6 ms·

A new twist on using ‘personalized’ stem cells for studying dementia

87 points by elorant 6y ago

timy2shoes 6y ago
I think the overall goal assumes that genetics causes Alzheimer's, which is (in my opinion) a questionable assumption. That's not to say that the production of model systems for Alzheimer's will be useful, but will it be worth the tens or hundreds of millions of dollars that this will cost? ¯\_(ツ)_/¯
- WalterBright 6y ago
  The book "The End of Alzheimers" makes a case that there are 36 causes of Alzheimers. It's the combination of those causes that results in the disease. The more of those causes a person has, the more likely they'll develop Alzheimers. This is why research and treatments that focus on only one cause have all been stymied and went nowhere. The book's treatment program is to address as many of the causes as possible.
- MetaWhirledPeas 6y ago
  As long as it's not diverting funds from anything more promising then spend all the money you want I say. Try everything. You may fail more often but you'll find the right answer faster.
  - timy2shoes 6y ago
    With a limited NIH budget this will necessarily divert funds from other endeavors. In addition, I think such programs entrench the large lab bias prevalent in academia right now.
- kgin 6y ago
  Gene therapy can treat diseases that aren't specifically caused by genetics.
  - timy2shoes 6y ago
    Yes, but that would require knowing how to rescue the phenotype, in this case healthy neurons and connections. Alzheimer's is not like Parkinson's, which you can (most likely, see the recent work from BlueRock) treat by replacing dopaminergic neurons or rescuing the dopamine production.
benrapscallion 6y ago
There’s a remarkable amount of hyperbole in this article (but not the original publication). In plain language, this is a project to generate, characterize, and openly share the data for iPSC models (and presumably neurons from them) bearing 100 APOE disease-associated mutations. It must be remembered that one reason many AD drugs have failed is because models don’t capture the disease accurately and that may well turn out to be the case here.
- kick_in_the_doo 6y ago
  Do AD drugs attempt to reduce the concentration of APOE in the brain? If so, is it known if these drugs either failed to reduce the concentration of APOE, or succeeded in reducing concentration but still didn't work?
  - benrapscallion 6y ago
    “Reduce APOE” is an oversimplified view. The mechanisms by which the AD-associated E4 genotype (arg112, arg158) results in disease are still poorly understood. The main therapeutic hypothesis for AD is to reduce the levels of pathogenic plaques and aggregates using antibodies.
    - kick_in_the_doo 6y ago
      Interesting. And these studies have shown that medicine which reduces these plaques doesn't actually help with AD symptoms?
- dang 6y ago
  I've pinched the title from https://www.ninds.nih.gov/News-Events/News-and-Press-Releases/Press-Releases/NIH-scientists-try-new-twist-using-personalized-stem-cells https://www.ninds.nih.gov/News-Events/News-and-Press-Release..., which the OP points to, since it seems less hyperbolic and more precise. Not sure if the article itself should be changed also...
mjfl 6y ago
As someone who does research in biology and therapeutics, it seems to me that Alzheimer's research is such a dismal field. We don't have a good idea of what causes it, not only do we not have good animal models, we have misleading animal models which reflect some of the traits of Alzheimer's but nothing translates to humans. There was this mouse model they made which developed these plaques like in Alzheimers and they found they could clear them with brain stimulation pretty well - but trying it in humans there was no effect.
- freewilly1040 6y ago
  > There was this mouse model they made which developed these plaques like in Alzheimers and they found they could clear them with brain stimulation pretty well - but trying it in humans there was no effect. Rinse and repeat many times over, I think. This dynamic is what pushed me away from the field in general, the knowledge that I could spend my whole career working on a mouse model that there's reason for only tepid confidence in.
  - bumby 6y ago
    There’s a Twitter feed dedicated to this caveat https://mobile.twitter.com/justsaysinmice?lang=en https://mobile.twitter.com/justsaysinmice?lang=en
    - mjfl 6y ago
      For diseases where the causal mechanism is known very well, mouse models aren't that bad: Rett syndrome, hemophilia, spinal muscular atrophy. It gets to be a problem where the disease is poorly defined and the cause is unknown: Alzheimers, schizophrenia, ADHD, etc. It is very important that people have this discrimination power and not jump to "All of this is bad" or "All of this is good".
      - ghodith 6y ago
        Also in a lot of cases it’s the best we’ve got. You might be able to use monkeys but even that doesn’t change a lot of the problems. If you move from animal models you aren’t going to suddenly be able to start experimenting on humans.
paulpauper 6y ago
The problem with AD is by the time the symptoms appear, the brain is already irreparable ravaged. The damage is actually macroscopically visible. Treatment would have to begin long before symptoms show, which would mean identifying people who are at risk.
- deleted 6y ago
  [deleted]
- kgin 6y ago
  I think any person newly diagnosed with alzheimers would jump at the chance to stop its progression.
  - JamesBarney 6y ago
    Once you get an alzheimer's diagnosis your brain is pretty ravaged. The diseases process probably starts decades before most diagnoses.
    - prepend 6y ago
      And I think anyone newly diagnosed would love to have progression stopped at diagnosis. What’s your point? It’s not a total cure and restoration, but it’s better than now- where your brain is ravaged at diagnosis and gets worse until death.
      - JamesBarney 6y ago
        The problem is what would halt progression at diagnosis isn't necessarily the same thing that would halt progression 20 years earlier. And there is evidence to suggest this is the case.
        prepend 6y ago
        Right, but these are separate things that would both be beneficial. They should be exclusive pursuits. Currently we have neither. I would prefer some preventative therapy that makes it never happen. I would also like a therapy that halts progression once diagnosed.
halfmatthalfcat 6y ago
_Crush_ Alzheimer's.
gervwyk 6y ago
There is a fascinating episode on Alzheimer treatment using some sort of frequency exposure [0], I don’t know much about this but radiolab made me really excited that there could be an end to Alzheimers one day soon. Studies like this and the hopeful potential benefits unlocked with crispr also! https://www.wnycstudios.org/podcasts/radiolab/articles/bringing-gamma-back https://www.wnycstudios.org/podcasts/radiolab/articles/bring...
- dd36 6y ago
  Interesting. Hopefully it doesn’t suffer from the mouse model flaw.
The_rationalist 6y ago
Unrelated: Tofisopam has been shown to have groundbreaking efficacy on reverting cognitive impairment: https://pubmed.ncbi.nlm.nih.gov/31981560/ https://pubmed.ncbi.nlm.nih.gov/31981560/ btw I believe that Tifasopam is the best long term anxyolitic medication out there: No tolerance No cognitive impairment No sedation No side effects Very potent

87 points by elorant 6y ago

I think the overall goal assumes that genetics causes Alzheimer's, which is (in my opinion) a questionable assumption. That's not to say that the production of model systems for Alzheimer's will be useful, but will it be worth the tens or hundreds of millions of dollars that this will cost? ¯\_(ツ)_/¯

WalterBright 6y ago
The book "The End of Alzheimers" makes a case that there are 36 causes of Alzheimers. It's the combination of those causes that results in the disease. The more of those causes a person has, the more likely they'll develop Alzheimers. This is why research and treatments that focus on only one cause have all been stymied and went nowhere. The book's treatment program is to address as many of the causes as possible.
MetaWhirledPeas 6y ago
As long as it's not diverting funds from anything more promising then spend all the money you want I say. Try everything. You may fail more often but you'll find the right answer faster.
- timy2shoes 6y ago
  With a limited NIH budget this will necessarily divert funds from other endeavors. In addition, I think such programs entrench the large lab bias prevalent in academia right now.
kgin 6y ago
Gene therapy can treat diseases that aren't specifically caused by genetics.
- timy2shoes 6y ago
  Yes, but that would require knowing how to rescue the phenotype, in this case healthy neurons and connections. Alzheimer's is not like Parkinson's, which you can (most likely, see the recent work from BlueRock) treat by replacing dopaminergic neurons or rescuing the dopamine production.

benrapscallion 6y ago

There’s a remarkable amount of hyperbole in this article (but not the original publication). In plain language, this is a project to generate, characterize, and openly share the data for iPSC models (and presumably neurons from them) bearing 100 APOE disease-associated mutations. It must be remembered that one reason many AD drugs have failed is because models don’t capture the disease accurately and that may well turn out to be the case here.

kick_in_the_doo 6y ago
Do AD drugs attempt to reduce the concentration of APOE in the brain? If so, is it known if these drugs either failed to reduce the concentration of APOE, or succeeded in reducing concentration but still didn't work?
- benrapscallion 6y ago
  “Reduce APOE” is an oversimplified view. The mechanisms by which the AD-associated E4 genotype (arg112, arg158) results in disease are still poorly understood. The main therapeutic hypothesis for AD is to reduce the levels of pathogenic plaques and aggregates using antibodies.
  - kick_in_the_doo 6y ago
    Interesting. And these studies have shown that medicine which reduces these plaques doesn't actually help with AD symptoms?
dang 6y ago
I've pinched the title from https://www.ninds.nih.gov/News-Events/News-and-Press-Releases/Press-Releases/NIH-scientists-try-new-twist-using-personalized-stem-cells https://www.ninds.nih.gov/News-Events/News-and-Press-Release..., which the OP points to, since it seems less hyperbolic and more precise. Not sure if the article itself should be changed also...

mjfl 6y ago

As someone who does research in biology and therapeutics, it seems to me that Alzheimer's research is such a dismal field. We don't have a good idea of what causes it, not only do we not have good animal models, we have misleading animal models which reflect some of the traits of Alzheimer's but nothing translates to humans. There was this mouse model they made which developed these plaques like in Alzheimers and they found they could clear them with brain stimulation pretty well - but trying it in humans there was no effect.

freewilly1040 6y ago
> There was this mouse model they made which developed these plaques like in Alzheimers and they found they could clear them with brain stimulation pretty well - but trying it in humans there was no effect. Rinse and repeat many times over, I think. This dynamic is what pushed me away from the field in general, the knowledge that I could spend my whole career working on a mouse model that there's reason for only tepid confidence in.
- bumby 6y ago
  There’s a Twitter feed dedicated to this caveat https://mobile.twitter.com/justsaysinmice?lang=en https://mobile.twitter.com/justsaysinmice?lang=en
  - mjfl 6y ago
    For diseases where the causal mechanism is known very well, mouse models aren't that bad: Rett syndrome, hemophilia, spinal muscular atrophy. It gets to be a problem where the disease is poorly defined and the cause is unknown: Alzheimers, schizophrenia, ADHD, etc. It is very important that people have this discrimination power and not jump to "All of this is bad" or "All of this is good".
    - ghodith 6y ago
      Also in a lot of cases it’s the best we’ve got. You might be able to use monkeys but even that doesn’t change a lot of the problems. If you move from animal models you aren’t going to suddenly be able to start experimenting on humans.

paulpauper 6y ago

The problem with AD is by the time the symptoms appear, the brain is already irreparable ravaged. The damage is actually macroscopically visible. Treatment would have to begin long before symptoms show, which would mean identifying people who are at risk.

deleted 6y ago
[deleted]
kgin 6y ago
I think any person newly diagnosed with alzheimers would jump at the chance to stop its progression.
- JamesBarney 6y ago
  Once you get an alzheimer's diagnosis your brain is pretty ravaged. The diseases process probably starts decades before most diagnoses.
  - prepend 6y ago
    And I think anyone newly diagnosed would love to have progression stopped at diagnosis. What’s your point? It’s not a total cure and restoration, but it’s better than now- where your brain is ravaged at diagnosis and gets worse until death.
    - JamesBarney 6y ago
      The problem is what would halt progression at diagnosis isn't necessarily the same thing that would halt progression 20 years earlier. And there is evidence to suggest this is the case.
      - prepend 6y ago
        Right, but these are separate things that would both be beneficial. They should be exclusive pursuits. Currently we have neither. I would prefer some preventative therapy that makes it never happen. I would also like a therapy that halts progression once diagnosed.

halfmatthalfcat 6y ago

_Crush_ Alzheimer's.

gervwyk 6y ago

There is a fascinating episode on Alzheimer treatment using some sort of frequency exposure [0], I don’t know much about this but radiolab made me really excited that there could be an end to Alzheimers one day soon. Studies like this and the hopeful potential benefits unlocked with crispr also! https://www.wnycstudios.org/podcasts/radiolab/articles/bringing-gamma-back https://www.wnycstudios.org/podcasts/radiolab/articles/bring...

dd36 6y ago
Interesting. Hopefully it doesn’t suffer from the mouse model flaw.

The_rationalist 6y ago

Unrelated: Tofisopam has been shown to have groundbreaking efficacy on reverting cognitive impairment: https://pubmed.ncbi.nlm.nih.gov/31981560/ https://pubmed.ncbi.nlm.nih.gov/31981560/ btw I believe that Tifasopam is the best long term anxyolitic medication out there: No tolerance No cognitive impairment No sedation No side effects Very potent