JunkDNA

I have fond memories of playing the original Falcon on my Amiga 500. It felt like magic after years of playing F15 Strike Eagle on the Apple IIc. Hearing real sound effects kicking in the afterburner and getting too close to the ground ("Pull Up! Pull Up!") were all so satisfying.

I remember being so excited when Falcon 3.0 came out. But it just felt like a let down. The graphics were amazing for the time and it seemed so realistic, but for me the realism is what killed all the fun. As a kid, I didn't actually want to BE an expert F16 pilot. I just wanted to feel like I was. I didn't want to have to learn all the systems and controls.

This article isn’t particularly helpful. It focuses on a ton of specific OpenAI business decisions that aren’t necessarily generalizable to the rest of the industry. OpenAI itself might be out over its skis, but what I’m asking about is the meta-accusation that AI in general is heavily subsidized. When the music stops, what does the price of AI look like? The going rate for chat bots like ChatGPT is $20/month. Does that go to $40 a month? $400? $4,000?

I keep seeing this charge that AI companies have an “Uber problem” meaning the business is heavily subsidized by VC. Is there any analysis that has been done that explains how this breaks down (training vs inference and what current pricing is)? At least with Uber you had a cab fare as a benchmark. But what should, for example, ChatGPT actually cost me per month without the VC subsidy? How far off are we?

Exactly. If you are an L7 and making an average L7 salary, nobody should have to squint and tie themselves in knots to figure out the connection between your contribution and your employer’s revenue. You are a Ferrari that is purchased new each year.

There’s a place where you can work on things that don’t generate revenue but are morally/technically interesting: it’s called “academia”.

They’re not using mRNA. They are using a viral vector that contains DNA.

I’m not sure if it’s a false memory or not but I believe there was a pretty cool demo that used this as the background music as well.

Bingo. I wish I could upvote this comment more. All the geeks get distracted by words like “cloud” or “virtual” and forget that all this stuff we depend on has a physical presence at some point in the real world. That physical presence necessitates humans interacting with other humans. Humans interacting with humans falls squarely in the “things governments poke their noses into” bucket. It’s like the early days of Napster when people were all hot for “peer to peer”, as if that tech was some magic that was going to make record labels and governments throw up their hands over copyrights.

I highly recommend the piece by Derek Lowe down thread, but the tldr is basically that researchers have believed amyloid plaques cause the symptoms of Alzheimer's and so the theory is that if you eliminate them, you can treat the disease. This drug gets rid of them. But the gold standard is whether or not the drug actually helps people, not whether it meets a technical definition of "working".

This is the drug equivalent of an engineer following a requirements document and saying to a product manager, "Hey, you said the form has to be submitted through the website. You can see here when I hit submit, it submits! The website doesn't save the data anywhere because that wasn't in the requirements".

I was on one of the teams that refuted the claims of horizontal gene transfer in the original human genome paper. The bar for establishing a true case of horizontal transfer in vertebrates is high. It’s really improbable given the required sequence of events laid out in the article. It’s one thing for some DNA to get picked up by random cells in the organism (happens with viral infection all the time). Getting to the germline cells and becoming inherited is a whole other story given that vertebrates have evolved mechanisms to guard against this specific scenario.

In business, many times the lack of any decision (good or bad) wastes valuable time. Especially for leaders, unblocking teams to move forward has real value beyond whether or not the actual decision is optimal. A great many decisions are reversible. If your decision is reversible (even at some expense), it may be better to just decide and move on. In many cases, you don't have perfect information anyway, so trying to make the right decision causes you to delay the very experiments necessary to get you to an optimum outcome.

USB remains the only connector I use where I routinely get the orientation wrong 3 times.

It’s not a vaccine if you don’t have efficacy data. You can go snort all kinds of peptides all day long, that doesn’t mean you’re going to actually have something useful happen.

Do you know why we’ve developed all these complex rules about how to test whether drugs and vaccines work? It’s because humans have reliably demonstrated over and over that we have no friggin’ clue how our bodies actually work. I worked in drug discovery. The one thing that all failed drug candidates had in common was that they all looked like surefire bets right up until the point where the data came rolling in. The reason all these complex studies and checks and balances are in place is because ~200 years of human experience making vaccines and medicine has given us some small amount of humility.

Speculation on the other thread is too many people have flagged the other post.

My daughter now 10 was diagnosed with a severe egg allergy around the time she turned 1. We aren't vegans and I love all kinds of things with egg (including home made pasta).

We tried so many egg replacers and were just not that impressed. I was resigned to giving up a whole bunch of foods I love. Aquafaba finally let us have so many normal meals back. You don't realize how many foods have egg in them (especially in restaurants: Orange Julius I'm looking at you! Who puts egg in fruit smoothies?!).

We use it to make pancakes, waffles, cakes, and even brownies (we found most egg replacers to be an utter disaster with many brownie recipes).

I would argue what makes the world a better place is ensuring companies have to innovate on their own. That’s what leads to breakthroughs and new things. Constraints often breed innovation. What is the incentive to sink billions into R&D if someone can sit on the sidelines and just take what you have developed? Look at the situation right now: we have multiple vaccine candidates from multiple companies because they all had significant incentive to develop them not because they were necessarily going to make a lot of money off this particular vaccine, but because they could accelerate R&D on tech they can use for other therapies. Some of these vaccine candidates appear to be mediocre at best. If we didn’t have a competitive marketplace we wouldn’t have gotten the best vaccine possible in the shortest timeframe possible.

There is sometimes specific information about the actual manufacturing process or synthesis that companies provide. Given that this is an entirely new vaccine technology that has never been used before, there was probably quite a bit of confidential manufacturing content supplied as supplemental material to satisfy regulators.

You are correct that the regulators are generally concerned with safety and efficacy of the final product, not the sausage making. But if the sausage making is super complex and/or novel that could potentially have an impact on safety and efficacy. So the company may have been asked to give some amount of detail there. For example: given this vaccine requires cold temperatures or it breaks down, how are they guaranteeing the cold chain in the manufacturing process? (I'm just using this as an illustration of the flavor of question someone on the committee might have)

Given how new this vaccine tech is, there are probably quite a few manufacturing-related efficiencies and techniques that Pfizer does not want competitors getting access to. Not because they're going to copy this specific vaccine, but because it allows them accelerate efforts in this area for other vaccines.

It was a murky situation, but LYMErix comes to mind: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2870557/

Syapse here! We are a real-world data company working across life science (pharma), hospitals, and with the FDA. We want to use real-world evidence to improve the outcomes of cancer patients. When many think of Health IT, they think primarily of patient tools, which are important. However, lots of decisions are made between pharma, hospitals, regulators and health plans that effect us; and aren't always grounded in what happens in the "real-world". We are hoping to help those decision-makers make better decisions for oncology patients using data, analytics and expertise.

It didn't come across in my post in retrospect, but just want to say clearly I love this idea and the ambitious nature of it. I think when someone works in drug discovery, it's hard to escape this feeling that there has to be a better, faster, cheaper way. But at the same time, the reality of seeing how little we actually understand about biological systems on display each and every day tends to be quite a downer! The world sorely needs more of this kind of thinking.

A few random thoughts I'm curious about (full disclosure: I worked in anti-infectives R&D as a bioinformatician early in my career for a major pharma)

1) One big challenge in synthesis is ensuring compound purity. Even when I was working in pharma, it was often the case that some of the compounds in the screening library could be contaminated with intermediates. This is murder for any kind of anti-infectives research because you end up with false-positives for toxic intermediates. Since your assay is often, "does the compound kill the bug?" the answer for most chemicals is, "yes!". How do you ensure the purity of what you deliver to your customers? If I'm a medicinal chemist wanting to try this, I want to know that I'm not getting a vial of brick dust back.

2) Just because you have a mechanism to synthesize, doesn't mean the yield is going to be great. Does your algorithm factor in yield when selecting the route?

3) When I started reading your post I thought, "Hats off to these folks, this is a super hard problem that no shortage of extremely smart people have spent years trying to solve." Then I got to the moonshot section! The number of small molecule antiviral drugs with efficacy is vanishingly small. I understand why you would try to tackle this, but it truly is a moonshot.

4) I can't help but wonder what Derek Lowe (https://blogs.sciencemag.org/pipeline/) thinks of all this, have you guys tried to reach out to him?

I'm glad you posted this because when I saw the headline to this article my first reaction was, "Wait, this isn't news to me, I fired a ton of these things in that video game". Then I thought, "No, probably a false memory."

Spending more on marketing than R&D has been a favorite thing to zero in on but it's not really a useful metric. See here: https://blogs.sciencemag.org/pipeline/archives/2013/05/23/an...

There is a fundamental difference between a CEO at company operating at GSK's scale and for example, a few hundred person startup biotech. It's a mistake that engineers and domain experts make to assume the CEO always needs to be technical. In small companies, this can be a benefit because the CEO is effectively the leader of everything and often has their hands in a lot. But that just does not scale to a company the size of GSK. The challenges of leading a company of the size of GSK are fundamentally different and start to look a lot more like the challenges of leading other big, multinationals.

Have you ever been in an executive leadership position that required you to make tough decisions? As someone who recently has entered this realm, let me tell you: most of the decisions in front of you are essentially choices between a whole bunch of options that all have one thing in common: they totally suck. You learn quickly that you are going to make harmful decisions because sometimes a good option isn’t in the hand life has dealt you. It’s the nature of the gig. A true executive leader makes a decision quickly and moves on. When they recognize they have made a bad decision (often with more data now available), they change their mind. Most bad leaders are incapable of doing this last bit. They dig in and hold their ground. The good ones just switch. They won’t even admit it because of ego (Steve Jobs is a great example outside politics of someone with this behavior).

If the US had gone into lockdown in January, the ACLU might have sued the government in court (or another civil liberties org). The UAW would have fought GM on shutting down the plants (let alone the shareholders!). College students would be protesting encroachment on civil liberties. Businesses would have been screaming. The stock market would have gone into a tailspin. People in a free society would have flouted the orders out of civil disobedience. For all this stuff to actually work in a free country, a significant percentage of the population has to believe the threat and cooperate. I’m a highly educated person with a degree in molecular biology. I know all about viral illness and epidemics. Even I did not come around on the severity of this until last week (Despite reading all the articles!). It just pattern matched against all the other pandemics that were a big deal in Asia and elsewhere, but didn’t really impact daily life in the US.

Back in the late 90’s and early 00’s, there were a ton of cpu platforms around: SGI MIPS, DEC Alpha’s, Intel, Sun SPARC, etc... while I will admit it was a colossal pain working somewhere that had all of those, it was often possible to recompile from source to get things to run. I’m not suggesting it’s trivial, but given the incredible investment in ARM in the mobile space, the wind is at least at your back today. It certainly has got to be much easier than it was in the days of being the only person in the world trying to recompile an obscure open source scientific computing package for DEC Alpha. Commercial software is a different beast, but even there, the incentive will be high to do a port if lots of people start migrating to this.

Thank you for this write-up. I recently (last ~3 weeks) started working with a coach for the very first time in my career. I think I've been nibbling around the edges of a lot of what you address directly here. What I'm only now starting to have the haziest notion of is how many so-called limitations and struggles might actually be almost total fabrications of the emotional part of my mind. I wish I had been working with a coach a lot earlier in my career.

I believe many (most?) US hospitals have switched to secure paging services delivered via smartphone. HIPAA pretty much requires it.

Do you have any support for the claims you just made? Synthetically made DNA is not going to give people viruses or cancer when physically applied. It’s hard for me to imagine it doing much of anything even if inhaled/consumed. Similarly, the replication and purification of synthetic DNA is trivially easy to purify of any contaminants.

The discipline of science (and its sibling mathematics) has been one of the great achievements of human civilization. It has been so astonishingly successful, we can’t even fathom there being any phenomena beyond its reach, given enough time and enough foundational understanding. Because I like to stretch my mind in uncomfortable directions, I often wonder: is there something else? Something that can lead us to Truth other than mathematics and science? Has human civilization gotten stuck in a local maximum where it appears as though we now have a means for understanding the entire universe, but there is another whole level we are as yet too primitive to reach? I worry that as a species we haven’t spent enough time trying to answer this question.

I’m not arguing that there aren’t people who have legit reasons to want to pay less for email services. I’m arguing that if the OP wants to run a profitable business, targeting that particular demographic is unwise. Hobbyist/tinkerer types have high quality expectations and will absolutely suck more support time and energy than, say, a busy dentist’s office who just wants to pay money and have their email work for 20 employees.