Author Archives: theusernamewhichismine

Coda to my thoughts on Civilization 6

I recently wrote about how the AI in Civ 6 seems to be worse at its own game than previous Civ games. I want to give a shoutout to the youtuber Sulla whose “AI survivor” series put this into sharp contrast for me. Sulla sets up games of Civilization 4 that pit the AIs entirely against each other, with no player involvement. He then looks to see how it all turns out.

In Civilization 4, the AIs will usually manage to conquer each other. The games start with 8 AIs and it’s never been the case that they all survive to reach the end of the game. On the other hand in Civ 6 I rarely see even a single AI get eliminated unless I’m doing the eliminating. It just goes to show how passive the Civ 6 AIs are, and how utterly incapable they are at using 1upt and the rules of their own game.

Just something to think about.

Civilization 4 thoughts

Playing Civ 6 made me nostalgic for Civ 4, so I made it my project to get better at it.  I’ve been watching videos from Sullla’s channel (a big Civ lp-er) and have learned a lot of good stuff that helped me in Civ 4

Now to start with this victory wasn’t exactly easy.  I took the most broken, OP leader in Civ 4 (Huana Capac) and used a map-type that the AI does really poorly in (highlands with dense peaks, AI pathfinding screws up).  Even then I did a tiny bit of save-scumming at the beginning to fight off the barbarians.  But once things were going, I found that a Civ 4 game can be really easy… when it acts like a Civ 6 game.  Let me explain:

The reason Highlands map is so easy is as I said the AI’s pathfinding screws up.  I never got war declared on me during my Emperor level game, my only neighbor was Charlemagne who loved me because I adopted his religion, and my other close neighbors fought inconclusive wars amongst each other with no territory changing hands.  This let me sit back and tech away, *and that’s also how I won my Civ 6 deity game*.  It’s made me definitely appreciate that one of the big things holding back Civ 6 difficulty is the AIs’ inability to conquer each other and snowball out of control.  In a normal Civ 4 game one or more AIs will declare war, conquer their neighbor, and suddenly roll right up to the player’s boarders with the world’s largest army in tow.  A successful conqueror loses relatively few units to gain a lot of territory, and unsuccessful one throws away all their production producing units.  This helps AIs snowball when they focus on conquest. I don’t know exactly why Civ 6 AI is unable to conquer each other (OK I do, it’s 1upt) but this failure is a large part of the reason why I think they aren’t able to challenge a player once you escape the early game and are in the midgame.  No single AI will be so far ahead of everyone as to be unstoppable, everyone is usually around the same size.

So that’s a bunch of random thoughts, but it’s what I thought of when playing Civ 4.

Civilization (the game) thoughts

I don’t know if I’ve blogged about Civilization 6 before.  The game has received its final DLCs and the devs have all but left to work on Civ 7, so I guess being 5 years late is the perfect time to talk about it.  Warning, this is a long post.  Also warning, I do enjoy Civ 6 and pretty much every Civ game I’ve ever played, but I will be very critical in this post.

To step back a moment, I’ve played every Civilization game since 3.  Most Civ games have a difficulty scale with funny little names, but basically there are 8ish levels of difficulty, and the AI gets progressively more bonuses as difficulty increases.  In 3, I could barely win on difficulty 3 of 8.  In Civ 4, I could reliably win on difficulty 5 of 8, and sometimes 6 of 8 (Emperor) with the right setups.  In Civ 5, I could win on 6 of 8 reliably, and once managed 7 or 8 using a broken setup and a lot of savescumming.  

Difficulty level 8 of 8 is always called Deity, and it is always an exceptional challenge with the AI receiving ludicrous bonuses to every single statistic.  I have never beaten any Civ game on Deity.  Until Civ 6.

Civilization 6 was the first game I beat on Deity and the crazy thing is I don’t actually think I’m better at Civ 6 than I was at Civ 4 or 5.  I know I’m bad at Civ 3, but that’s because I hate the trading mechanics.  But with Civ 6, I genuinely think it’s just an easier game than its predecessors in an interesting and perhaps bad way.

To start off, let’s discuss how the Civ games make higher level AIs difficult.  They don’t particularly add any new mechanics or strategies, they just give the AIs big multiples to everything they do.  At high levels, an AI city will grow 50% faster, train units 50% faster, build buildings 50% faster, and they start with free technologies.  At the highest difficulty of Deity, the AI also gets to start with 2 settlers to the player’s 1.  That means that on Deity, the AI will start with twice as many cities as the player does, and each city will be 50% more productive.  

That’s a big hole to dig yourself out of, but the player has much better knowledge of the game mechanics and so a very good player can still win, even on Deity.  

The thing is that the AIs understood the game mechanics in 4 and 5 a hell of a lot better than they do in 6.  Some would say 6 is more complex, but I don’t buy that, I think in many ways it has (thankfully) been made simpler and more streamlined for easier access.  But I do think the Civ 6 AI understands its own game a lot worse than 4 and 5.  

It comes down to “one unit per tile” or 1upt as it’s known in Civ circles.  In Civ 4, you could stack as many buildings and as many units on a tile as you wanted.  Want your city to have a forge, a market, a theatre, and be garrisoned by 10 archer units?  Go ahead.  Civ 5 changed this in that only 1 archer unit can ever fit on any tile, but they didn’t update the AIs to make them good at this new system.  There’s a complex juggling act that is needed to make all your units be effective when you can’t stack them all on a tile.  And the AI is not good at this juggling act.

In Civ 4 the AI wasn’t great but it was at least smart enough to gather a dozen units and march towards the nearest city.  If you only had a single archer in that city, well even Alexander the Great can’t win against those odds.  But in Civ 5, the AIs will gather a dozen units, and they will all get in each other’s way as they fail to march against an enemy city.  A single archer in Civ 5 can indeed pick off their enemies one by one, defeating a dozen units without taking a scratch.

So with 1upt, wars in Civilization became heavily player-favored, as no amount of enemy numerical advantage could make up for their incompetence.  However the Civ 5 AIs still had ungodly bonuses that could let them tech up and win the game through other means.

Civ 6 then decided to “unstack the cities,” doing to cities what 1upt had done to military units.  Now you could no longer have a forge, a market, and a theatre all in one place.  They had to be spread across the map of your city.  To make this mechanic fun, they added “adjacency bonuses” so that buildings work a lot better when they’re near things that help them.  If a market is near a river, then it can trade with far away places easier and it makes more gold.  If a theatre is near a world wonder, then it’s in a more beautiful part of town and produces more culture.  The player is encouraged to use these adjacency bonuses to get the most out of their buildings.  The AI… cannot do this to save its life.

Just like 1upt led to the AI being terrible at war, districts led to the AI being terrible at peace.  They have no ability to manage districts or even look for the best spots to place them.  You’ll often conquer an AI city and see districts placed in just such a way that they have zero adjacency bonus, which is hard to do if you know even just look at the tooltips.  They also seem to hyperfocus on research to the expense of all else, which doesn’t really help them.

But on deity the AI is still hard.  In fact, Deity AIs in Civ 6 are the hardest they’ve ever been, getting to start the game with three free settlers and a good sized army while the player starts with a single settler and a warrior.

But this gives a game against Deity AIs a sort of strange difficulty curve.  On turn 1 every single AI is more than three times as strong as you because they start with 3 settlers and their cities get free bonuses.  But as the turns go on the player makes more and more good choices while the AIs make poor ones.  Eventually the player pulls ahead of the AIs, and then starts to “snowball” from there.  Snowballing in strategy games is when the strongest ones in the game get even stronger over time relative to their peers.  Players always snowball better than the AI and so once a player is stronger than the AI, they’ll never ever be weaker again.  

So in a game against Civ 6 deity AIs, the first few turns are the hardest by far, and you can die within the first 10 turns easily.  But if you just make it to turn 50, you’re golden, untouchable even.  The AI isn’t skilled at getting any kind of victory, so even with their huge bonuses you can snowball out ahead of them and get whatever victory you want at your leisure.  This difficulty curve existed in every Civ game, but it is at its harshest in Civ 6 because the AIs have never been worse at playing their own game.

So while I have gotten my first Deity-level victory in Civ 6, I don’t actually feel like I’m all that good at it.  I feel like I’m playing chess against a 5-year-old only they’ve replaced all their pawns with queens.  I feel like this is definitely something that needs to be improved upon in Civ 7.  “Better AI!” isn’t exactly a hype-worthy back-of-the-box quote, but these are primarily single player games and I feel the single player experience is paramount.  I think I’d enjoy my time much more if I felt that my victories were from being out-maneuvered and outplanned, rather than because my opponents got free stuff at the start.  And I think it would be more fun if I could be ahead all game and then a smart AI could sneak up and overtake me in the lategame.  As it stands, once we’re out of the classical age, I’m golden.

I know no one at Firaxis games reads my blog, but if someone could tell John Civilization to fix his AI, that’d be great.

Understanding the lack of free lunch in the student loans debate

I’d guess my opinion matches most Americans about the Supreme Court’s student loan decision. The online response has been rather mental though. There’s been a number of people hyping up “obvious” solutions that have very very obvious problems that they don’t want to confront. So I’d like to speak about some of those.

Student loans should be dischargable in bankruptcy. The entire reason that Joe Biden supported student loans not being dischargable was so that poor students with no assets would be able to get the loans. The only reason someone will give you a loan is because they want their money back with interest. If they don’t think you’ll pay them back, they either won’t give you the loan or will demand exorbitant interest rates. The people who will get loans are either rich enough that they can obviously afford to repay, or are using the loan to buy an asset which can be repossessed if they refuse to pay. Poor students don’t fall into those categories, so for a long time they were locked out of student loans.

If student loans become dischargable, then banks will fear that certain students will rack up student loans and then immediately declare bankruptcy upon graduation. The graduate will have no assets to repossess, and so the bank is SoL. Banks will then only give loans to individuals with enough assets to repossess, or who are already wealthy enough to pay it back easily. Making loans dischargable would reduce the number of poor people who can go to college, and thereby increase income inequality. If you think that’s a good trade-off then we can have that debate, but this isn’t a consequence-free solution.

Loans should have no interest. This is the same as saying there should not be any student loans. Again, the reason people give out loans is because they expect to make back their money with interest. Without interest, there is no reason to ever write student loans. And so again, college becomes unreachable for those not already rich.

College should be free, provided by the government. This is a defensible policy, but too many people imagine a world without trade-offs, and those must be considered. People who think college should be free often point to Europe but don’t even understand that college is in fact not always free. In Germany, where college is free, only 1/3 of adults have a post-secondary degree or certificate, compared to around 1/2 of Americans. The exact numbers vary depending on how you count, but there is a clear divide, higher education is more rationed in Germany than it is in America.

The German system means that not everyone is even allowed to try to go to University, and those that do go usually face fewer teachers per student, (meaning they have to teach themselves more) and less assistance overall. I’m sure a lot of people would immediately fire back that this is a good thing, not everyone needs to go to University. But the thing is they’re usually talking about other people. They would never be able to look themselves in the mirror and admit that they be one of the 2/3 of people who just aren’t good enough to be accepted into a German University. Because higher education is not as rationed in America, more people can go.

Then there are the universities that actually do have fees. On paper these are lower than American fees, in practice many Americans qualify for financial aid that makes college free or at least cheaper than European college. In Belgium, tuition fees are about 1000 euros a year. I paid less than that in my undergrad (around 1000 dollars a year) because I received a good scholarship. And I was not an exceptional student at an exceptional university, if I was I might have gotten a full ride.

There are many reasons to despise the ever increasing cost of American universities. Most of the money goes to administrative bloat, almost nothing is spent to improve student lives or increase professor’s pay. Even the most “socially conscious” Universities will still pay millions of dollars to water their perfect lawns rather than pay the staff or grad students a living wage. But the student loan debate comes with trade-offs, and we must confront them if we want to change the system. Cakeism will get us nowhere.

If the weavers get replaced by machines, who will buy the clothes?

I’ve seen way too many articles about AI casting doom and gloom that it will “replace millions of jobs” and that this will lead to societal destruction as the now job-less replacees have no more money to spend.  The common refrain is “when AIs replace the workers, who will buy the products?”

This is just another fundamental misunderstanding of AI and technology.  AI is a multiplier of human effort, and what once took 10 men now takes 1.  That doesn’t mean that 9 men will be homeless on the street because their jobs are “replaced.”  The gains reaped from productivity are reinvested back into the economy and new jobs are created.

When the loom replaced hand-spinning weavers, those weavers were replaced.  But they could eventually find new jobs in the factories that produced looms, and in other factories that were being developed.  When computers replaced human calculators, those calculators could now find jobs programming and producing computers.

For centuries now, millenia even, technology has multiplied human effort.  It used to take dozens of people to move a single rock, until several thousand years ago someone had the bright idea of using ropes, pullies, and wheels.  Then suddenly rocks could be moved easily.  But that just in turn meant the demand for moving rocks shot up to meet this newer, cheaper equilibrium, and great wonders like the Pyramids and Stonehenge were suddenly built.

The same will be true of AI.  AI will produce as many new jobs as it creates.  There will be people to produce the AI, people to train the AI, people to ensure the AI has guardrails and doesn’t do something that gets the company trending on Twitter.  And there will be ever more people to use the AI because demand is not stable and demand for products will rise to meet the increase in supply generated by the AI.  People will want more and more stuff and that will lead to more and more people using AI to produce it.

This is something that people get hung up on, they think that demand is stable.  So when something that multiplies human effort gets created, they assume that since the same amount of products can be produced with less effort, that everyone will get fired.  Except that demand is not stable, people have infinite wants and finite amounts of money. 

Technological progress creates higher paying jobs, subsistence farmers become factory workers, factory workers become skilled workers, skilled workers enter the knowledge economy of R&D.  These new higher paying jobs create people who want more stuff because they always want more stuff, and now have the money to pay for it.  This in turn increases demand, leading to more people being employed in the industry even though jobs are being “replaced” by machines.

To bring it all back to weavers, more people are working in the textile industry now than at any point in human history, even though we replaced weavers with looms long ago.

AI will certainly upend some jobs.  Some people will be unable or unwilling to find new jobs, and governments should work to support them with unemployment insurance and retraining programs.  But it will create so many new jobs as well.  People aren’t satisfied with how many video games they can purchase right now, how much they can go out to restaurants, how much housing they can purchase, etc.  People always want more, and as they move into higher paying jobs which use AI they will demand more.  That in turn will create demand for the jobs producing those things or training the AIs that produce those things. 

It has all happened before and it will happen again.  Every generation thinks that theirs is the most important time in the universe, that their problems are unique and that nothing will ever be the same.  Less than three years ago we had people thinking that “nothing will ever be the same” due to COVID, and yet in just 3 short years we’ve seen life mostly go back to normal.  A few changes on the margins, a little more work from home and a little more consciousness about staying home when sick, but life continued despite the once-a-century upheaval.

Life will also continue after AI.  AI will one day be studied alongside the plow, the loom, and the computer.  A labor-saving device that is an integral part of the economy, but didn’t lead to its downfall.

Corporate Greed is over, now comes corporate generosity

If you’ve been to the grocery store recently, you have probably seen an incredible sight. Eggs are now selling for less than they did in 2022. Walmart says they’ll sell me eggs for 1.19$ a dozen, and Target will sell them for 0.99$ with a special discount. Considering that at the beginning of 2023, eggs were selling for as much as 5$ a dozen, this comedown is remarkable.

It gets to the heart of a discussion about the origins of inflation though. The classical definition of inflation is too much money chasing too few goods. That means that when either the money supply is increased or their is a shortage of goods, we should expect to see inflation. This thesis does seem to have played out in 2021-2023. The money supply was increased enormously in 2020 and 2021, while COVID restrictions meant the supply of goods was constrained and could not rise quickly to meet it.

But that isn’t the definition that has been gaining traction. Recently folks have pointed to corporate greed as the primary driver of inflation. Under this thesis, inflation is not driven by the money supply or the goods supply, but by corporate greed in and of itself. If corporations weren’t greedy, they wouldn’t raise prices. But if prices go up because corporations are greedy, doesn’t that mean they go down because corporations are generous?

I’d like to see someone like Bernie Sanders explain the fall in egg prices. Why aren’t Walmart and Target just being greedy like all the other companies? If it’s so easy to raise egg prices by being greedy, then what mechanism could possibly make prices fall? What possible reason could their be for a fundamentally greedy company to willingly lower prices and receive less money?

For that matter, why is Exxon-Mobile being so damn generous? Over the past year, crude oil prices have gone from 100$ to just 70$. Exxon-Mobile was public enemy number 1 when gas prices were high, and was blamed for being too greedy. Have they now become generous instead? Have all the oil companies become generous? Why are the oil companies so much more generous than all the other companies?

It gets to the heart of the problem, inflation isn’t driven by corporate greed. Corporate greed is a constant, I’d go so far as to say human greed is a constant. Corporations (on average) demand the highest possible price for their goods that the market will bear. Laborers (again on average) also demand the highest possible price for their labor that the market will bear. No one ever willingly takes a pay cut without good reason, good reason usually being they have no other choice.

If corporations want to raise their prices above what the market will accept, then they’d be like me walking up to my boss and demanding a million dollar salary. They won’t get what they want no matter how hard they try. If Walmart raises the price of eggs, then Target can steal all of their business by keeping its egg prices low. People stop buying eggs at Walmart, they instead buy eggs from Target or from one of the hundreds of small and independent retailers that still dot America. Grocery stores are not a monopoly in our country, they do not have the power to set prices on their own. They are always in competition with each other and prices reflect that competition.

By the same token, if I demand a million dollar salary, my boss just won’t pay it. If I say I’ll quit if I don’t get it, he’ll show me the door. I am competing with hundreds of other workers in my field and so I cannot raise the price of my labor over and above what others are charging or else I’ll get replaced. It is a fact that many people ignore, but there is a market for labor just as their is a market for any other good. And the labor market has sellers (workers) and buyers (employers) just like any other. So when trying to answer questions about (say) the egg market, it’s useful to first think about how it works in the labor market. We are probably all more familiar the labor market with since if you’re reading this blog you’ve likely worked in your life.

So, in the labor market, can the sellers of labor (the workers) raise their prices just by being greedy? No, of course not. Without some decrease in supply or increase in demand, the price (salary) of laborers doesn’t go up, and workers who refuse to work for the market raise simply won’t receive job offers. It’s the same with corporations and it’s the same with goods inflation. Prices of goods aren’t driven by greed. They’re driven by supply shortages and a glut of money, both of which are in part exacerbated by government policies.

The current administration has continued Trump’s protectionist trade policies, which prevent American companies from being forced to compete with overseas companies. And both congressional spending and the Federal Reserve’s balance sheet have expanded considerably, bringing more and more money into the money supply. Too much money chasing too few goods, that is what causes inflation.

The AI pause letter seems really dumb

I’m late to the party again, but a few months ago a letter began circulating requesting that AI development “pause” for at least 6 months. Separately, AI developers like Sam Altman have called for regulation of their own industry. These things are supposedly happening because of fears that AI development could get out of control and harm us, or even kill us all in the words of professional insanocrat Eliezer Yudkowsky, who went so far as to suggest we should bomb data centers to prevent the creation of a rogue AI.

To get my thoughts out there, this is nothing more than moat building and fear-mongering. Computers certainly opened up new avenues for crime and harm, but banning them or pausing development of semiconductors in the 80s would have been stupid and harmful. Lives were genuinely saved because computers made it possible for us to discover new drugs and cure diseases. The harm computers caused was overwhelmed by the good they brought, and I have yet to see any genuine argument made that AI will be different. Will it be easier to spread misinformation and steal identities? Maybe, but that was true of computers too. On the other hand the insane ramblings about how robots will kill us all seem to mostly amount to sci-fi nerds having watched a lot of Terminator and the Matrix and being unable to separate reality from fiction.

Instead, these pushes for regulation seem like moat-building of the highest order. The easiest way to maintain a monopoly or oligopoly is to build giant regulatory walls that ensure no one else can enter your market. I think it’s obvious Sam Altman doesn’t actually want any regulation that would threaten his own business, he threatened to leave the EU over new regulation. Instead he wants the kind of regulation that is expensive to comply with but doesn’t actually prevent his company from doing anything it wants to do. He wants to create huge barriers to entry where he can continue developing his company without competition from new startups.

The letter to “pause” development also seems nakedly self-serving, one of the signatories was Elon Musk, and immediately after Musk called for said pause he turned around and bought thousands of graphics cards to improve Twitter’s AI. It seems the pause in research should only apply to other people so that Elon Musk has the chance to catch up. And I think that’s likely the case with most of the famous signatories of the pause letter, people who realize they’ve been blindsided and are scrambling to catch up.

Finally we have the “bomb data centers” crazies who are worried the Terminator, the Paperclip Maximizer or Roko’s Basilisk will come to kill them. This viewpoint involves a lot of magical thinking as it is never explained just how an AI will find a way to recursively improve itself to the point it can escape the confinement of its server farm and kill us all. In fact at times these folks have explicitly rebuked any such speculation on how an AI can escape in favor of asserting that it just will escape and have claimed that speculation on how is meaningless. This is of course in contrast to more reasonable end-of-the-world scenarios like climate change or nuclear proliferation, where there is a very clear through-line as to how these things could cause the end of humanity.

Like I said it I take this viewpoint the least seriously, but I want to end with my own speculation about Yudkowsky himself. Other members of his caucus have indeed demanded that AI research be halted, but I think Yudkowsky skipped straight to the “bomb data centers” point of view both because he’s desperate for attention and because he wants to shift the Overton Window.

Yudkowsky has in fact spent much of his adult life railing about the dangers of AI and how they’ll kill us all, and in this one moment where the rest of the world is at least amenable to the fears of AI harm, they aren’t listening to him but are instead listening (quite reasonably) to the actual experts in the field like Sam Altman and other AI researchers. Yudkowsky wants to maintain the limelight and the best way to do so is often to make the most over-the-top dramatic pronouncements in the hopes of getting picked up and spread by both detractors, supporters and people who just think he’s crazy.

Secondarily he would probably agree with AI regulation, but he doesn’t want that to be his public platform because he thinks that’s too reasonable. If some people are pushing for regulating AI and some people are against it, then the compromise from politicians who are trying to seem “reasonable” would be for a bit of light regulation which for him wouldn’t go far enough. Yudkowsky instead wants to make his platform something insanely outside the bounds of reasonableness, so that in order to “compromise” with him, you’ll have to meet him in the middle at a point that would include much more onerous AI regulation. He’s just taking an extreme position so he has something to negotiate away and still claim victory.

Personally? I don’t want any AI regulation. I can go to the store right now and buy any computer I want. I can to go to a cafe and use the internet without giving away any of my real personal information. And I can download and install any program I want as long as I have the money and/or bandwidth. And that’s a good thing. Sure I could buy a computer and use it to commit crimes, but that’s no reason to regulate who can buy computers or what type they can get, which is exactly what the AI regulators want to happen with AI. Computers are a net positive to society, and the crimes you can commit on them like fraud and theft were already crimes people committed before computers existed. Computers allow some people to be better criminals, so we prosecute those people when they commit crimes. But computers allow other people to cure cancer, so we don’t restrict who can have one and how powerful it can be. The same is true of AI. It’s a tool like any other, so let’s treat it like one.

A possible cure for Duchenne Muscular Dystrophy

Sarepta Therapeutics may have a cure out for Duschenne Muscular Dystrophy (DMD). It’s called SRP-9001, and while I hesitate to say it’s a Dragonball Z reference, I’m not sure why else it has that number. Either way it’s an interesting piece of work and I thought I’d write about it and what I know about it.

DMD is caused by a mutation in the protein dystrophin, a protein which is vital for keeping the muscle fibers stiff and sound. Our muscles move because muscle fibers pull themselves together, which shrinks their volume along an axis and therefor pulls together anything they are attached to. The muscle cell pulling on itself creates an incredible amount of force, and dystrophin is necessary to make sure that that force doesn’t damage the muscle cell itself. When dystrophin is mutated in DMD, the muscle cells pulling on themselves will indeed begin to cause deformations and destruction of the muscle cell itself, which leads to the characteristic wasting away of DMD sufferers. The expected lifespan of someone with DMD is only around 20-30 years.

Dystrophin is a massive protein, fully 0.1% of the human genome is made up of just the dystrophin gene. However a number of the mutations which cause DMD are point mutations, mutations in a single DNA nucleotide. If just that one nucleotide could be fixed, in theory the disease could be cured. For a long time genetic engineering and CRISPR/Cas9 has targeted DMD for treatments based on this idea of just fixing that one nucleotide.

However, Sarepta seems to be working on an entirely new theory. Deliver a complete gene to the patient which can replace the functionality of the non-functional dystrophin. This is called micro-dystrophin and it is less than half the length of true dystrophin. However it still contains some of the necessary domains of dystrophin like the actin-binding-domain. This is important because of how genetic engineering in humans actually works (these days). How do you get a new gene into a human? Normally, you must use a virus. But the viruses of choice (like AAV) are actually so small that the complete dystrophin gene simply would not fit in them. Micro-dystrophin, being so much smaller, is needed in order to fit the treatment into a virus.

So the idea would be that DMD patients cannot produce working dystrophin, but when SRP-9001 is given to them it would give them the genes to create micro-dystrophin for themselves. Then once their muscles begin creating this micro-dystrophin, it would spread throughout the muscle cell and take up the job of strengthening and stiffening the muscle cell just like normal dystrophin does. In this way the decay of their muscles would slow and hopefully they’d live much much longer.

SRP-9001’s road to FDA approval is not yet fully formed. They’ve done some nice clinical trials where they’ve shown that their genetic engineering drug does successfully deliver micro-dystrophin genes into the patients, and that the patients then use those genes to produce the micro-dystrophin protein. However as of right now they are still doing Phase 3 clinical trials and still awaiting the FDA to give them expedited approval. That approval won’t come until June 22nd at the earliest, but I believe it would still make it the first FDA-approved treatment for DMD.

So what’s going on with Amyloid Beta and Alzheimer’s disease?

This will be a very #streamsofconsciousness post where I ramble a bit about my work.

As I’ve said before I study Amyloid Beta in Alzheimer’s disease. I am very new to this field, so much of what is surprising to me might be old hat to the experts. But I’m quite flummoxed on what exactly Amyloid Beta is doing both in diseased and healthy brains. When I started this job, I read papers indicating that Amyloid Beta (henceforth AB) forms these large filaments, and like a bull in a china shop those large filaments will sort of knock around and cause damage. Damaging the brain in that way is obviously a hazard, and would lead to exactly the type of neuro-degeneration that is a hallmark of Alzheimer’s disease.

So because of this, it’s my job to extract these large AB filaments and take pictures of them. That way we can see exactly what they look like and why it is that they do so much damage. But then this simple picture changed. AB is made up of thousands of individual peptides, and I read papers saying these individual peptides might actually be what causes the disease by disrupting the neurons and causing them to die. But if that’s the case, then what are the filaments doing? Are they still causing damage by being big and huge, or are they entirely benign and a red herring? If they are benign, then my studying them and taking pictures of them might be leading us down a dead end.

And now I found that AB is also necessary for the development of a healthy brain. Now this in itself is not too out there, any medicine can turn into poison if the dose is wrong. So this could easily be too much of a good thing, or a good thing in the wrong place, that while normally AB helps a brain, in Alzheimer’s disease something has gone wrong to cause AB to kill nerve cells. But still it’s surprising.

The paper I read indicates that AB is necessary for process of synaptic plasticity. No time to get into the whole details, but synaptic plasticity underlies the formation of memories in the brain. Mice who do not have AB have a harder time forming memories and completing tasks than mice with AB. So now I’m at the point where actually AB is necessary for the formation of memories of a healthy brain, but then sOmEtHiNg happens and it caused Alzheimer’s disease, which is characterized by deficiencies in memories. So what is happening?!?!?

I… don’t know. I don’t know if anyone knows. But I wish I had the tools to study this further. The difficulty is that I’m not sure if I do. My setup is geared towards looking at those giant AB filaments I talked about earlier. Filaments have a big, rigid form and you can do structural analysis on them to get what is essentially a 3D model. But all these papers talking about the role of AB in healthy brains, they are talking about it in the small monomeric form. Small monomers don’t form rigid structures in quite the same way, they are more akin to a floppy noodle, there’s no rigid form to hang your hat on and so no clean 3D model can be made for them. So maybe I’m using the wrong tool for the wrong job. Or maybe it really IS the filaments that are doing the damage. I’m just not sure at this time and it’s racking my brain trying to know where I should go next.

This is a bit hard to post

I’m not going to share this post to any of my social media, but I wonder if it would be cathartic to put this out in writing

I’ve been feeling a little jealous of how many of my friends seem to be succeeding in their jobs and their research while I’m not. I’m not getting the data I want so I can publish papers, I’m struggling at writing as much and as well as I would like, and since I don’t work in industry I’m not making as much money or getting the promotional opportunities I want.

I’m just feeling a lot of jealously right now and that’s making it hard for me to sometimes talk about my own trajectory and the trajectory of others.