Tag Archives: Personal

The danger of small patterns

As I’ve probably said before, I work as a researcher. When you’re doing difficult or expensive research, you don’t usually have the time or money to do a whole lot of replications. That goes doubly if you’re working with patients or patient samples. But since science is all about finding patterns, how can you find patterns in a small dataset?

There are statistical tools that can help with this, but even before you get to the hypothesis testing phase, you need to know which direction your hypothesis will go in. For that, we tend to look at the small patterns which aren’t yet statistically significant and try to see what they mean. The danger here is when you don’t get data in a reasonable amount of time, you want to work on your project but you don’t have data to work on. So you go back to whatever you have, the “small patterns” and start extrapolating from there. “If this pattern holds, what could it mean for this disease?”

Then you can start getting attached to a hypothesis that has no data to back it. When you do get data, you may start to interpret it in light of the small pattern you already detected, a pattern which may not even hold. That’s the problem with small patterns, you get to thinking they mean more than they do.

The human brain is a pattern matching machine. Our first calendars came about from noticing that the seasons of a year came in patterns, and that certain stars in the sky could be seen during the hot season while others could be seen during the colder one. But people also thought they detected patterns about how certain things happened on earth when certain stars were seen in the sky. One pattern between stars and the sky held true, there is a correlation between which stars you can see and the season in your local area. But another pattern was false. Yet both patterns were studied and believed for thousands of years.

I hope I don’t get attached to bad patterns for quite so long as that, but it’s hard to avoid. When you’ve got all the time in the world and not enough data, you get attached to these small patterns that you think you detect. And that can hold true even when the pattern is no longer real.

Invest in what you know? How much do I need to know?

I’m a biochemical scientist. I’ve published papers. I’ve got degrees. As an investor, I’ve often been given the advice (whether from friends or randos on the internet) that to “invest in what you know” is the safest kind of investment. For me personally though, I’ve avoided investing in any particular biotech or med-tech companies outside of passive ETFs, because I feel like while I know a lot about biochemistry in general I don’t know enough in specific to have any kind of advantage in those areas. I know about Alzheimer’s disease, but I don’t know much about pharmacology so how would I discriminate between two Alzheimer’s drug companies I wanted to invest in? I know about CRISPR/Cas, but I don’t know enough about its delivery system in humans to feel confident that I could pick the winners in today’s more crowded CRISPR field. There are a lot of areas of biology that I feel I have a little knowledge, but not enough to give me an edge.

Maybe there’s a Dunning-Kruger effect here though, because while I can’t explain what cloud computing is besides “it’s like renting another person’s computer,” I have thrown a bunch of money into Microsoft and been happily watching it grow. I like my Microsoft products and my office suite, so I feel good enough about them that I feel they’re doing alright. Yet I clearly know a hell of a lot less about Microsoft than I do any of the biotech companies of the world, so why do I feel so confident investing here?

I don’t know, it’s hard to psycho-analyze myself, but am I making all the wrong moves? Should I focus on investing in biotech companies, confident that my background would give me an edge in picking the winners and avoiding the losers? For now, ETFs for me I guess, but I’ll keep blogging about them since they’re fun.

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.

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.

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.

Why do we still not know what causes Alzheimer’s disease?

Between 1901 and 1906, Alois Alzheimer began collecting data on the disease that would eventually bear his name. A patient with memory deficiency was autopsied after her death and her brain was found to contain amyloid plaques and neurofibrillary tangles. Around a half century prior in 1861, Guillaume-Benjamin-Amand Duchenne had described a disease that would bear his name, a form of muscular dystrophy, and like Alzheimer he had patient samples for study. In the next century and more both diseases would be studied and reported on, Duschenne Muscular Dystrophy was eventually linked to a single protein called dystrophin, and a number of FDA-approved treatments exist which target dystrophin and improve patient outcomes. Alzheimer’s disease was also linked to a protein, the amyloid plaques found by Alois contained a protein called amyloid beta. But while both diseases seem to have known causes, treatments for Alzheimer’s disease remain ineffective. What’s more, there is a growing body of evidence that the amyloid beta hypothesis for Alzheimer’s disease is on shaky ground. How is it that more than a century of study has not allowed us to even understand Alzheimer’s disease?

First, it must be said that the amyloid beta (Aβ) hypothesis for Alzheimer’s Disease (AD) didn’t come out of nowhere. Not only were the amyloid plaques found in Alzheimer’s patients coming from Aβ, but genetic evidence showed that the mutations associated with AD all seemed to affect the Aβ pathway. If the diagnostic criteria for AD included Aβ, and genetic evidence supported a role for Aβ, it seemed Aβ must surely be the cause of the disease. And further biochemical evidence supported a role for Aβ, for example when Aβ was shown to cause neuronal cell death in cultured nerve cells. The Aβ hypothesis even connects well with other diseases, Aβ acts as an aggregating prion and aggregating prions are known to cause other neurodegenerative diseases such as Creutzfeldt-Jakob Disease and Kuru. Note that some biochemists say a protein is only a prion if it comes from the prion gene of the human body, but like champagne this definition is expanding. So the Aβ hypothesis isn’t a hypothesis without support, it has strong biochemical evidence at the genomic and proteomic level, and fits in well with other brain diseases. It can certainly be said that Aβ proponents have ignored or downplayed evidence against the Aβ hypothesis, but that behavior is common in all disciplines. Science advances one funeral at a time.

Second, it should be recognized that AD is a difficult disease to study involving a difficult organ to study. AD affects memory and behavior by affecting the brain, those are processes and an organ that are still very opaque to us in general let alone in the context of AD. So AD is a disease we don’t understand affecting processes we don’t understand in an organ we don’t understand. Maybe we should feel grateful we even have drug candidates to begin with?

To bring this back to my own work, let me give you an example of the very small problem I am working on and the difficulties I am facing in getting data. We have a theory that there are different subtypes of AD. There is the rapid-onset (r-AD) subtype and the slow-onset or traditional (t-AD) subtype. We believe that this difference may be structural in nature, that the proteins causing r-AD and t-AD are the same but that they have different shapes. To this end, I am studying the structural variations of sarkosyl-insoluble proteins from AD patients.

OK what does that mean? I start by requesting patient samples from deceased AD patients matching either the r-AD or t-AD subtype. This is difficult because not everyone really agrees on the diagnostic criteria of these two subtypes (already we have problems!). Then once I have a patient sample, I perform a sarkosyl extraction. Sarkosyl is just a detergent like the one you wash your clothes with. A detergent can dissolve some things (like the dirt on your clothes) while not dissolving other things (like the pigments coloring your clothes). Previous studies have shown that the proteins causing AD are sarkosyl insoluble, so just like how laundry detergent will wash away dirt while leaving behind pigments, I can use sarkosyl to wash away non-AD proteins and keep the AD-causing proteins. These sarkosyl insoluble proteins include Aβ, but also include things like Tau and alpha-synuclein which some people hypothesize are the true cause of AD. The sarkosyl extraction is difficult, and I seem to fail at it as often as I succeed, am I just bad at my job or is this all really really hard? I hope it’s the latter but you never know. Then, once I’ve extracted the material I need from the patient’s brain, I use a variety of techniques to try to test our theory about AD. I can see if the extracts from r-AD and t-AD brains have different affects on neuronal organoids (artificial culture of cells that resembles an organ, in this case a brain), I can image the extracts with electron microscopy, I can take structural measurements with NMR, and so far all the data is frustratingly vague. I haven’t been at this job super long, but I can tell you I am not finding the One True Cause of Alzheimer’s disease any time soon.

And I think my struggles are fairly representative of the AD-researching community at large, or at least the ones I’ve talked to. It’s a disease that can only be studied biochemically post-mortem, the samples you get are both very limited and highly variable, it’s hard to relate the biochemistry back to the behavior and memory because we don’t have very good theories about that stuff to begin with, and we’re trying to use all the latest and greatest techniques to study this but we’re still struggling to get strong evidence to support our theories. After a century and more of study, we still don’t seem to be anywhere close to curing Alzheimer’s, we can’t really treat it, and we barely understand it. It can be frustrating and difficult work