to the LHC that other particle physicists believe has little chance of finding anything new.

I can't name of a global bio experiment looking for international funding to build a massive project.

This unfortunately isn't the case. There is friction because there is a fork in the road for particle physics. If we build or extend the LHC it is fundamentally a p-p hadron collider collider.

There is significant new evidence of new physics in hadron/lepton interactions and from the neutrino sector. Neutrinos are tricky but we feel we have a handle on these, which is pushing more people to want to build a large clean lepton collider either an e-e or u-u collider. The problem with a purely leptop collider is that it doesn't tell us too much about hadron physics (hence why the lhc differs so much from Tevatron).

The community itself has elected those who are in charge to review the proposals from the people with different ideas to allow us to form a coherent argument to go to funding councils/countries with.

I cannot name any other academic field which has managed to achieve such a level of international self-governence when designing projects on such a scale.

> I've not come across this level of narrow thinking in physics

String theory?

hurhurhur big think... string theory has at the very least given useful tools for particle and field theory as a research area, saying this doesn't work is like complaining that I can't take home a jar of magnons to show someone

besides there's tonnes of theory people I know who work on completely unrelated theory problems and ways of working that predate or have come after the dawn of string-theory, complaining this hasn't panned out into M-thoery is to a point of almost being absurdist

...but VC and private equity funding for biotech has been available in the 90s too?

It was an order of magnitude more difficult to raise VC money for biotech back then.

These days you can even raise a seed with no experimental data. That was extraordinarily unusual even well into the 2000s.

There are articles around discussing how in case of Alzheimer's it was impossible to get VC funding for immune ideas, even though they already had interesting evidence.

The same cabal was also blocking them.

I think you need to be an insider to realize how incredibly political most research in medicine is.

I have to ask, do you have experience in this area? Because it doesn't agree with my limited experience and I'm curious when/where you were involved with biotech startups and funding in the 90s/early 00s.

I'm an outsider, but to quote credible external sources, Science AAAS writer Derek Lowe documented that the biotech startup scene was large and relatively easier to get investments in from 1991 to 1994, with stagnation in 2012 [0].

McKinsey separately reported that there has since been another boom in the biotech sector in the 2020s [1].

[0] https://www.science.org/content/blog-post/biotech-class-earl...

[1] https://www.mckinsey.com/industries/life-sciences/our-insigh...

> boom in the biotech sector in the 2020s

Thanks, McKinsey, that's a great use of your consulting superpowers. Hey, was there a boom in artificial intelligence around 2015 as well? For $65,000 an hour, I'm sure you'll be happy to tell us.

I was in grad school at that time, in a program that heavily emphasized bio-entrepneurship. It was not easy to get money to start a biotech company at the time. The only ones I can recall required a star professor, a working technology, a university patent, and even then, most of them failed or pivoted.

these days as in this decade, or right now?

Apparently VCs are clamping down on loose funding in the current climate, or thats not the case in biotech?

But, somatic mutations are still the cause, it's just most of the time the immune system gets rid of the mutant cells.

> less politically driven funding agencies

what agencies are more free from politicians manipulating their funding? (this sounds hopeful)

I was referring to academic politics. That is, professors steering funding to their niches and trying to dry out alternative ideas.

I think DARPA and other agencies trying to imitate them (e.g. Wellcome Leap) are less prone to manipulation and much more fact-driven. Howard Hughes Medical Institute is also good.

As a European, I hate ERC. In some cases, they have not even bothered to discontinue funding principal investigators known to have committed fraud and who had to retract major publications.