They have a lot of anecdotal, observational, and emerging RCT evidence on their effects on substance consumption and abuse.

The biggest effect and best tested is on alcohol use disorder. Mechanistically we don't know if it's through some complex reward mechanism, or something simpler like "alcohol is a calorie and you consume fewer calories." The JAMA study showed that GLP-1 reduce Heavy Drinking Days (>2 drinks/day), but did not reduce overall drinking days. This would imply the simple mechanism -> it's hard to drink a lot of calories even if you do enjoy a drink.

More anecdotal evidence showing this effect in opiates, but nothing in an RCT yet.

So far, nothing has worked in stimulants. Cocaine and Meth abuse are insanely difficult to manage therapeutically right now.

Basic research creates foundation knowledge that can drive medical innovation, but rarely does academic research create final composition of matter. Private funded work is all the non-research components of drug discovery - optimization of molecules, regulatory work, commercialization, etc...

To imply that private companies reap the rewards of basic research without contribute much is ignoring the many other components of translational work.

First-gen GLP-1 goes off patent in 2031 (e.g. semaglutide). Seems far off, but is frighteningly close for Novo. Tirzepatide gets genericized in 2039 and has better efficacy, which is why Lilly is in such a strong position right now.

There is an enormous amount of biotech work to develop next-gen versions that have better half-lives, lower adverse events, and most importantly, have long patent lives. But it seems base GLP-1 are good enough that we should see massive societal change starting next decade.

Lilly is probably in an even stronger position if retatrutide continues to look as good as it has in the current trials. Better weight loss than tirzepatide, and recent results have shown it has excellent results on reducing fat deposits in the liver... and NAFLD is the leading cause of severe liver disease in the world.

Yes absolutely. Even if you have already been exposed, the vaccine has been shown to prevent manifestations and/or recurrence of HPV-induced pathologies. It's not necessarily in standard of care, but the literature is pretty overwhelming here.

My pithy observation - Early stage investors are fantastic at extrapolating from minimal data points. Late stage investors are fantastic at extrapolating from many noisy data points. They screw up because the methods for each of their extrapolation functions are entirely different, so much so that they manifest as cultural differences in investment firms.

> I wouldn’t be surprised if companies threw billions of dollars worth of research to make it happen

Well you are correct. Altos labs (https://altoslabs.com/) is basically every "who's who" in science doing this with billions of dollars. Including Wolf Reik who is featured in the article.

Although I don't think the majority of these companies will go on to make billions selling drugs, I think the past ten years of VC and pharma funding of basic life sciences researches is likely to pay off in many unexpected ways.

The field of molecular biology didn't exist before World War II; after, a number of funding managers at NIH recognized that there was an incipient science to augment biochemistry and other fields, and funded it through places like Rockefeller Institute (https://pubmed.ncbi.nlm.nih.gov/25862750/).

The long term impact of these early scientists and funders who recognized the potential of MB has been enormous; it lead to the discovery of recombinant DNA, and many other important things which produced an explosion of research.

where I drive to work every day, there was only one biotech (Genentech) campus and now there are probably 20-30 different companies with enormous well-outfitted research labs all stuffed into one little corner of South San Francisco. "Overnight", biotech became a huge industry- overshadowed by the enormous tech industry- but in many ways, the "tech" part is ripe for disruption in ways that look just like the tech industry in 1997.

Either way, it will be interesting to see what is the state of the art 30-40 years from now, assuming the research infrastructure continues apace.

Go through a staffing agency. They will manage background checks and can introduce you to many people across a variety of skill sets.

Background checks only tell you if they've been caught before. It's the first step, but it shouldn't be the only step.

I am VC. I invest in hard tech. That said, opinions are my own.

Unless you come in with a strong background reputation or intro from the top 1% of our network, I would probably not read a document that takes 30min. I cannot imagine many people would without enough incentive.

Think about it this way, if you're going to commit to watching a movie, do you do research beforehand to choose? The common joke is you spend more time searching for recommendations than just watching. The psychology is we want to de-risk committing our energy/attention. This similarly applies to founders sending technical tracts. We do eventually read a tremendous amount of technical details (lit reviews, white papers, etc...) but only after we have understood that the opportunity is worth the effort.

Okay, all that said, there is a deeper code smell here. I think you are likely mixing product implementation with market opportunity. Description of the implementation of your product takes lots of time and explanation as you state above. BUT, you should not be doing that in your first pitch. The first meeting should be explanation of the market opportunity. You aren't selling your product. You are selling your market. If I'm sold on the market, I want to hear why your product captures it afterwards, not before.

What do you do with easier tech but weak reputation?

Imagine a silly crazy pitch for wind powered Tesla for Shipping.

The market is very large. The concept uses existing components at reasonable pricing. Some clever engineering tricks really improve the numbers. It is cheaper than existing green proposals. There is a detailed excel simulation to play with.

There also appears to be a strong lasting network effect (!!)

At what stage do you write the first million dollar cheque to unqualified founders?

I wish it was as easy as a nerd insisting on the technical details rather than the big picture. What we do today with AI is backward-looking automation on a grander and fuzzier scale — lots of money to be made here, but it’s actually the complete opposite of intelligence. I’m stumped on getting this point across (no royal road to geometry?) and without it I have to compete with threatening war chests on the wrong playing field.

I chatted with an affiliate of the counterparty to the bet here - a couple years before the bet ended but clearly when they were gonna lose. They did say two interesting things I'll relay here without necessarily agreeing:

1. Their major thinking is that the growth of index funds is driven by volume of new investors, not necessarily market performance. At some point we hit the diminishing returns of new money into indexes. When that happens we'll see their "guaranteed" growth slow and you'll need to turn to hedge funds for alpha. He thought 10 years was enough for this to play out. Obviously wrong on timing, but not necessarily wrong on outcome.

2. One of the conditions of the bet was that they have lunch once a year to discuss bet progress. Given that charity lunches with Warren are going for 4.5mm today, they essentially got 10 lunches for 100k each. That is...quite valuable for a hedge fund manager.

Now, nobody can sell a loss better than a hedge fund, so I take with a grain of salt. But it is some food for thought.

For 1) alpha is what you don't want when investing in index funds. Index funds can only stop working if they stop being able to track the market. That can happen if they're such a big part of the market that trading is effectively broken, but 10 years would definitely not be enough to reach that point.

On 1; Is there any data to suggest that inflows to index funds are pouring significantly more money into companies within an index than if people invested directly or with hedge funds?

Absolutely. The ETF space has exploded enormously over the past decade as the Fed pumps trillions of dollars into risk assets.

Having spent most of my career as a hedge fund trader, I absolutely agree with Buffet. But I think a decade of the largest monetary interventions skew the numbers massively in favor of a long only passive investor.

I cannot comment on a full macro basis, but it is definitely true that being listed on an index such as S&P 500 will spike the market cap. TSLA was a recent example here. Matt Levine has an interesting piece on this (as usual) regarding trading on index inclusion as securities fraud: https://www.bloomberg.com/opinion/articles/2021-01-05/dystop...

My experience has been to say "yes" to everything in early career when you are not in demand. Then slowly transition to saying "no" as your career develops. The transition point from "yes" to "no" is when you develop more unique and valuable skill sets.

When all you have to offer is energy, excitement, and smarts - "yes" opens doors, creates relationships, and gives you opportunities to learn. That's how you grow, not only in career, but in relationships.

After you can bring more differentiated value to an opportunity, you're going to be in more demand and need to filter the best use of your time and energy.

The Steve Job's part is absolutely correct when you are sitting in Steve Jobs' position. As a thought experiment, probably every Fortune 500 CEO would want to have a 1-2 hr meeting with Jobs circa 2008. That would be 500-1000 hours of meetings where arguably they would derive more value than he would. So while it would be insane for most to pass up on these meetings, he obviously would need to.

Don't confuse the "yes" vs "no" periods of your life.