Tag Archives: alzheimers

Social sciences need to learn the lessons chemistry learned long ago

I’ve blogged before about my time in cryo-EM studying Alzheimer’s, but I want to bring you a quandry:

Cryo-EM can only study things that are stable and rigid in shape. It relies on bouncing electrons off of something and seeing how they bounce back. You can’t use cryo-EM to check the shape of water or oil, because that’s something that takes lots of different shapes depending on the moment to moment interactions of the many molecules floating around. You might even say water or oil *have no shape*, so finding their shape with cryo-EM is a fool’s errand.

So in cryo-EM, I studied Tau filaments. Tau filaments are long, braided “ropes” made of Tau. They look a little bit like this:

We can study them in cryo-EM because that rope-like structure makes them stable and rigid (compared to water or oil at least). I studied Tau filaments because Tau is implicated as causing Alzheimer’s disease, but there’s a problem: we believe “small Tau oligomers” cause Alzheimer’s not the filaments themselves. The small tau oligomers are like tiny pieces of cotton lint making up a larger rope, they don’t have a strongly defined “shape,” and so you cannot study them with cryo-EM, you can only study the filaments.

So how did I get around the fact that I was studying something *which didn’t actually cause the disease I wanted to study?* I got around it with strong evidence for a pathway that I could latch onto. Let me explain:

The Tau oligomers (the tiny pieces that are like cotton lint) do 2 things: they cause Alzheimer’s, but they also build up into large Tau filaments (the large rope-like structures). The exact shape of the filament “rope” depends strongly on the interactions of the oligomer “lint.” Even though I can’t study the lint itself, studying the rope it created lets me *infer* what the lint originally looked like.

To be fair, there are several weak links in this inference. What if our understanding of how the “lint” of the oligomers creates the “rope” of the filaments is flawed? Then when we try to recover what the structure of the oligomers through looking at the filaments, we get answers that are way off from reality. What if Tau doesn’t actually cause Alzheimer’s? Then all my studying doesn’t actually help us cure the disease.

These weak links must me known and rebutted with other evidence. In this case there is a lot of published literature on how the oligomers create the filaments, so we believe that part is correct. And while the Alzheimer’s field does remain in flux, Tau is widely implicated as a key causative agent in at least some forms of the disease. We don’t know these things for sure, but we have strong evidence, and that lets me build up my inference to say “studying the shape of the filaments will let me study the molecular nature of Alzheimer’s disease,” even if I’m not studying the disease directly.

Chemistry has a very long history, stretching back to quantum mechanics, benzene’s structure, and beyond, of trying to study things we cannot actually measure directly. We use inferences everywhere to study these difficult things until some great new tool comes along and lets us study them directly. These days any undergrad can stick benzene in an x-ray crystallography machine and find its structure, but that structure was discovered over a century ago when all we had to go on was bonding properties discovered by burning it. Inference was key to discovering benzene’s structure, and it’s key to my research today.

But sociology seems like it can’t help itself here. It doesn’t want to do the difficult work of finding small connections which let us study a larger problem indirectly. It seems like sociology wants to study a BIG problem DIRECTLY, and somehow find something that no one else has found over the literal millennia that humans have been studying themselves.

I was convinced to write this post when I saw the below figures passed around on social media:

If you don’t like reading science papers don’t worry, I don’t either, so let me explain:

These researchers wanted to study how anger makes people better or worse at performing a task. This in itself is FRAUGHT with problems though: how do you measure if someone is angry or not? How do you do so *objectively*? How do you do so in a controlled research setting, with ethical constraints like “not smacking them in the face over and over”? And even if you can rigidly define anger: how do you measure if anger causes someone to do better or worse at a task, vs if doing worse at a task makes people angry?

These researchers solved this problem by ignoring it. Here’s there method: give people 400-500 milliseconds (which is near the lower limit of average human reaction time) to click on a block on a computer screen. They take between more than 300 seconds on average because that’s about how fast average humans can reasonably react. NEXT: give them only 100 milliseconds to click on the block. This is *faster than humans can actually react*, so any clicks that happen in this timeframe are random guesses, “pre-clicks” (where the participant starts clicking before they see anything, in expectation that something is coming), and importantly: CLICKS MADE SIGNIFICANTLY AFTER THE 100 MILLISECONDS ARE NOT REGISTERED, because the block has disappeared from the screen and the person can’t move to click on it anymore.

What they found is that when people are given only 100 milliseconds to click on a block, the only successful clicks they make happen at around 100 milliseconds: these are usually pre-clicks and random guesses.

What does this have to do with anger? Nothing at all, literally nothing. But here’s the title of the paper:

“Anger has benefits for attaining goals.” Uhbuhwuh?

The researchers make the *completely* unsupported chain of conclusions that:

  • Giving people less time to complete the task made them angrier (unsupported, unmeasured by the study)
  • Because they were angrier, they completed the clicking task in less time: 100 millisecond vs >300 milliseconds
    • They do not at ALL address the issue that since the people were only given 100 milliseconds, they could not by definition take 300 seconds to complete the task
  • This lab setting click-on-a-block experiment is generalizable to any action or goal-oriented task where people might be angry (wholly unsupported by the study design)

The real conclusion of this paper is that “when you give people less time, they try to complete something in the less time they have been allotted.” Big whoop. But the authors wanted a sexy conclusion that would get them on the journal’s cover and the BBC, and they got it.

This is bad science, but it’s perpetuated by a cycle of sociologists and reporters who don’t care about bad science. For all that the BBC and British government wrings its hands about online disinformation, their science reporters might be the single biggest source of disinformation in the whole British Isles.

Now to be fair, just because something is bad science doesn’t mean it isn’t *true*. Aristarchus of Samon proposed a heliocentric model of the solar system *millennia* before Copernicus. He did so because Fire is the more noble element compared to Earth, and the center is the nobler position to be in. Therefore the Sun (made of fire) must be in the center with the Earth (made of earth) circling around it. This is bad science, even if it came to the right conclusion.

By the same token, it’s possible that anger really does make people faster at a clicking task, and perhaps better at achieving one’s goals overall. But this paper’s bad science doesn’t support that.

Now back to cryo-EM: we wanted to study how the structure of Tau filaments connect to Alzheimer’s, but we couldn’t do it directly. We had to painstakingly create a chain of inference across decades of empirical research to learn that Tau oligomers probably are part of the Alzheimer’s degeneration, and that the structure of Tau oligomers can be recovered by studying the shape of the filaments. We couldn’t study what we wanted directly in chemistry, but we found a chain of reasoning that let us study it indirectly.

Sociology could do the same thing. It’s hard to objectively measure anger, but could you create an objective measure? Or could you find some fMRI state, some epinephrine cascade state, some blood vessel dilation state, or some other molecular clue which *tracks directly with anger* and can be measured objectively? Yes you could do that in principle. And you could then use objective measurement to run tangible experiments relating anger to task completion. Give people a hard task, let them get angry, and see if as they get angry they get better, or do the people who keep their tempers actually get better? I don’t know, but with objective measurements of anger you might be able to do this.

Instead we have a paper using circular reasoning to construct a conclusion from data which could never have falsified their conclusion to begin with. We have terrible, bad science and we deserve better. Sociologists need to call this out from *within* the discipline, the calls can’t all come from without, or eventually the people who fund sociology will get tired of funding absolute garbage.

So whatever happened with Aduhelm?

Aduhelm and Leqimbi were hot news a few years ago. They are both antibodies that work as anti-Alzheimer’s disease drugs by binding to and hopefully destroying amyloid beta. The hypothesis that amyloid beta is the causative agent of Alzheimer’s, and that reducing amyloid beta will lessen the disease, is known as the Amyloid Hypothesis. And while the Amyloid Hypothesis is still the most widely supported, I wonder if the failures of Aduhelm and Leqimbi to make much of a dent to Alzheimer’s disease has damaged the hypothesis somewhat.

Because think about it, the whole job of an antibody is to help your body clear a foreign object. When antibodies bind to something, they trigger your immune system to destroy it. And this is why you get inflammation whenever you get a cut or scrape, antibodies will bind to whatever microscopic dirt and bacteria that enter your body, and your immune system flooding that area to destroy them is felt by you as inflammation.

And we know that Aduhelm and Leqimbi are working as antibodies against amyloid beta. They bind strongly to amyloid beta, they induce inflammation when given to Alzheimer’s patients (although inflammation in the brain can cause multiple side effects), and tests show that they seem to be reducing the amount of amyloid beta in the patients who take them.

Yet the prognosis for Alzheimer’s is not much better with these drugs than without them. Maybe they just aren’t destroying *enough* amyloid beta, but they are barely reducing the rate at which Alzheimer’s patients decline in mental faculty, and are not at all causing patients to improve and regain their mental state. Maybe the brain just *can’t* be fixed once it’s been damaged by amyloid beta, but you’d hope that there would at least be some improvement for patients if the Amyloid hypothesis is correct.

This has caused the field to seemingly split, with many still supporting the Amyloid hypothesis but saying these drugs don’t target amyloid beta correctly, with others now fractured in trying to study the many, many other possible causes of Alzheimer’s diesease. Tau, ApoE, neurotransmitters, there’s lots of other stuff that might cause this disease, but I want to focus on the final hail mary of the Amyloid hypothesis: that the drugs aren’t targeting amyloid beta correctly.

Because it’s honestly not the stupidest idea. One thing I learned when I researched this topic was the variety of forms and flavors that *any* protein can come in, and amyloid beta is no different.

When it’s normally synthesized, amyloid beta is an unfolded protein, called “intrinsically disordered” because it doesn’t take a defined shape. Through some unknown mechanism, multiple proteins can then cluster together to form aggregates, again of no defined shape. But these aggregates can fold into a very stable structure called a protofilament, and protofilaments can further stabilize into large, long filaments.

Each of these different structures of amyloid beta, from the monomers to the aggregates to the filaments, will have a slightly different overall shape and will bind slightly differently to antibodies. One reason given for why Aduheim causes more brain bleeds than Leqimbi is because Aduheim binds to the large filaments of amyloid beta, which are often found in the blood vessels of the brain. By siccing the body’s immune system on these large filaments, the blood vessels get caught in the crossfire, and bleeding often results.

Meanwhile other antibodies are more prone to target other forms of amyloid beta, such as the protofilaments or the amorphous aggregates.

But what amyloid beta does or what it looks like in its intrinsically disordered state is still unknown, and still very hard to study. All our techniques for studying small proteins like this require them to have a defined shape. Our instruments are like a camera, and amyloid beta is like a hummingbird flapping its wings too fast. We can’t see what those wings look like because they just look like a blur to our cameras.

So maybe we’ve been looking at the wrong forms of amyloid beta, rather than the filaments and protofilaments which are easy to extract, see, and study, maybe we should have been looking at the intrinsically disordered monomers all along, and we only studied the filaments and protofilaments because we were *able* to study them, not because they were actually important.

There’s a parable I heard in philosophy class about a drunk man looking for his keys. He keeps searching under the bright streetlight but can never seem to find them. But he’s only searching under the streetlight because *that’s where he can see*, he isn’t searching because *that’s where his keys are*.

Endlessly searching the only places you *can* search won’t necessarily bring results, you may instead need to alter your methods to search where you currently can’t. And if the Amyloid hypothesis is to be proven true, that will probably be necessary. Because right now I’ve heard nothing to write home about Aduheim and Leqimbi, many doctors won’t even proscribe them because the risk of brain bleeds is greater than the reward of very marginally slowing a patient’s mental decline, not even reversing the decline.

I no longer directly research Alzheimer’s disease, but the field is in a sad place when just 4 years ago it seemed like it was on the cusp of a breakthrough.