Can a molecule that makes mice smarter heal a human brain? | Hacker News Reader

Can a molecule that makes mice smarter heal a human brain?

statnews.com

116 pointsfraqed53 comments

FTA:

"To Walter’s dismay, some are buying ISRIB online and ingesting it, long before it’s been extensively tested...

Some outside scientists remain skeptical. They warn that interfering with vital cellular mechanisms, as ISRIB seems to do, could lead to a host of dangerous side effects. They caution that it will be years, or possibly decades, before it’s ready for testing in humans."

Cause, meet effect.

Isn't Flowers for Algernon required 7th-grade reading anymore? This isn't going to end well, people.

That was the first thing that leaped to mind for me as well, specifically the line, "P.S. please if you get a chanse put some flowrs on Algernons grave in the bak yard."

Kidding aside though, anytime the question of, "Does this thing in mice do this other thing in humans?" the answer is always, "Who the hell knows until after the study is complete?!"

I was thinking Understand in Ted Chaing's Stories of Your Life and Others.

Just the same set-up: new drug that can heal a person's damaged brain, turns him into a super-intelligent psycho.

I'll just leave this here: http://www.metafilter.com/98974/This-isnt-your-grandfathers-...

Although it's important to point out that he wasn't psycho, and his preferences don't seem directly shaped by the treatment..

I'm curious what you mean by "isn't going to end well." I don't want to spoil the book. Anyone who hasn't read it really should as it's an excellent read.

But, at any rate, the Charlie character starts off as mentally very simple and enjoys life, then after attaining intelligence quickly achieves many things most people wont in their whole lifetimes, though isn't super happy while doing these and insults those he feels are less intelligent, though eventually grows emotionally through them, then he returns to being simple and happy.

Really this is just everyones' life, starting as a baby and returning to dementia as an adult, for Charlie it's just flat and then a sudden spike rather than a gradual curve. Curious why you think it wont end well. I mean in the end everyone dies so it's true if you're very much against that, nothing ends well.

The real point of the book I thought was we shouldn't view the super intelligent or super simple as better or worse because we are all both better and worse cosmically. So ultimately everyone should stop being condescending generally.

At some distant point in the future we will understand biology so well that we can see the ways in which evolution produced local maxima for certain processes, and we will be able to see alternate versions that are more optimal but would (almost) never evolve on their own.

At that point, we will indeed be able to create artificial molecules or genes that make brains more efficient at using oxygen and sugar to produce rational organized thoughts. But I have no illusions that anything groundshaking will happen in my lifetime.

Unfortunately, the fastest way we have to advance is to tinker and learn from our mistakes. I will leave it to other people to volunteer for that process.

The human brain uses up 20% of our energy. There may be easy ways to increase intelligence, that evolution avoided because it costs more energy. But in the modern world constraints like that don't matter.

...ways in which evolution produced local maxima...

There is a compelling argument against any simple way to enhance people. It's that if a simple change even the addition of a single molecule could make people significantly better, evolution would have found that change already. With nature we are stuck with much more incremental change. So I agree that science may eventually find some nice enhancements but they will require more than a single molecule or gene change.

This isn't exactly true, since the human meaning of "enhance" is quite different from the evolutionary meaning. For example, iodine (an element, not even as big as a molecule) supplementation at the fetus and early childhood stages can, among other benefits, result in as much as a 13 point IQ increase from a previously deficient region's average. This is a huge enhancement by human standards. Why hasn't evolution found a way to have our bodies produce iodine automatically (perhaps by producing iodomethane like some algae?) at that stage of life, or maybe only by the mother when the child is in the womb or perhaps produced and distributed only with breast milk? Then even if you lack natural sources of iodine you'll still benefit. It should be easy, it's just a single element!

Well even for "simple" things like the addition of a single new element, or a single new molecule, or a single new protein, the details are complicated, and any mutation that depends on a prior mutation to be beneficial has to wait until the prior mutation is close to fixation and is common among the species. Evolution is slow and only cares about reproductive fitness, and can easily get trapped in local maxima and a species can even evolve to extinction. Because of that, it can miss obvious (to human intelligence) low hanging fruit. So I don't think that "evolution would have found it already" argument is very compelling. Evolution is dumb, it's amazing it works at all.

>> For example, iodine (an element, not even as big as a molecule) supplementation at the fetus and early childhood stages can, among other benefits, result in as much as a 13 point IQ increase from a previously deficient region's average. This is a huge enhancement by human standards. Why hasn't evolution found a way to have our bodies produce iodine automatically (perhaps by producing iodomethane like some algae?) at that stage of life, or maybe only by the mother when the child is in the womb or perhaps produced and distributed only with breast milk? Then even if you lack natural sources of iodine you'll still benefit. It should be easy, it's just a single element!

FYI Iodine is concentrated by the breasts so as to provide it to babies via milk for exactly this reason. Iodine is critical to a lot of things. What you overlook is that as an element (atom) there is no way for the body to "make" iodine. The only way to get it is through what you eat and drink. In my opinion, the thyroid hormones are mostly a way for the body to store iodine - they are numbered T1, T2, T3, and T4 based on the number of iodine atoms in the molecule. The thyroid gland also concentrates iodine for use in making these hormones, but ultimately the only way to get iodine is to consume it - which I highly recommend.

What's troubling to me about this drug is that broad-spectrum improvement of memory formation /does not/ seem to be a clear positive in many cases. It's certainly great for, say, studying for medicine, but it strikes me as an enormous liability in the event of trauma, or with respect to the many psychological difficulties that are associated with bad memories.

As I recall (and it's been years, so please forgive me if I'm mistaken), Charlie's increased intelligence lead directly to increased unhappiness. While literature obviously does not constitute any sort of conclusive evidence, I think that the point is well-taken: for all the merits of human intelligence, it also fucks us up pretty good.

I would guess that you are right simply because most drugs that initially show promise in mice fail during clinical trials in humans.

But it's also worth remembering that the trope in fiction of $REALLY_GOOD_THING turning out to be $BAD_THING in disguise is just that, dramatically convenient fiction. There's no natural "game balance" to the universe. Yet popular entertainment is very small-c conservative about human improvement; if vaccines were still the stuff of fiction rather than daily life, a TV drama would show that universal prevention of smallpox has some terrible side effect that turns out to be worse than just letting people get infected and die. Fortunately we know that to be false but it won't stop dramatists and those shaped by them for immediately looking at newer biomedical advances with the most crushing cynicism.

(Not really directed at you, since I take it you're joking a bit, but this was the comment that prompted my thoughts...)

> I would guess that you are right simply because most drugs that initially show promise in mice fail during clinical trials in humans.

What about the contrapositive... How many substances fail in mouse studies (and are discarded), yet would have been viable in humans? Any known examples of this?

I don't know off the top of my head of any drugs that work in humans but have intolerable problems in mice. I do know that some substances are much more toxic to other mammals than to us. For example, acetaminophen is very toxic to cats. Theobromine is much more toxic to dogs and cats than to humans. 2,3,7,8-Tetrachlorodibenzo-p-dioxin is rapidly lethal to guinea pigs at a level that might only cause skin problems and/or reproductive defects in humans.

Permethrine is highly lethal to cold-blooded animals and cats.

Not exactly a drug, but during animal testing of saccharin in the 1970s, saccharin was found to induce bladder cancer in mice in high doses. However, the mechanism of action was later found to be specific to rodents and not applicable to humans.

Minoxidil, the active ingredient in Rogaine, is lethal to cats.

Curiously, felines are apparently among the most resistant mammals to prions, maybe second to pigs.

Well, we certainly are lucky we didn't test the drug "chocolate" on dogs first.

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

Not sure if it applies though because it being severly harmful to rodents hasn't prevented us from looking into this substance closely. Quite the opposite.

Much of our human testing only happened after a human attempted to use it for suicide, unsuccessfully. If anything this example helps to prove the parent's point.

from your wikipedia link

After an incident in 1951, where a US Army inductee unsuccessfully attempted suicide with multiple doses of warfarin in rodenticide and recovered fully after presenting to a hospital, and being treated with vitamin K (by then known as a specific antidote),[70] studies began in the use of warfarin as a therapeutic anticoagulant. It was found to be generally superior to dicoumarol, and in 1954 was approved for medical use in humans. An early recipient of warfarin was US president Dwight Eisenhower, who was prescribed the drug after having a heart attack in 1955.[70]

http://dresdencodak.com/2009/09/22/caveman-science-fiction/

Maybe not vaccines, but certainly antibiotics fit the trope :)

Why?

My understanding is that the only problem we have with antibiotics is that they breed antibiotic resistant diseases; but that is not really worse than us not having antibiotics at all.

That's like using the titanic as an argument against cruise ships. It's one very specific scenario.

I am curious. Does anyone know someone who has tried this on themselves yet?

Some "life extension" site forum had a group buy for the stuff apparently. People posted some of their results:

http://www.longecity.org/forum/topic/68589-isrib-group-buy-n...

One quote: So far I'm very much surprised about the effect on the overall cognition. My personal experiences are, that ISRIB definitely has it's effects on memory consolidation, but in my experience it doesn't only influence the long term memory formation (as JPC suggested), but the short term memory as well. It mens practicaly, that while reading a text, it is way much easier to remember the words, expression, and contexts as well (after 1-2 days). For instance currently I'm studying medicine basics again (I will enter a residency program soon), the subjects floaded with unique expressions related to molecular biology, basics of anatomy etc.. meaning, they are not very easy to link while memorizing even for a medical professional (they are meant to be boring..), and so far, after two days (meaning the text I read on friday) I can still remember a lot sharper on the names of for example cellular proteins, special basic physiological mechanisms than before, it is very obvious to me. I have to add, that I would value my memory above the average (as far as I can asses), but lately I somehow got slower by memorisation (I think it is an aging effect, and that was one of the reasons, why I started to search for some chemical hacking of my brain..).

Sample size of 1, no blinding, no verification of the substance received. Quite worthless.

Placebo effect is strong enough children recognised as more intelligent by chance do act and measure smarter.

He's studying medicine, not statistics :-)

Many major innovations occurred from individuals experimenting on themselves. In fact, it's one of the few ways to make progress when you have overbearing regulatory agencies.

You should be glad that many enterprising "sample sizes of one" are willing to become anecdata for everyone else. They push the boundaries so that maybe, just maybe, we get the benefits of these advances within our lifetimes rather than after many generations of careful study (ie. too late for me).

Carry on, intrepid experimenters! Some of us appreciate your reckless abandon.

But we can't know from a sample of one whether the placebo effect was in play, or whether the individual's response was atypical.

How do you think humanity learned about new medicines before clinical studies? A journey of a thousand miles starts with a single step; or in this case, a single experimenter.

This is also how people learn about the dangers of fan death, how carrots help improve your night vision, and that bulls are enraged by the color red.

Those examples seem super consequential compared to all the medical advancements that we got... I would gladly keep the medical advancements in exchange for turning off fans inside, eating more carrots, and avoiding red around bulls (or just avoiding bulls altogether; they stink).

Thankfully, humans like to try new things and then apply cause-and-effect reasoning to create good, new hypothesis (based by early citizen science evidence). I suspect that trait has massive benefits in our evolution. I hope people don't get put off by calls for "rigorous science" and keep experimenting on their own... and that the scientific establishment latches on to good ideas to do more rigorous studies! [The two aren't mutually exclusive! It's not zero sum!]

It may not be science but it's not worthless. Where do we get our testable hypotheses from?

I don't know if it's strictly necessary to write this after every personal experience. It might be better to save this comment for when people compare anecdotes against studies.

Note this comment is also applicable to literally the entire body of software engineering knowledge.

One person claimed to have had it synthesized and taken it awhile back (linked from the article) http://www.longecity.org/forum/topic/68589-isrib-group-buy-n...

I see that you can buy it from Aldrich: http://www.sigmaaldrich.com/catalog/product/sigma/sml0843?la...

90$ for 5mg, required single dosage appears to several times this... Could get expensive.

How does this now-patented "ISRIB" molecule compare to Leonard Guarente's research[1][2] on nicotinamide riboside and pterostilbene supplementation?

[1]: http://nymag.com/scienceofus/2016/08/is-elysium-healths-basi...

[2]: https://news.ycombinator.com/item?id=12345526

An interesting new approach. Let's wait for the studies to follow.

He is mistaken about "nothing" in case of brain trauma. Racetams have been shown to be mildly effective.

What if the drug only makes mice be more nervous or active and that's why they found the submerged platform more quickly?

What's the difference between healing a brain and just generally improving a brain?

A semi-facetious question, perhaps? Healing at least is a return to a baseline, "generally improving" is more subjective. I would tend to expect that changing any system as complex as the human brain would have the potential for improving some things, while impairing others. Not that it would impossible to find a compound that only produced changes we considered positive, without any we considered negative - just unlikely.

Not facetious at all.

If I take that molecule and find that I can acquire perfect pitch as an adult or easily learn a new language, was my brain "damaged" prior to taking the drug?

Different, clearly, but the 'damage' (or 'healing') would be subjective, wouldn't it? Since most of our organ systems return to the mean, I still suspect it's more likely that taking it when you have no reason to would be more likely to cause negative changes, rather than positive ones - but brave people are apparently willing to make that gamble.

The fact that you can patent a molecule blows my mind.

This is how big pharma works.

Yep, isolate lovastatin from red yeast, patent it, market it, and then try to make the supplements take it out since they're not FDA regulated.

BTW, red yeast rice did wonders for my blood work.

Yeah, fuck that.

The article's title on statnews.com bugs me, I admit I have not investigated this case, but...

I suspect it wasn't that graying old man that discovered that molecule, but that man's brilliant but underpaid post-doc that discovered that molecule.

Walter (Main Investigator), gave credit to Carmela Sidrauski his Post-Doc. He said if it were not for her, they would not have looked at it. The chemical itself was kicked out by a massive screening of small molecules, but originally not looked at because it was not very soluble.

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