A woman with a rare genetic mutation that has protected her from dementia
nytimes.com
nytimes.com
- 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 APOE3ch gene variant. The study indicates this mutation was primarily responsible for protecting the patient from Alzheimer's.
- Imaging tests showed she did have large amounts of amyloid protein deposits, but the amount of tau tangles, was relatively low.
- Experiments have shown this APOE3ch gene variant reduces ability of APOE to bind to certain sugars called heparin sulphate proteoglycans (HSPG). APOE <-> HSPG binding has been implicated as one mechanism that may contribute to amyloid + tau protein deposits.
Sorry if this sounds silly, I have just a very rough understanding of genetics.
A more indepth analysis of the patient's mutation and mechanism(s) of action:
https://www.genomeweb.com/sequencing/early-onset-alzheimers-...
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.
Despite what people below say, understanding the pathways involved is significant because drugs can be made to replicate the same biological effect to block the disease. This is what biopharma looks for.
[1]https://www.nytimes.com/2017/07/14/opinion/sunday/alzheimers... [2] https://en.wikipedia.org/wiki/Tsiman%C3%A9 [3] http://tsimane.anth.ucsb.edu/index.html
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 more time with grandchildren freeing up the parents to be more productive. They can also pass down wisdom, techniques that could benefit grandchild.
To oversimplify a bit, you can think of most mutations as neutral, in terms of reproductive fitness. People (and populations) accumulate them all the time, just by chance. Occasionally, one that was previous neutral becomes beneficial when the environment changes - say, when it confers immunity to a virus, or helps with synthesizing an amino acid that's in short supply. This is why having a big population with lots of variation is beneficial and why bottlenecks hurt the viability of a species.
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.
Maybe we could use that gene in the future on patients at the onset of regular Alzheimers.
Humans are in a very unique place with our sentient minds and understanding of the world. It'd be nice if we could compare ourselves to other species, but we haven't found any yet, and they're likely to be billions of light years away, or extinct, or both.
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).
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 deactivate metabolic pathways at runtime in a single cell, much less a whole organism. And especially not in a critical organ such as the brain. And how would you introduce the new gene and ensure that the correct dosing is delivered? This type of thinking stems from a lack of familiarity with biochemistry, the molecular biology of genetics, and cell physiology.
Onasemnogene abeparvovec is a biologic drug consisting of AAV9 virus capsids that contains a SMN1 transgene along with synthetic promoters. Upon administration, the AAV9 viral vector delivers the SMN1 transgene to the affected motor neuron, where it leads to an increase in SMN protein.
The point is, while research innovation regarding gene therapy, CRISPR CAS9, etc takes time and money, it IS indeed possible. Your post suggests a type of thinking that stems from an abundance of ignorance.
Ouch. In their defense of their 'ignorance' of gene therapy, Zolgensma was just approved this spring, it's literally one of two in vivo gene therapies, and it's only approved for kids < 2, which is a developmentally special sort of group.
On the other hand, they're almost certainly correct that there's no straight path from this one patient to a therapy. For SMA, we've known about the affected genes for nearly 30 years (https://www.ncbi.nlm.nih.gov/pubmed/2320125). The pathways are not totally trivial--there's some weirdness involving alternative splicing--but it's not impossible to wrap your head around what goes wrong. For AZ, we have no idea. Untold amounts of blood and treasure have been sunk into the idea that plaques were the problem, and despite some promising initial data, that hasn't panned out[0]. This is exciting because it suggests a new set of pathways to explore. The rest is hype and speculation: I'd be gobsmacked if there were a viable therapy in the next ten years.
[0] Or maybe not. Biogen seems to be taking yet another whack at it.
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.
"Accidentally" as part of a natural process for sure. But that doesn't take away the validity of them being the creators of it.
Figuring how to do this is non-trivial.
(Maybe some kind of decentralized and anonymized project with voluntary participants? Some googling found https://www.labiotech.eu/features/blockchain-control-genomic...)
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).