fgimenez

[Note that I work in this field and have co-founded a CNS AAV company]

This isn't the correct takeaway. AAV are one of the most complex drug modalities and carry considerable risk when used incorrectly. This story is tragic and violates pretty much every ethical consideration for a clinician researcher. Especially ones that are treating children of desperate parents.

That said, AAV are one of the most powerful delivery mechanism we have to deliver gene therapies to the brain. Uniqure has shown the first efficiacious treatment of Huntington's disease with intraparenchymal delivery of AAV5, Zolgensma is a brain targeted AAV9 to treat SMA, Kebilidi is an intraparenchymal AAV2 that treats AADC deficiency.

The general approach should be to keep dose as low as possible and minimally expose the periphery. AAV9 at large doses delivered intrathecally without standardized immunosuppression is simply insane.

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.

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.

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

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.

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.

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.

This is such a cool idea. The gap between the "aha" moment of a programming challenge and the implementation is high for me since I don't get to code very much anymore. Can't wait to check it out!

Really depends on the type of cold email. If an investment banker cold emails me with a “hot deal” I delete immediately. If a founder sends me a template email in a space I clearly dont invest, I delete. If a dev sends me an email with interesting insight or project and the ask is an easy to answer question, I’ll respond. Might go out of my way and chat if I’m impressed.