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A woman with a rare genetic mutation that has protected her from dementia

nytimes.com

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Re: A woman with a rare genetic mutation that has protected her from dementia

#31

Post by hirenj »

gzer0 wrote: post #15

Quick summary of the findings: - Patient had a PSEN1 E280A mutation, which predisposes you to a 99.9% risk of developing early-onset Alzheimer's. - Patient was expected to have Alzheimer's by 50. She is currently 70, with very little signs of cognitive decline. Although she has large amounts of amyloid proteins (hallmark of Alzheimer's) it has not reduced her cognitive capacity. - Patient had two copies of the APOE3c…

I never realised that the APOE variant bound heparin sulfate (HS). HS is actually a cool molecule (glycan) from the perspective of its ability to encode information in its pattern of sulfation.

The signals can be mixed and the precise binding partners for a single molecule can be programmed in. How this is all regulated, and the extent this happens in nature is still being worked out.

Re: A woman with a rare genetic mutation that has protected her from dementia

#32

Post by justinclift »

buboard wrote: post #18
huac wrote: post #12

I wonder if one of the major pharma companies will develop an anti-dementia drug from this finding, and then if she (or her family) will see any of the billions in revenues they'll make.

Thats absurd. She neither created nor detected the mutation. I agree that dna patents should not exist though. We share so much of it.

She, or her parents, literally created the mutation they're researching.

"Accidentally" as part of a natural process for sure. But that doesn't take away the validity of them being the creators of it.

Re: A woman with a rare genetic mutation that has protected her from dementia

#33

Post by beardedman »

thelittleone wrote: post #27

This make me curious about mutations and human evolution. By 50 years of age she has past her (natural) maternal age. So it's not like women with that mutation would bear more children. How would such a mutation help her lineage? But that same question, more broadly, how do mutations that benefit people past their child bearing age factor into human evolution? I suppose mentally healthy grandparents are able to spend…

I agree.

One thing that strikes me is how many go undocumented - including mutations that cause HIV immunity.

I think it's incredibly interesting that perhaps 5000 years from now some mutations would be well established - but that we aren't aware of now (as they happen).

Re: A woman with a rare genetic mutation that has protected her from dementia

#34

Post by busyant »

echelon wrote: post #19
huac wrote: post #12

I wonder if one of the major pharma companies will develop an anti-dementia drug from this finding, and then if she (or her family) will see any of the billions in revenues they'll make.

They won't earn anything. This might lead to discovering a receptor or metabolic pathway mechanism for attack, but the mutation isn't a part of any solution that will be distributed to patients. This mutation is merely a suggestion for a gradient in solution space to explore. In case you're thinking that this variant of the gene can be introduced into Alzheimers patients, that is impossible. You can't safely deactiva…

> You can't safely deactivate metabolic pathways at runtime in a single cell

While I generally agree with your sentiment that it would be remarkably difficult to genetically modify the brain tissue of an adult, you have no idea if your statement is true or not.

In fact, this is the whole point of CRISPR and similar forms of "gene therapy." Yes. You probably can't modify the genome of all cells in a large multi-cellular organism like us, but there may be ways of modifying selected/important tissues.

> This type of thinking stems from a lack of familiarity with biochemistry, the molecular biology of genetics, and cell physiology.

This is not warranted either.

Re: A woman with a rare genetic mutation that has protected her from dementia

#35

Post by ElFitz »

thelittleone wrote: post #27

This make me curious about mutations and human evolution. By 50 years of age she has past her (natural) maternal age. So it's not like women with that mutation would bear more children. How would such a mutation help her lineage? But that same question, more broadly, how do mutations that benefit people past their child bearing age factor into human evolution? I suppose mentally healthy grandparents are able to spend…

I remember reading something where they explained that cultures where they kept the grandmothers around tended to have better outcome for both the mother and the baby when their daughters gave birth.

It isn't really surprising, when you think of it, and it's probably just one of many examples where aging better, past child bearing age, improves the chances of a lineage.

Re: A woman with a rare genetic mutation that has protected her from dementia

#36

Post by rkagerer »

While I'm loath to endorse any sort of widespread "big data" on our genetics, I can't help but wonder what other gems we might glean if metrics like genes and medical outcomes of everyone ever born were somehow made safely available to researchers.

(Maybe some kind of decentralized and anonymized project with voluntary participants? Some googling found https://www.labiotech.eu/features/blockchain-control-genomic...)

Re: A woman with a rare genetic mutation that has protected her from dementia

#37

Post by raducu »

gzer0 wrote: post #15

Quick summary of the findings: - Patient had a PSEN1 E280A mutation, which predisposes you to a 99.9% risk of developing early-onset Alzheimer's. - Patient was expected to have Alzheimer's by 50. She is currently 70, with very little signs of cognitive decline. Although she has large amounts of amyloid proteins (hallmark of Alzheimer's) it has not reduced her cognitive capacity. - Patient had two copies of the APOE3c…

Could someone use CRISPR to inject two copies of APOE3ch in regular Akzheimer's patiens?

Sorry if this sounds silly, I have just a very rough understanding of genetics.

Re: A woman with a rare genetic mutation that has protected her from dementia

#38

Post by raducu »

thelittleone wrote: post #27

This make me curious about mutations and human evolution. By 50 years of age she has past her (natural) maternal age. So it's not like women with that mutation would bear more children. How would such a mutation help her lineage? But that same question, more broadly, how do mutations that benefit people past their child bearing age factor into human evolution? I suppose mentally healthy grandparents are able to spend…

It doesn't, that's why not everybody has that gene; if Alzheimers was something you developed as a teen, I'm sure that mutation would spread and soon everybody would have it.

Maybe we could use that gene in the future on patients at the onset of regular Alzheimers.

Re: A woman with a rare genetic mutation that has protected her from dementia

#39

Post by youdontknowtho »

raducu wrote: post #37
gzer0 wrote: post #15

Quick summary of the findings: - Patient had a PSEN1 E280A mutation, which predisposes you to a 99.9% risk of developing early-onset Alzheimer's. - Patient was expected to have Alzheimer's by 50. She is currently 70, with very little signs of cognitive decline. Although she has large amounts of amyloid proteins (hallmark of Alzheimer's) it has not reduced her cognitive capacity. - Patient had two copies of the APOE3c…

Could someone use CRISPR to inject two copies of APOE3ch in regular Akzheimer's patiens? Sorry if this sounds silly, I have just a very rough understanding of genetics.

I was wondering the same thing. Again, sorry if this is obviously a weird question, but I also have a layman's understanding of genetics.

Re: A woman with a rare genetic mutation that has protected her from dementia

#40

Post by dekhn »

rkagerer wrote: post #36

While I'm loath to endorse any sort of widespread "big data" on our genetics, I can't help but wonder what other gems we might glean if metrics like genes and medical outcomes of everyone ever born were somehow made safely available to researchers. (Maybe some kind of decentralized and anonymized project with voluntary participants? Some googling found https://www.labiotech.eu/features/blockchain-control-genomic... )

This can't currently be done. Taking the US as an example, if your data is in EMRs, it's possible for researchers to access your data, but it depends on what you consented to. Obtaining additional consent- for example by mailing a letter to everybody in an org's EHR system- isn't super-effective because most people don't respond to these requests.

Orgs like GA4GH are trying to change consent forms for people who voluntarily take part in research so that other researchers can pull the EMR data and aggregate it for other research. This would only apply to people in the future, we don't normally have such open consent forms right now.

Personally I think it's unlikely that large orgs would agree to decentralized systems. Instead, they would run this on a major cloud provider using standard cloud features like encryption and IAM, as well as standard de-identification techniques.

In principle, if we had a single global database of billions of patients with both high dimensional data (genomes, images) and labels (medical outcomes such as "got flu again"), a lot could be done, but researchers have to be extremely careful. Most folks aren't trained to deal with big data and will immediately attempt to do all sorts of testing that is prone to false positives (data dredging/p-hacking is very common in medical fields, and it gets worse as you have more data).

Note that ultra-large GWAS studies are being done, on datasets with millions of patients, and the results are interesting; you can explain, for example, variance of height using genomic variation data, up to a limit (height is only partially determined by our genome, as is true of effectively any large-scale coarse-grained phenotypic trait).

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