Author Archives: theusernamewhichismine

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

Driving in the rain SUCKS

I’m tired. A friend of mine transferred colleges over the winter break, and after his other friend with a pickup truck got sick it fell to me to get him to his new town so he could move into his apartment in time for the Spring Semester. And DAMN did it rain on us! Sheets of water like rivers falling out of the sky! Cars on the highway not giving a damn! I felt even if I were to turn on my high beams on I would barely see the next car in front of me! The three hour round trip was a hell of a journey that I do not want to repeat, but I’m glad at least that my friend is safe in his new apartment.

Preemptively declaring victory on the “will Twitter die” prediction

It’s a new year, and with twitter still operating as usual I’d like to preemptively declare victory on my prediction that Twitter will not die in the next year. I’ll still have a full update on the 1 year anniversary of that post, but I think we have had enough time to at least take stock of things.

First I’d like to lay some ground rules. There was definitely a lot of misplaced hyperbole surrounding Elon Musk’s purchase of twitter. A number of articles about how the platform was dying, or unsafe. Some semi-major journalism outlets like CBS news even left twitter (for about a day, before rejoining). But a common defense mechanism for people who are publicly wrong is the “I was only joking” defense aka Schrodinger’s douchebag. I want to be clear that a lot of organizations like CBS were definitely acting like twitter would implode any minute, and so it’s important to note why these people were very wrong and what we can learn from this.

First note: is twitter dying because advertisers are fleeing it? Hard to say because advertisers are fleeing all companies right now. Advertisers fleeing Facebook (in the midst of a pandemic-related recession) didn’t stop that company from reaching a valuation of 1 trillion not long after, so stories about certain advertisers fleeing twitter aren’t really informative. At any time, with any company, you can always find some advertisers fleeing a platform, sometimes it says a lot more about the advertisers (losing money, can’t afford) than the platform (still growing). Considering the fact that the US economy is still not doing good (growth is expected to be zero or negative in 2023), then it’s natural that advertisers are fleeing twitter just as they are fleeing google advertisement. So without evidence that more advertisers are fleeing Twitter than are currently fleeing google and Facebook/Meta, then we can’t declare the death of twitter any more than we can declare the death of the other tech giants.

Second note: did twitter’s codebase collapse? Not at all, it still works fine. In the wake of thousands of firings of software engineers, some asked whether the software that underpins twitter wouldn’t collapse soon after. This seems like a farcical suggestion to me, a well run company should only put software into production if the code is ready for prime-time. If the code needs daily maintenance to sustain basic functionality, then it should be in testing not in the hands of users. The suggestion that twitter would collapse soon after it’s exodus of engineers was implicitly a suggestion that the company was a dumpster fire of near-unworkable code prior to Musk’s purchase. More puzzling was that it was former engineers making these claims. I get that they were unhappy to lose their jobs and there was likely a lot of emotions running high, but if you’re implying that the code you previously were responsible for was a dumpster fire that barely hung together, then I don’t know what company would want to hire you afterwards. Most tech companies try to have higher standards.

It’s too early to tell if twitter truly is dying, we’ll have better data next year on user totals and engagement. Certainly Musk’s freewheeling personality could be scaring off both advertisers and users, but some could also be drawn to it like a car crash. Whatever the eventual result, it’s clear that the short-term predictions of doom were widely off the mark (just as I said previously)

Science Update: why is Jose Romero spreading vaccine disinformation?

In November, the CDC declared it would expand wastewater testing for the detection of polio in America. The polio virus has unfortunately returned to American shores, decades after we had thought it eradicated. Jose Romero is CDC NCIRD (National Center for Immunization and Respiratory Diseases) director, and had this to say:

“When will we know that we’re out of the woods? When we get our vaccine rates at the national level — 93 or 94 percent — to have herd immunity in the community,” Romero said, referring to when enough individuals have been vaccinated so their collective immunity prevents the virus from circulating in that population

Via Washington Post

A fine sentiment, and a call for greater vaccination. Which would be all well and good if Romero’s statement on vaccines causing herd immunity wasn’t total disinformation. Before I get to why this statement is false, I first want to discuss why I’m writing this and why this is important. American public health has taken a blow over the past several years and in many ways this can be traced back to people’s growing distrust of public health officials. The causes for this distrust are varied, but because of the mistrust it is imperative that public health officials deliver accurate and relevant information to the public to help regain the public’s trust. I find it hard to believe that Jose Romero, who is an MD and the CDC NCIRD director, does not know or realize that his statement is false. I find it more likely that he is telling a public health white lie of the type that has become all too common, saying something false in order to encourage behavior he’d like to see. In this case, he wants to encourage more vaccine uptake, so instead of saying the truth (that the American polio vaccine only protects the recipient from paralytic polio and does not promote herd immunity or reduce community spread), he is saying something that he thinks will get more unvaccinated people to want to get the vaccine. The problem is that what he’s saying is wrong, actual scientists can tell us he’s wrong, and agenda-driven actors can then use his wrongness to discredit whatever else he is trying to say.

It you want two MDs to explain why Jose is wrong, This Week in Virology has you covered, but I will explain as best I can.

The polio virus is known to cause paralysis, but this is a secondary effect, the virus primarily infects the intestines. About 90% of people infected with polio will develop either no symptoms, or mild symptoms (fatigue, fever, diarrhea etc) but not paralysis. In 1% of polio infection the virus then spreads throughout the central nervous system, causing damage to nerve cells which leads to muscle paralysis. There are two main classes of vaccine that can protect against polio, the oral polio vaccine (OPM) and the inactivated poliovirus vaccine (IPV). It’s important to note that America only uses the IPV. The OPM contains a weakened form of the virus which is capable of replicating, and because it can replicate this weakened virus can then be passed on to others, infecting them as well and potentially causing paralysis in them. However this vaccine allows the entire immune system to come in contact with the virus and build defenses against it. The IPV does not contain a virus, only pieces of the virus are injected into the patient. Because of this, the virus cannot replicate and thus cannot be spread to others, but it also does not immunize as strongly as the OPM. So what if someone who received the IPV comes into contact with poliovirus? They are not so strongly immunized, so the virus can still replicate inside them and be excreted in the stool. But they are immunized enough to be protected against the major polio symptoms especially paralysis.

So to recap: the OPM is effective at preventing people from acquiring and spreading polio, but because it contains an actual virus, there are major downsides that must be considered. The IPV is not effective at preventing people from acquiring and spreading polio, but it prevents all the worst symptoms and has less downsides to its use. America only uses the IPV, so increasing our vaccination uptake will not prevent the acquiring or spreading of poliovirus and will not lead to herd immunity. The vaccine used in America only prevents people from getting paralyzed if they get infected with polio.

I think Jose Romero (or his staff) must know this, but I think they (like too many public health officials) are trying to influence behavior by shading the truth. This is a pattern of behavior that Josh Barro has also chronicled, dishonest framing has been used to obscure the truth for ostensibly noble ends. But lying doesn’t help, when people realize you’ve lied they become far less likely to trust you later. And for our nation’s public health community to continue this further decline in trust could prove disastrous.

“Market Capitulation” is a circular argument

Will the market recover in the new year? Or do we still have a ways to go? Bears online have been going on and on about “capitulation” as in “nothing will change until we finally have capitulation.” Capitulation in normal terms means surrender, so in financial terms it means the point where investors finally give up holding and sell their shares at a loss. According to Investopedia capitulation is also the point where the investment hits its bottom. Prima facia this is a circular argument, “we won’t hit the bottom until we’ve reached the bottom” is another way to phrase it. But even dumber, this is a backwards looking argument that cannot be used for predictions. Over the year of 2022, $SPY (a popular ETF that tracks the performance of the S&P 500) hit it’s 52 week low in November at 348$ per share (it currently trades at 382$). Who’s to say that that wasn’t the capitulation, and it won’t go below that? When the S&P500 hit 666 in 2009, that was the bottom of the bear market, yet many people still didn’t believe it, expecting that there was still more pain to endure. It wasn’t until a while later that we realized no, that really was the bottom, there’s no more “capitulation” after that. So I don’t put any stock in people talking about “market capitulation.”

You can make resolutions at any time

Small post today. New Year’s is often the time for resolutions, demands from yourself to yourself that you will change yourself in the future. But it doesn’t have to be the only time, I’ve made resolutions to myself throughout this year and will likely do so into next year too. I haven’t kept to all of them but I’ve always tried my best. I want to be always improving, not just when it’s popular to do so.

Talk to type

My cousin only uses her phone to text, and only texts by using talk to type, she says things and the phone will write her message. During Christmas she was texting with friends while speaking with the family, but didn’t realize some of her more uncharitable remarks were being picked up and typed by her phone. I think she’ll have a lot of explaining to do to her friends.

Short post today: green hydrogen isn’t always

“Green” hydrogen power has become something of a minor meme industry. Hydrogen power (or “fuel cells”) is used to burn elemental hydrogen with elemental oxygen producing only water as a waste product. This industry has long been the fantasy of those who want to reduce our reliance on fossil fuels and prevent the accumulation of carbon in our atmosphere, the problem is that the most economical way of producing elemental hydrogen does neither. Hydrogen is usually produced from natural gas, but “green hydrogen,” could theoretically be created by splitting water into hydrogen and oxygen. Recently I read a story of a company seeking out tax breaks to produce green hydrogen from water, but the company isn’t interested in installing solar or wind power and using that for their purposes, they want to simply buy power from the grid and use it directly. The problem is that most of America’s grid isn’t actually powered by green power but by fossil fuels. This so called “green hydrogen” would simply use the electricity from fossil fuels to produce hydrogen, with no analysis done as to whether this would produce more or less greenhouse gases than producing hydrogen from natural gas instead. In this case then, green hydrogen may not be so green.

An excerpt from my Christmas letter

My Christmas letter this year was a bit personal, but there is a small part of it that I do want to broadcast to the world

I went to a Christmas party with my extended family, and I got a look around at the folks my age, older, and younger, and I thought about what my life is and what I hope it will be. I don’t know if I’m on a path that will lead me where I want to go, and I’m not sure what I could do to change it. I still want to get my continue my work in science, I still think I’m a good enough writer to work in scientific or technical communication as well, and I think I’m a good enough analyst to even understand financials and the work “under the hood.” Yet I haven’t reached a level in my career that gives me the comfort and freedom I truly want. I know none of us gets all we want, we’re always left with these self-doubts and self-reflections, wondering if our choices will take us where we want to go, but these days I feel overwhelmed by my doubts and fears about my own future. A lot of young friends I know joke about existential fears they feel, that Climate Change or Nuclear War will kill us all within a few decades, but then those same friends go about their day without seeming to feel any ill effects from the dread. What’s the opposite of existential? I feel a very personal dread every day and I do think it’s keeping me from doing my best, the fear of failure may be causing me to fail, and I don’t like it but don’t know how to avoid it. Whatever comes, I want you all to know that I will keep trying, keep striving, keep working towards my goals and towards the work I hope will help everyone. I don’t know what the future will bring me, but I promise to always try.

Interpretatio graeca for Chinese myths and legends

I’ve been reading an interesting book from 1931. It discusses the motifs and references used in Chinese art, highlighting the Taoist, Confucian, and Buddhist stories that many of them derive from. However the book has a problem in that the authors were clearly trying to relate every Chinese story back to the stories they were more familiar with, mainly Indian Buddhist stories but also Roman/Greek ones as well. The Romans used to do this all the time, they called it “interpretatio graeca.” The Romans figured that every god or goddess in every culture was merely a manifestation of a god they were already familiar with, so they would “interpret” foreign gods as being the same or similar to their Roman/Greek gods. So Ra, the chief god of the Egyptians, got conflated with Apollo in Roman writings because since they shared a sun motif they must be identical, right? But Ra was not the same as Apollo, and Chinese myths are not the same as Indian myths, yet the authors of this book keep conflating the two and interpreting Chinese myths through a lens of Indian myths.

The book itself is called Outlines of Chinese Symbolism & Art Motives (sic) by C.A.S. Williams. In many respects it works well as an overview of the history and stories that make up a lot of Chinese art, and a primer into Chinese art culture. And yet it falls into this trap again and again of trying to interpret everything unfamiliar through the lens of the familiar. I understand perhaps that for the reader this can make things easier, saying that “This god is the king of the gods, he rules the sky and causes lightning to happen” may be harder to remember than saying “he’s like Zeus,” but saying “he’s like Zeus” brings a bunch of inaccurate assumptions that really aren’t true to what the Chinese sky god is actually like.

I wonder if this is in part because of out-dated theories in comparative religion. There was a vibe for a time of assuming that all myths and legends were just borrowed or stolen from earlier cultures. Jupiter and Zeus weren’t an original idea, they must have been borrowed by the Greeks and Romans from some previous culture that had a sky god wielding thunderbolts and ruling the other gods. The theory went on to say that every single sky-god in history was just a borrowing of a borrowing from an “original” sky god that was dreamed up 10,000 years ago. But the other option is to realize that “sky god causes thunder” is an easy thing for different people to come up with independently. Assuming that every myth in history was borrowed from somewhere else is also how you got inaccurate claims that for example “Jesus was just re-branded Mithra” and other ahistorical nonsense. It’s a very human feeling to want to related everything back to something you already know well, but it doesn’t lead to good history and so it should not be a feeling used in Academic writing.

Still, for a book from 1931 Outlines is surprisingly good, I enjoy being able to read the characters and phrases it writes in original Chinese, and learning the meaning behind some of them with it’s usually accurate descriptions of etymology. The descriptions of myth and stories generally seem accurate and the nonstop conflations with Indian myths can be ignored. I got this for 6$ at a used book store and I think it was worth the money.