How an outsider bucked prevailing Alzheimer's theory, clawed for validation | Hacker News Reader

How an outsider bucked prevailing Alzheimer's theory, clawed for validation

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129 pointsdogan32 comments

One of things I like about the Howard Hughes Medical Institute (HHMI) is that they find great scientists and just fund them. The scientists can research whatever they want as long as they keep producing. I always wondered if a hybrid approach to funding would work well at the government level. The current, permission-based process would remain in place for new researchers to prove themselves, and then an HHMI-style process for researchers who have proven themselves. There would be checks in place and if the funded researchers stop performing then they have to go back to the normal process. There are several details that would have to be worked out to guard against politics, etc. I think this may overcome the government agencies tendency to reject truly new ideas especially when they contradict the prevailing theory.

Disagree vehemently. HHMI funds what’s fashionable. Find me a HHMI investigator without a recent CNS paper. As with Nobel prizes, the true innovators always seem to make their discoveries outside the power circle.

How do the many innovations of bell labs fit your hypothesis?

He (or she)'s not disagreeing with the notion that unfettered funding produces innovation, he (or she)'s disagreeing with the notion that HHMI provides unfettered funding.

Part of the beauty of Bell Labs was that it wasn't necessarily all about fame and grandstanding- a lot of folks who were working there were just normal, unassuming New Jersey folk who put in a good days work messing around with whatever they were tasked with. The only analogous example to that sort of dynamic today might be amongst the workers at large government agencies like NIST and the NIH; it's unlikely that many of them will ever become rockstars in today's research climate, but they dutifully carry out experiments nonetheless.

> The only analogous example to that sort of dynamic today might be amongst the workers at large government agencies like NIST and the NIH

Drop into a DoE research facility. (Most will give tours to U.S. citizens.) Same playful approach to tinkering with whatever.

Holds true for biomedical sciences, which is what hhmi focuses on.

HHMI is more about biology and Medicine then about telecom and computing.

Reminds me of Lockheed's Skunkworks. I've heard lots of businessmen say they're going to recreate skunkworks, but with improvements.

The improvements, of course, make it not a skunkworks and these efforts never deliver skunkworks performance.

Could the government create a skunkworks? Not likely, because they fought against Kelly Johnson constantly over how he ran it.

I bet Paul Allen could have done it, because he had a track record of funding competent people and letting them do what they wanted.

I’m in the midst of listening to the Skunk Works audiobook. And it’s fascinating. It had been on my list of things to read but I just couldn’t wait. I bit the bullet and bought the audiobook. It’s worth every penny.

That's a great read. There's also "Kelly":

https://www.amazon.com/Kelly-More-Than-Share-All/dp/08747449...

The book by Leo janos?

Yes, him and Ben R. Rich.

> The scientists can research whatever they want as long as they keep producing.

How is that different from (publication pressure in) academia?

There isn't a grant process as far as I know. They don't have to worry about money.

This isn't a particularly surprising story considering the history of science. To give an example of how this sort of thing played out historically, Marshall Nirenberg was basically persona non grata (or at least dutifully ignored) at many scientific conferences prior to his postdoc's discovery of the codon for phenylalanine. At the time, he was working at the NIH, which was considered very low prestige by many contemporary scientists. Somewhat fortuitously, Francis Crick heard a lecture by Nirenberg at a conference in 1961 and considered it good enough to bring to the attention of the other key players of the day, and Nirenberg was elevated from obscurity to stardom. For whatever reason, Nirenberg's postdoc never really achieved stardom, despite being the individual who actually made the discovery.

For more information:

https://www.telegraph.co.uk/news/science/science-news/854683...

Semmelweis was literally thrown into an insane asylum and died not long after, following a beating by the guards. Einstein worked in a patent office, unable to get a university job like he wanted until after his theory was proven correct. It took years to get the evidence he needed.

https://en.m.wikipedia.org/wiki/Ignaz_Semmelweis

Nirenberg had it easy, compared to Ignaz Semmelweis, Barbara McClintock, Dan Shechter and likely many others I am unaware of - who were shunned for many years.

The scientific method is awesome. The scientific community, not as much - although I admit I have no idea how a system with better false positive / false negative ROC will look.

Amyloid-beta is associated with sleep deprivation. This new research could suggest that sleep is an essential component of the immune system.

If so, then the plaques it forms might be the brain’s last-ditch effort to protect itself from microbes, a sort of Spider-Man silk that binds up pathogens to keep them from damaging the brain. Maybe they save the brain from pathogens in the short term only to themselves prove toxic over the long term.

I really like the thinking here.

Similarly: In people with CF, calcium and glutathione build up in the cells. High levels of calcium are associated with cell death, so much of the CF community believes calcium is harmful.

I believe the calcium and glutathione are desperate efforts to buffer the cell in the face of deranged cell chemistry. I believe the high calcium is indicative of other things being really bad and the body trying desperately to compensate.

If this guy wants another outside-the-box research project, there you go. I would love to see that looked into.

Edit: Is it me, or does the article actually switch from saying amyloid-beta to saying beta-amyloid midway through?

This month, however, he got an unheard-of email from NIH: The agency had found some extra money lying around in its budget. Would he please respond to the reviewers and resubmit his proposal? An over-the-moon Moir did. He expects to hear back in a few weeks.

Yay! I hope he gets it.

That's really interesting. The correlation of amyloid plaques and alzheimers has always seemed to me like a classic case of the ambiguity of correlation and causality (i.e., cause or symptom?!). Sounds like the same deal with calcium in CF

It's also similar to how LDL cholesterol starts plugging damaged arteries and most blame it for heart disease.

This seems to be referencing the path to mainstream exposure for the infectious theory of Alzheimer's. Prior discussions (not the same link) on HN, posted for reference because they touch on the past research that was previously posted here:

https://news.ycombinator.com/item?id=18306381 (this one's a comment I made associating the cortisol/Alz risk to the microbial Alz connection; it's nothing more than a hypothesis)

https://news.ycombinator.com/item?id=17446016

https://news.ycombinator.com/item?id=17540512

https://news.ycombinator.com/item?id=17540094 (this is the parent link for the antiviral risk reduction study -- a good read, comments and source article)

There's a decent amount of reading when scholar-googling:

https://scholar.google.com/scholar?q=hsv1+alzheimers

Moir's paper specifically: the relationship between β-Amyloid and viruses in the brain:

https://www.cell.com/neuron/fulltext/S0896-6273(18)30526-9 (study link)

There's also research pointing to sleep's function as helping clear out plaques such as beta-amyloid.

https://news.ycombinator.com/item?id=16026655

Finally, there's at least a bit of research pointing to boosted susceptibility of herpes viral infections when carrying ApoE4:

https://scholar.google.com/scholar?q=hsv1+apoe4

The novel conclusion from all of this, which I suspect is being actively investigated, is that there's a potentially complicated interplay of an enhanced viral infection (HSV/HHV enabled by ApoE4) + evolutionary defense going into overdrive (β-Amyloid) + (potentially) sleep deprivation keeping the body from clearing out the residue -> disease.

---

I'm particularly motivated to track this research because of its prevalence in my family background and because, from what I can tell, I've thus far managed to avoid the environmental trigger-pull. I can already tell you I'll probably go on (val)acyclovir lifetime if I'm ever diagnosed with any particular strain, as it looks like active infection, with outbreaks, is what's likely to act as the first domino to tip.

From a previous discussion, beta-ameloyd isn't well studied, but it appears to be a viral catch-all, attaching to many viruses. The reason herpes is so significant is because it uses time-release capsules to continually reinfect a host user, and continually caught in the beta-ameloid. So herpes sufferers have more beta-ameloid to clear away most nights.

Yup. Working thread here:

https://news.ycombinator.com/item?id=18306921

(between you and me, incidentally.)

if you have a blood parasite, the virus will hide inside the parasite and re-infect you, and it won't matter if you are on a drug that kills the virus (unless the drug can get into the parasite and kill it as well). Even worse the virus could theoretically hide in your DNA or immune system as instructions-to-run-later, and your system could screw up and accidentally re-create it -- I am not sure how exactly that would work but it is worth exploring the possibility. If it was easy to kill, it'd be dead by now.

I apologize -- I think I'm missing the question...

The working hypothesis now is that if the root cause is pathogenic, then suppressing the pathogen(s) should delay or even prevent onset of the disorder by warding off collateral damage from the innate immune response. Applied: An indefinite (Val)acyclovir supplement should suppress recurring outbreaks of latent Herpes-class viruses, thereby avoiding the immune response which is speculated to eventually lead to Alzheimer's and Dementia-class disorders. All the other ancillary links (e.g. cortisol -> increase in risk, sleep deprivation -> increase in risk) may be explained through the same vehicle (e.g. cortisol -> increase in Herpes-class virus reactivation, sleep deprivation -> impairment in processes used to flush the brain, hastening onset of collateral damage from immune byproducts e.g. beta-amyloid), and it's the many different connections which may have thrown researchers off the scent.

If it took this long to potentially understand the connection, it would explain why "If it was easy to kill, it'd be dead by now" doesn't apply here.

Hopefully I answered your question, but I should restate that I don't quite understand what you asked :/

This all makes sense. APOE literally carries viruses around the body : https://bit.ly/2oRVFSr

> Complaints about being denied NIH funding are as common among biomedical researchers as spilled test tubes after a Saturday night lab kegger.

Comedy in science writing?

> Complaints about being denied NIH funding are as common among biomedical researchers as spilled test tubes after a Saturday night lab kegger

Is this supposed to mean complaints are common?

The article is littered with references to beer. As though the target demographic alcoholics who enjoy PopSci.

Scientific / conference culture has a somewhat concerning relationship with alcohol, which was a contributing factor to my ultimately leaving science. The amount of pressure to go out to a pub with your colleagues was much higher for me than it was in my current job, in large part because serious discussions and informal deals that could directly impact your academic career tend to happen in these sorts of contexts. I suspected that a lot of my co-workers in science were high functioning alcoholics.

Yes. It's not particularly surprising, though, since research grants is basically a field with much higher demand than supply.

Yup. And the NIH even has pretty reports to hit you over the head with just how depressing the situation actually is for researchers (especially if you're young).

https://report.nih.gov/NIHDatabook/Charts/Default.aspx?chart...

https://report.nih.gov/DisplayRePORT.aspx?rid=827

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