Gene editing solution not far away?

Insights and discussion from the cutting edge with reference to journal articles and other research papers.
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Brian4
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Gene editing solution not far away?

Post by Brian4 »

The Self-Inactivating KamiCas9 System for the Editing of CNS Disease Genes

This is really hopeful.

I'm going to look up Nicole Déglon (principle author of above) at

http://www.isscr.org/meetings-events/ev ... h-congress

(Any of our European members planning to go to that conference?)

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Re: Gene editing solution not far away?

Post by Verax »

Here is an overview of gene editing and amyloid "Genome-editing applications of CRISPR–Cas9 to promote in vitro studies of Alzheimer’s disease," Clin Interv Aging. 2018; 13: 221–233. Published online 2018 Feb 7. doi:10.2147/CIA.S155145 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5808714/

There has been much discussion elsewhere from this paper: Nagata et al. "Generation of App knock-in mice reveals deletion mutations protective against Alzheimer’s disease-like pathology" in Nature Communications Jan 7 2018 doi:10.1038/s41467-018-04238-0 https://www.nature.com/articles/s41467-018-04238-0

I would not want to have false hopes about CRISPR and ApoE. Maybe these discoveries will lead to better pharmaceuticals rather than direct gene editing of us poor suffering or asymptomatic humans. An encouraging similar narrative might be that of the discovery of a mutation that has a protective effect against HIV infection (although raising risk of West Nile virus), CCR5-delta32 https://en.wikipedia.org/wiki/CCR5 . Knowing more about the biochemical process has led to more effective HIV antivirals.

I am amazed reading about human evolution and how my ancestors' genes evolved in response to the environment. Mutations can be for good as well as random bolts of lightning that harm us! Although much of the population of Europe was wiped out in the Black Death plague, a few developed resistance to Yersinia or whatever it was that caused it. A few people have been found in Iceland through genome wide studies who inherited mutations that protect against HIV. Viruses can hijack the immune system macrophages and turn our bodies against us. Our bodies respond by mobilizing whatever resources are available (often those that had been used for different purposes.) There are trade-offs in order to help survival and reproduction. When we take on Mother Nature's job here with tools such as CRISPR we need to be very careful. https://www.the-scientist.com/?articles ... inst-HIV-/
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Re: Gene editing solution not far away?

Post by floramaria »

Because I am among the people who found the concept of gene editing frightening, I read Siddartha Mukerjee’s book, The Gene: An Intimate History, to try to understand the whole topic better, and put recent developments into context.
Though it was published in 2016 and the technology is advancing quickly, it did help me to understand both the promise and the threats of gene editing. And it left me feeling more fearful than before. I agree with Verax about the need to proceed with caution. In the race for “cures”, I am concerned that is not happening.
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Re: Gene editing solution not far away?

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Agree strongly with the need for caution. Assumed that went without saying.

Actually, we probably should stress caution more, and more broadly, for example with dietary choices. A radical change in dietary macro ratios could do more harm than a mis-edited SNP or two. Who knows.
I would not want to have false hopes about CRISPR and ApoE.
Nor would I. But I'm hopeful, cautiously, though I don't think falsely, that the technology will benefit everyone immensely within 5–10 years, be it as a research tool, or a genome modifying technique.

The real danger, in my view, involves altering the germ line. That's what really scares me. I'd want to have all the children I plan to have before editing myself....
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Re: Gene editing solution not far away?

Post by Verax »

More of us need to realize that gene editing as with CRISPR is not the same as the GMO (genetically modified organism) method used for instance to make patented Roundup-resistant maize. Gene editing uses tools to knock out or re-arrange genes that occur naturally in the same organism, while genetic modification generally transplants genes from one organism to another. The former is more like natural experiments with mutations as in conventional crop breeding, and does not produce scary or proprietary hybrid beings new to our experience. For example, the bacterial disease citrus greening threatens all citrus crops and no immune varieties have been found to genetically modify the current citrus crops that are propagated by rootstocks not seeds. Gene editing with CRISPR is actively trialed to find some resistance that natural mutations so far have not.

In the case of AD, there are various types and onsets, and using gene editing on mice might help to discover more of the mechanisms so therapy including lifestyle modifications as diet in midlife can help prevent it. We with E4 who are nearing the age of onset of LOAD but without symptoms can experiment with RCTs that share data and yet untested n=1 experiments such as diet and if our experiences can be shared then it may help the next generation. We shouldn't depend on gene editing to repair our genes or the genomes of our descendants.
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Re: Gene editing solution not far away?

Post by Brian4 »

By the way, here's an even more recent paper, showing an improvement in the precision of the editing:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834764/

Fascinating work.

I actually used CRISPR-Cas9 myself last weekend to gene-edit some yeast. It was part of a small workshop put on by one of the DIY biohacker community spaces that are springing up all over the US (and, I believe, to a limited degree elsewhere). Powerful and easy.
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Re: Gene editing solution not far away?

Post by Fiver »

Interesting question!

Once CRISPR and related technology is refined it will allow us to eliminate the root causes of AD without changing the germ line. To change E4 to E3, for example, as was recently accomplished in a human cell line. Sure, it'll be complicated. Risky, especially at first. And expensive. And society will have to male some big decisions about it. But it'll do a lot more than diet and exercise ever will. I suspect there will be a long, long line of volunteers. Someday - who knows when - It'll be a brave new world.

If we accept genetic modification - placing new genes into organisms that would never have obtained them through evolution - it seems hard to argue too much about changing a G to a C to convert one natural allele to another.
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Re: Gene editing solution not far away?

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I was quite excited about CRISPR, though it might take years and years to work through the clinical trials process.

What I had overlooked was that embryo selection technology has been in use for many decades.
Combining embryo selection with the results from large scale GWAS should be expected to have highly disruptive social effects even in the shortish-to-medium term.

For example, a very large GWAS in Educational Attainment is expected to be published soon in Nature Genetics. This 1.1 million GWAS found 37 SD of EA (ball park 200 IQ points of intelligence). When they move the sample size up to 2-3 million the entire genetic architecture of EA might unlock revealing possibly 100 SD of EA or possibly 750 IQ points. There is no particularly compelling reason why this could not happen within the next 2-3 years. Selecting the optimal embryos would create people with dramatically higher intelligence and this would have very extreme socio-politico-technological consequences. Of course nearly any other polygenic human trait could be likewise selected for or against.

https://www.thessgac.org/data

Humanity needs to prepare itself for extreme techno disruption. A mere 15 IQ enhancement would increase our psychometric potential by 10 fold. IQ enhancement into the hundreds of points would have very profound implications for the future development path of the approaching new humanoid species.
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Re: Gene editing solution not far away?

Post by Verax »

J11 wrote:I embryo selection technology has been in use for many decades.
Combining embryo selection with the results from large scale GWAS should be expected to have highly disruptive social effects even in the shortish-to-medium term.
Why wait for GWAS and CRISPR? We E4 carriers were selected against by E3s (according to this interesting paper by a couple of clever Stanford undergraduates) some 7,000 years ago by patrilineal clans who transitioned from our E4 hunter-gatherer heritage to E3 agropastoralism and violently obliterated genetic competion and created the Y Chromosome Neolithic bottleneck until the Neolithic population explosion and control of warfare by government monopoly. Mother Nature edits our genes, maybe very rapidly, to adapt to the environment. Can we do better at editing with CRISPR the ApoE4 gene to adapt to a sedentary Western diet and lifestyle like E3s or E2s--or should we all drastically change to the healthy lifestyle our E4 bodies still need in spite of that Neolithic bottleneck? https://www.nature.com/articles/s41467-018-04375-6
"Cultural hitchhiking and competition between patrilineal kin groups explain the post-Neolithic Y-chromosome bottleneck"
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Re: Gene editing solution not far away?

Post by J11 »

Interesting!

Yet, what is approaching has never happened before. Up till now cognitive evolution has been far slower than watching the paint dry.
There might have been a 1 point change in IQ over 1,000 years. Even such a small change as that has resulted in clear shifts in what humans could achieve. With current genetic technology with an economically reasonable selection intensity, IQ could now shift by 10 IQ points. It could keep shifting upwards by a similar amount probably for centuries. Of course as soon as the intelligence feedbacks onto itself, IQs would be expected into the 100s.

There should be absolutely no doubt: human reality is about to be profoundly disrupted. We will soon be on a technology curve that points straight up: The Singularity. It had been thought that this essentially endpoint of human existence would have occurred somewhere near 2045. Given the current genetic technology, this endpoint is probably closer to 2030.
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