Author Archives: theusernamewhichismine

Rest in Peace, Shamus Young

Yesterday, I wrote a post where I offhandedly mentioned the death of Shamus Young.  I had done so because during the post I remembered a decade old post of his (that I still can’t find!) that had so succinctly explained everything I was talking about.  I finished the blog post, and while looking for Shamus’ post so I could link to it, I learned that he had died last year. 

I’m pretty late to the party on this one, I haven’t been following him for a few years.  But I first heard about him when he published DM of the Rings around a decade and a half ago, and for a while he was my main source of gaming news and reviews.  I first played Oblivion because of a post he wrote about it, same with Morrowind and even the original X-Com.  I got a lot of my early gaming exposure from him and his blog, and I still think a lot about some of the things I read from him.  My previous post on Skyrim is based heavily on a post I remember him writing about Oblivion and RPGs in general, and a lot of the concepts he wrote about still come back to me.  Learning that he had passed, at what seems like an early age, kind of hits me.  I was never more than a lurker to his blog, and I don’t really know what I wanted to say with this post.  I’m so late to the party and was no more than a reader, so I can’t really share in the grief with others.  But I just wanted to say that he was incredibly fun and funny, and I’m glad I got to read him.

If you’ve never read it, DM of the Rings is well worth your time.  Farewell to a really cool guy.

The circle of Skyrim

This probably won’t be controversial, but The Elder Scrolls: Skyrim is a pretty good game. For what it is, I’d say it’s a masterpiece. There’s certainly some parts I don’t enjoy, (the guild quests can be lame, the main plot meanders, the civil war is undercooked), but none of those bring down the enjoyment of what Skyrim actually is. Skyrim is a time waster, expertly designed and developed to have you spend hours upon hours without even realizing you’re doing so, ensuring that at any moment there are 5 different activities you could be doing and a dozen different goals you could be working towards. I remember first thinking about this topic due to a post written by the late Shamus Young, but I can’t remember the exact post so I’m sorry I cannot link directly. Here’s how a few hours of Skyrim may play out:

  • Load up the game and dive into some dungeon. There’s tons of the map and the combat is engaging enough to make this enjoyable. You may even get some nice loot depending on where you dive: rare materials, dragon souls, even a Word Wall to give you new powers
  • With the dungeon now thoroughly dived, make your way back to town. It’s here that the time wasting really begins. You can sell your loot to merchants, use the proceeds to buy better gear or a house in town. You can buy training in a skill, unlocking more perks you can use out in the world. There are 3 different crafting-based skills and your loot may well suit all 3, so you can run around town crafting new weapons and items with the loot you acquired. These and other time sinks give you ways to keep strengthening your character, making you better able to head back into the world and fight.
  • DING! You leveled up! Since Skyrim uses the “learn by doing” system of level-ups, just crafting stuff will advance your skills and earn you new perk points, which can be spent to unlock new abilities
  • New abilities in tow, you may head back out into the world to try them out, plus you have whatever sweet loot you got out of your last dungeon. Maybe you can disarm opponents now thanks to a Word Wall you found, plus maybe you have a fancy new Dwarven Blade courtesy of the Smithing perk you just bought.
  • Having now dived a few more dungeons you may be getting bored with the combat, new perks or no. Fear not, the game still has ways of entertaining you, in town you may learn of an interesting new quest which could break up the monotony of combat, or decide to join one of the factions for a different flavor of gameplay. The factions themselves will give you a bit of story and their own quests, again breaking up the monotony and keeping you engaged even if all you’re doing is running around doing more fighting and gathering more loot.
  • And since you’re doing more fighting and gathering more loot, you need to keep heading back into town, spending more time running about the shops and skill trainers, leveling up further and further and buying more and more new cool abilities to try out in the world
  • And the world itself may have fun quests. Go into a random dungeon? Hey there’s a guy here wanting to kill the people looting his family’s crypt. Well that’s what I was just about to do, but I’ll fight on the side of justice this time. These quests out in the world do even more to frame the repetitive fighting and make it still feel “fresh” even as you hack your 1000th bandit to pieces. You may be doing the same thing over and over again, but it never really feels like it
  • And the maximum carry weight even feeds into this. We all know how much it sucks to be overencoumbered with all your loot, but that’s a GREAT incentive to head back into town to sell or use it all, again letting you spend time there, power up, and again want to go back out into the world.

Skyrim does an amazing job at making a super simple combat and leveling system keep you engaged for hours. The fact that every moment feels fresh and new, and the fact that every activity pushes you towards doing other activities, is a testament to how fun the game is. Running around town makes me want to use my new gear and go dungeon diving, gathering a bunch of loot in dungeons makes me want to go back to town and cash it in. The quests and questlines are all enjoyable enough to make the umpteenth Draugr crypt still feel engaging, and there are enough memorable characters sprinkled around the make the world feel real and alive. I only write this post because I just lost an entire weekend to Skyrim, and I hope I can get this game out of me so I can get back to work later, but this decade old game is still really really good.

Maker vs Taker states

Last year, Elon Musk paid over 11 billion dollars in income tax, more than the amount paid by every single person I know COMBINED. Yet for all that I have no desire to see him get special privileges, or to have his complaints be heard over other people’s. I know we live in the real world where money buys access, but we should all strive to live in a better world where all are presumed equal regardless of wealth. So if Elon Musk shouldn’t get special favors, why should California or New Jersey?

California and New Jersey have been described as “maker” states, in comparison to “taker” states like Mississippi and New Mexico. California and New Jersey residents pay much more to the federal government than their state collectively receives, and vice versa for Mississippi and Mexico. This has led some lawmakers, like Josh Gottheimer (D-NJ) to call out the “moocher” states, and say that laws should be written to benefit the people of his “maker” state, by lowering their tax burden or enacting their preferred policies.

I’ve seen this exact line of reasoning before all across social media. When Republicans complain about the priorities of the government, Democrats come out of the woodwork to say that since blue states pay more tax, red states need to shut up and put up. Yet this is an absurd, Romney-esque line of reasoning that would have been utter heresy in 2012, the idea that wealthier groups of people should be heard over the voices of poorer groups. The next time Gottheimer complains about Musk, will he remember to shut up and put up since Musk pays more taxes than almost his entire state populations combined?

I think this belies the maddening hypocrisy of the maker/taker argument, it was true when Romney said it and it’s true when Gottheimer and lefties online say it. There is ALWAYS someone richer than you, and if you wouldn’t bend the knee to them then no one should bend the knee to you. Furthermore we live in a democracy, one man one vote. The votes of the poor carry just as much weight as the votes of the rich, and there is no special provision that says otherwise. That goes for poor people just as much as poor states. If Democrats want to be the party of the people, I’d better never hear another one of them insinuate that rich voters matter more than poor voters.

Beam Therapeutics: what’s so special about prime editing?

Beam Therapeutics is another biotech company often mentioned in the same vein as Ginkgo Bioworks, Amyris, and Twist Bioscience, and since I’ve blogged about all three of those I might as well blog about Beam. Unlike Ginkgo and Twist, Beam isn’t a shovel salesman in a gold rush, they’re actually trying to create drugs and sell them, in this case they’re trying to break into or perhaps even create the cutting edge industry of medical genetics, changing people’s genes for the better. I’ll briefly discuss the science of their technology, but I feel like the science surrounding their technology deserves the most focus.

Beam has a novel form of CRISPR/Cas gene editing called prime editing. In both normal CRISPR/Cas and prime editing, genetic information is inserted into a living organism by way of novel DNA, guide-nucleotides and a DNA cutting enzyme. The guide-nucleotides direct the information to the specific part of the genome where it is needed, the DNA cutting enzyme excises a specific segment of host DNA, and hopefully DNA repair mechanisms allow the novel DNA to be inserted in its place. These techniques always rely in part of the host’s own DNA repair mechanisms, you have to cut DNA to insert novel DNA and that cut must then be stitched back up. Most CRISPR/Cas systems create double-stranded breaks while prime editing creates just single stranded breaks, and this greatly eases the burden of the host DNA repair mechanisms allowing inserts to go in smoothly and with far less likelihood of catastrophic effects. Double stranded breaks can introduce mutations, cancers, or cause a cell to commit cell-suicide to save the rest of the body from its own mutations and cancers. Because Beam is using prime editing, their DNA editing should have less off-target effects and far less chances to go wrong.

So the upside for Beam is that they’re doing gene editing in what could be the safest, most effective way possible. The downside is that gene editing itself is still just half the battle.

When I look at a lot of gene editing companies, I quickly find all kinds of data on the safety of their edits, the amount of DNA they can insert or delete, and impressive diagrams about how their editing molecules work. I rarely see much info about delivery systems, and that’s because delivering an edit is still somewhat of an Achilles’s heel of this technology. In a lab setting you can grow any cell you want in any conditions you want, so delivering the editing machinery (the DNA, the guide-nucleotides, the enzymes) is child’s play. But actual humans are not so easy, our cells are not readily accessible and our body has a number of defense mechanisms that have evolved to keep things out and that includes gene editors. To give you an idea of what these defenses are like, biology has its own gene editors in the form of retroviruses which insert their DNA into organisms like us in order to force our body to produce more viral progeny, a process which often kills the host. Retroviruses package their edit machinery in a protein capsid which sometimes sits inside a lipid (aka fatty) envelope, and so the human body has a lot of tools to recognize foreign capsids and envelopes and destroy them on sight. These same processes can be used to recognize and destroy a lot of the delivery systems that could otherwise be harnessed for gene editing.

Some companies side-step delivery entirely, if it’s hard to bring gene editing to cells why not just bring the cells to gene editing. This was the approach Vertex Pharmaceuticals used in its sickle cell anemia drug, blood stems cells were extracted from patients and edited in a test tube, before being reinserted into the patients in order to grow, divide, and start producing non-sickled red blood cells. This approach works great if you’re working on blood-based illnesses, since blood cells and blood stem cells are by far the easiest to extract and reinsert into the human body. But for other illnesses you need a delivery method which, like a virus, is able to enter the organism and change its cells’ DNA from within.

So if Beam Therapeutics wants to deliver a genetic payload using their prime editing technology, they’re going to need a delivery system which obeys the following rules

  • It must be able to evade the immune system and any other systems which would degrade it before it finds its target cells
  • It must be able to be targeted towards certain cells so that it doesn’t have off target effects
  • It must be able to enter targeted cells and deliver its genetic package

So let’s look at the options.

Viruses have already been mentioned, and they can be engineered in such a way as to deliver a genetic package without causing any disease. However as mentioned they are quickly recognized and dispatched by the immune system whenever their are found, their protein shells being easy targets for our bodies’ adaptive immune system. Normal viruses get around this by reproducing enough to outcompete the immune system that is targeting them, but we don’t want to infect patients we just want to cure them, so using viruses that reproduce is off the table for gene editing.

A variety of purely lipid-based structures exist which can ferry a genetic package through the body. Our cell membranes are made of phospholipids, and phospholipids will naturally form compartments whenever they are immersed in water. Phospholipids also have the propensity to fuse with each other, allowing their internal compartments to be shared and anything inside them to move from one to the other. Packaging a gene editor inside phospholipids would be less likely to trigger the immune system, and they can be created in such a way that they target a particular cell type to deliver their genetic package. However random phospholipids can be easily degraded by the body, limiting how long they can circulate to find their target cell. Furthermore their propensity to fuse is both a blessing and a curse, allowing them to easily deliver their genetic package to targets but also making them just as likely to deliver it to any random cell they bump into instead. This means a lot of off-target delivery and the possibility for plenty of off-target effects

At the other end of the scale are nanoparticles made of metals or other compounds. Many methods exist to attach drugs to the outside of a nanoparticle and target that nanoparticle to a cell, however this in turn leaves the drug free to be interacted with and targeted by the immune system. For many drugs this is fine, but prime editing uses foreign proteins, DNA and free nucleotides and the body is downright paranoid about finding those things hanging around since that usually means the body has either a cancer or an infection. To that end, the body destroys them on site and triggers an immune response, which would severely curtain any use of nanoparticles to deliver a genetic package. Nanoparticles can also be designed hollow to allow for the prime editing machinery to fit snugly inside them, but this can lead to the machinery just falling out of the nanoparticle in transit and being destroyed anyway. You might say “well not a hollow sphere that fully surrounds the machinery so it can’t fall out?” But it does need to get out eventually if it wants to edit the cell, and if it’s encased in a solid sphere of metal it can’t do that. Enzymes to breach the metal would be cool but are impractical in this case.

Between these two extremes we have a number of structures made of lipids, proteins, polymers or metals, and they all struggle with one of these points. They can’t encase the machinery, or they can’t easily deliver the machinery, or they trigger an immune response, or they degrade easily, or they often cause off-target delivery. Delivery to the target is Step 0 of both prime editing and gene editing in general, and for the most part this step is still unsolved. I’ve visited several seminars where viral packages for delivering CRISPR/Cas systems were discussed, and while these seem some of the most promising vectors for gene editing they still have the problem of triggering the body’s immune system and being destroyed by it. The seminars I’ve watched all discussed mitigating that problem, but none could sidestep it entirely.

I do believe that Beam therapeutics has technology that works, their prime editing is clearly a thing of beauty. Beam is currently working on treatments for sickle cell anemia, as is Vertex Pharmaceutical, and as are most gene editing companies because it’s a blood-based disease that is amenable to bringing the cells to the gene editing machinery instead of having to go vice versa. But for anything where you can’t bring the cells to the editing, Beam isn’t quite master of it’s own fate because for prime editing to reach the cells of the body it will need to be delivered in some way and currently that’s an unsolved problem. Even a system that works to deliver some packages won’t necessarily work for all of them as size and immunity considerations change with the specific nature of the genetic package you’re delivering. I would also be worried about Beam’s cash burn, they are essentially pre-revenue and will need to do a lot of research before any of their drugs get to market or can be sold to a bigger player. I think they can survive for a long while by selling stock since their price has held up a lot better than other biotechs I’ve blogged about, but that’s good for them and not for a shareholder. As long as interest rates keep going up, I’ll treat pre-revenue companies with a wary eye.

Writer for sale

Very small post today because I forgot to write one, but I hope tomorrow to write about Beam Therapeutics so watch this space!

Anyway, I have a job, but I’m always open to new ones. I’ve looked at becoming a stock writer. I know it’s not glamorous or 6-figured, but writing about biotech and pharmaceuticals is a something I enjoy and a job I think I’d be good at. Don’t take this blog as the only signal of my quality (or lack thereof) I write most of these last minute because I have my own 9-5 right now. But I think some of these posts that I’ve spent time on are actually good, and so if any of my readers know of good places that would pay for freelance writers, hit me up at theusernamewhichismine@gmail.com.

People buy stocks instead of ETFs because their values are different

I enjoy talking stocks, and whenever you hang around on the finance parts of the internet, you’ll inevitably run into the following sentiment:

Why are you even buying individual stocks? You should just buy a broad-market ETF. You’ll never beat the market so ETFs are the best and most reliable way to grow your money.

Bogleheads et al

I’ve written about the Efficient Market Hypothesis before and about the difficulties of stock picking. I understand and to an extent agree with the arguments that people in general cannot beat the market reliably over any significant length of time. Any good runs are transitory, purely luck based, and eventually fall back to earth (see $ARKK 2016-2021 and then 2021-today). But that isn’t the primary value most stick pickers are going for, they’re going for potential return not expected return.

When you buy a broad market ETF, what is your expected return? Well the ETF tracks the whole market and the market goes up 5-10% every year, so that’s the return you can expect. Some years you’re down 20% (like 2021), some years you’re up 30% (like 2019), but on average you get a 5-10% yearly return that will slowly grow your money. Slowly is the key word: investing in the stock market probably won’t make you rich, for the average American it won’t even make you a millionaire over the course of your entirely life, but it will give you a small leg up in the long run with very little risk to yourself.

So what’s the expected return for stock picking instead? Well, definitely less than 5-10%. The efficient market hypothesis and significant amounts of experimental data show that stock pickers broadly lose to the market over any significant timescale. They might be up 100% one year but are equally likely to lose it all the next. But the key here is that the expected return is not everyone’s return. The expected return is just the average of everyone’s return, and while on average people lose to the market there are always a lucky few that beat the market and some of them win big. There is at least one person out there who went all in on Tesla stock in 2013, sold in 2021 when Musk started acting weird, and made a truly life changing amount of money, and everyone who stock picks hopes to be like that person. Is it likely? Of course not, but it’s possible and that’s what keeps people going.

This may sound illogical to a bogglehead, and they may scoff and say the stock picker is no different that the casino gambler, but let’s try another example. What is the expected return of starting a small restaurant? Well, it takes a lot of capital investment to start a restaurant and 80% of them fail within the first 5 years of operation, so it’s safe to say that the expected return of a restaurants is actually negative. On average a person starting a restaurant will end up losing money, so are an restauranteurs as illogical as stock pickers? I’d argue no, the expected return isn’t as important to them as the potential return. A restaurant is an opportunity to make a life-changing amount of money, and while it’s clearly very uncommon, it happens often enough to continue enticing people to try it. The bogglehead could just as easily state that it’s more efficient for restauranteurs to not open up restaurants at all and they should instead invest in broad market ETFs, but if no one ever took risks like that then we’d never have new businesses at all.

Big gains require big risk, and I’d argue being content with your lot and investing like a bogglehead is no more “logical” than going all in on smart but high-risk plays, it’s simply a questions of values.

Amazon and PE

Conventional business indicators such as the price-earnings ratio, the price-to-book ratio, and discounted cash flows belong in the Bronze Age – so say the new economists. But if the old metrics don’t capture the potential of today’s fast-growth companies, some new formulas can.

PERManent Upside, WIRED Staff, February 2000

I think about the above quote a lot these day. At about the absolute peak of the dotcom bubble, there were writers and (supposedly) economists claiming that the foundation of the stock market had changed, and that what appeared to be overvalued tech stocks driven by computer-illiterate investors FOMO-ing into anything with a website were in fact some of the greatest stocks to own since sliced bread. PE, PB, DCF were useless in evaluating these stocks, they stood on their own through a new metric created just for them, PERM. No one knows, cares, or remembers what PERM stood for (you can read the linked article if you really want to), but it was supposed to prove that earnings weren’t important and that high PE stocks were still good deals. I think about this a lot because this is the same argument many have used on me regarding Amazon.

Amazon had a bad 2022, over the year it’s stock price cratered around 50% and it lost 1 trillion dollars in market cap. The old adage that “Amazon’s PE doesn’t matter” has seemed less and less true as it’s PE has gotten closer and closer to “normal.” Sure it’s still well above value stocks, even well above most tech stocks, but it’s not to far off from Walmart these days which would have been unthinkable just a few years ago. It may be that economic gravity is catching up to Amazon, and if so I’d like to share my theory as to why. Full disclosure, I did buy 10 shares of Amazon right after their latest stock split and have held them ever since. I’m down rather a lot on the investment and if what I’m about to say is accurate I’m soon to be down even more, so you can consider that data point as a hedge against my thesis and read on.

The conventional theory for why Amazon’s PE never mattered was that it invested almost every dollar of profit back into the business. By re-investing their profits rather than claiming them as earnings, Amazon avoided a lot of corporate taxes. And if Amazon’s reinvestments were wise, then the stockholders gained value tax-free rather than through taxable dividends. There’s also an argument that Amazon’s reinvestments were more efficient even outside of tax implications. Every dollar Amazon reinvested could create so much growth that it was better for an investor to let Amazon keep their money and grow than for an investor to demand Amazon hand money back to shareholders. When you look at what Amazon was investing in: cloud computing, content delivery, and an every increasing share of online shopping; this certainly seems to have been the case for the last decade or so, an investor gained more value by parking their money with Amazon than they would have parking their money with a company that handed earnings back to investors.

But perhaps something has changed, and changed drastically enough that Amazon’s PE lows won’t be temporary. Amazon’s revenue and earnings continue to grow year after year, but if its stock price continues to sink it’s PE may eventually reach downright normal levels. If that is the case then I think the reason why would be clear: investors no longer believe that a dollar re-invested by Amazon is worth quite so much more as it used to be. Amazon may be approaching the limits of its momentous growth, and may now start evolving into a “mature” company like Microsoft and Apple before it. In those cases a moderately high PE is still justified, I mean these are trillion-dollar tech companies, but they can’t be expected to continue their meteoric growth and so PEs in the 100s are no longer sensible. Amazon is famous for how much it re-invests, but the dollar amount of investment is less important that the future dollars that investment generates. In the past, Amazon’s future returns of ever re-invested dollar were great enough to justify a sky-high PE but that won’t last forever. Many companies that aren’t valued like Amazon re-invest a lot of their profits, the Red Queen Hypothesis makes as much sense in biology as it does in Economics “you have to run as fast as you can just to stand still.” Companies which re-invest a lot to maintain their dominance don’t necessarily get a premium over those that hand money back to shareholders but maintain dominance. And if Amazon reinvests a greater percent of its earnings vs Apple or Microsoft but doesn’t grow significantly faster than them, then it’s stock price shouldn’t command a premium either.

I think it’s possible that Amazon is indeed maturing into a company that will be valued by it’s PE just like all the other tech companies. That doesn’t mean it’s time to dump the stock, the revenue and earnings continue to grow and will probably catch up to the PE, or at least that’s just as likely as the PE falling to meet the revenue. Regardless of the mechanics, economic gravity will eventually catch up to Amazon just like it caught up to Tech stocks of the 2000s. Nothing is ever truly new.

Buses have only gotten worse during my adulthood

I’ve lived in cities my whole life and yet it seems like the bus systems in every city I’ve ever lived in have only gone downhill. When I first went to grad school, I used buses and trains to get around town to do my grocery shopping and whatnot. By the time I was graduating, the buses had all gotten so sketchy that I no longer used them. People smoked openly on them, there were always homeless people panhandling, and they just seemed a little too violent to be safe. I eventually left that city for my current one, and the buses are STILL crap but in another direction. They’re never on time, I’ve had multiple days where a bus just plain doesn’t show up, and now they’ve altered the route schedule to ensure that my bus MUST take a much longer time to reach it’s destination. When I started riding my route, I could get from A to B in 20 minutes give or take. They’ve now altered the route to make A to B take 30 minutes, and if traffic isn’t bad and the bus is a little early, the driver will stop on the side of the road to ensure it takes no less than 30 minutes.

I don’t know what buses have always been this bad, but it’s really putting me off public transportation in general. It’s even more galling when the cities I’ve lived in are demanding ever increasing funding for ever worsening service. At what point should the city cut its loses and say no, no new funding without fixing what you currently have. More money isn’t a cure all, countries other than mine have much better bus service at much lower cost, I know, I’ve been to them. The cities I’ve been to seem to have a cost disease, where they keep spending more and more to get worse and worse and the only conceivable cure is more money. It’s infuriating.

Small post: I’m currently drawn in my by own nostalgia

I got Christmas gifts from my friends last year, and near all of them gave me video games (which is exactly what I gave them, so neither of us can complain). And yet barely any of them have I installed and played, I’m finding myself more drawn in to the familiar comfort of old games I’ve played through a thousand times. I wonder if this is just a reaction to my current scenario, I’ve been very busy at work and haven’t had much time to sit down and get comfortable with new games. I hope this is just a phase I’m going through that won’t last, I don’t want to find myself stuck in a few games for the rest of time, but for right now I’m just sitting here content with what I have. I keep promising myself I’ll install and play my gifts, and I really hope I get the feeling to do so soon.

Science needs good communication, but it also needs basic literacy

I’m really bummed out today and this post will kind of be a rant. As with most biochemical scientists I have a lot of temperature-sensitive materials kept in a -80 degree freezer box. Pretty much all my work since I started this job is kept in that box, along with samples sent to me by collaborators. Well over the winter break, a certain someone (I won’t name who, but I know who) decided to clean out the freezer, and they apparently didn’t read MY INITIALS which were written on my box, so they thought my box belonged to someone else who no longer works here and they tossed it. All my research products, gone. Half my samples from collaborators, gone. My only solace is that I still have collaborator samples LEFT, at least I still have something kept in separate boxes only for organization reasons, but still the loss of all that work is really making me not want to do any more work today or maybe ever. And it isn’t even someone I know really well who did this, I don’t know if that makes it better or worse. It’s someone I know, I’ve been to lab parties with them, but I struggle to think of their face from memory.

I’ll need to take stock of how far this has set me back. I need to contact collaborators to get new samples if possible. I especially need to strongly remind them that this wasn’t MY fault, although I worry that a petty collaborator might be furious enough to break off contact over something like this and blame me anyway. Most of all I need to make a plan to go forward. I haven’t been the MOST successful at my craft, like I said previously I still don’t have an extraction protocol that works every time, but I need to find some way to do things after this. At least it’s the weekend tomorrow, I can discharge over the weekend and hope to come back with something, but I think today is a lost day for science. I just can’t get myself in the mood to do work after discovering this.