Scientists make precise edits to mitochondrial DNA for first time | Hacker News Reader

Scientists make precise edits to mitochondrial DNA for first time

nature.com

233 pointspseudolus43 comments

I used to be a mitochondrial engineer. This advance is fantastic, and not surprising. In 2006[0] they showed that you could get zinc fingers (similar to TALENs, which is what they use in paper) to site-specifically modify things in mitochondria. For reference, that is about 7 years before CRISPR was discovered.

Base editors were more recently discovered, so it was only a matter of time before they figured out how to do it in mitochondria.

I will be surprised if they figure out how to genetically transform mitochondria robustly (in humans, etc). That research has been going on for decades, and still hasn't been figured out. One day, it will be, and I'm looking forward to learning about how they do it. They figured out transformation of yeast mitochondria in the 80s, still haven't figured out human mitochondria.

I think it's going to do something with either RNA import + reverse transcription OR conjugation[1]. I tried RNA import in yeast, and it doesn't really work, but I think conjugation has real potential, especially now that they got endosymbiosis of E.coli working[2].

[0] https://www.pnas.org/content/103/52/19689 [1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC554353/ [2] https://doi.org/10.1073/pnas.1813143115

Do you think this is the start of the land rush for gene manipulation therapies?

Yep, pretty much. It’s a very interesting time - genetic therapies have extremely low marginal cost, but very high capital cost. Unlike software systems, they can mean life or death. Piracy of genetic therapies will be really interesting.

Someday we might not just have antivaxers, but “rogue vaxers” who develop vaccines to diseases that pharma ignore and DIY test themselves.

This seriously sounds like the plot of a dystopian sci-fi movie!

We have this today to an extent, here’s someone who tested a DIY gene editing cure for lactose intolerance on themselves https://youtu.be/aoczYXJeMY4

(Spoiler: it worked, very well in fact!)

Im a bit suspicious of the lactose experiment, mainly because there wasn’t hard data to back it up. Back then there was a spurt . AFAIK there are two people who have DIY gene engineered themselves and have actually gotten data to back it up, but only 1 who is public about it, and it wasn’t a cool experiment (just showed RNA transcription) so it isn’t even easy to find.

Josiah Zayner pretty much knows everyone who has tried DIY gene injection and over the last year or so there has actually been a decrease in people trying it (bit stale from 2019, but here is his presentation at BioHTP https://youtu.be/1QOFDpYnEgY?t=4904)

There's a host of rare diseases that originate from mtDNA mutations that this could have applications in. I know the tech/Silicon Valley crowd tends to love anti-aging stuff as well, so for all y'all into life extension stuff, this should interest you as well because of mitochondria's hypothesized role in aging[0].

[0] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4779179/

That link looks like a good read. Long so I bookmarked for later.

Yes, I have one of them, so I will be watching this. Probably entirely too long to market for it to be of help to me but it is nice to know that it will be coming for others.

One of my coworker's children died of a mtDNA mutation he was born with at three years old. My coworker never really got completely over the loss. They knew pretty early on what the prognosis was, but spent those three years giving the kid the best life they could.

I'm super excited to see work that might give this whole class of children a long life at some point in the future. Just a few years ago (pre CRISPR), it was just accepted as a shitty thing we couldn't do anything about.

I have been taking a high grade CoQ10 supplement.

CoQ10 is the primary antioxidant the human cell provides to protect and support mitochondria. It helps generate ATP within the mitochondria, the main energy driver we have.

CoQ10 is ubiquitous and produce within the body, however after the age of 20 levels start to drop, so it makes sense to consider supplements to top levels up if you're north of 30.

I love the stuff myself. I went from a tired feeling 45 year old with brain fog, to having a lot more energy and a mind keen to engage all day with whatever I have going on at work

https://examine.com/supplements/coenzyme-q10/#effect-matrix

For those interested in this substance, it is worth first noting that it is present in many common foods in notable quantities: https://en.wikipedia.org/wiki/Coq10#Dietary_concentrations

How did you disambiguate these claimed CoQ10 effects from the results of taping your mouth shut at night?

"Not only did it fix my apnoea [sic] and huge lack of energy during the day"

https://news.ycombinator.com/item?id=23432440

“apnoea” is the British spelling.

TIL, thanks, I didn't know that.

You should watch this excellent video by Dr Stanfield (actually, entire channel is excellent) in which he goes into Cochrane Medical Reviews among other research channels to dig into the science around all this stuff.

This video is his analysis of CoQ10: https://www.youtube.com/watch?v=I9UYRWLpXz8

Dr Stanfield recommends sulforaphane over C0Q10 and the science/medical evidence he presents is compelling; he has a few videos specifically on sulforaphane as well.

I would highly recommend anyone that is doubtful of vitamins and suppliments, particularly relating to aging/longevity - really give this YouTube channel a thorough review. It's hard to discount Cochrane Reviewed[0] backed data.

[0] https://www.cochranelibrary.com/

Sulforaphane? Queue up Dr. Rhonda Patrick!

https://www.foundmyfitness.com/episodes/sulforaphane

Those youtube comments are gold.

"It really is hard to belive she's in her 80's! Amazing."

"Do not listen to Rhonda... she's a shill for big broccoli!!"

I suffer from a genetic disease in my mitochondrial DNA (single, large-scale deletion), so this is great news for me.

I have been closely following mitochondrial research since I was diagnosed 12 years ago, and the progression in our knowledge about mitochondria have been exponential. Truly impressive.

My sincere appreciation for all researchers out there (even though I do not expect an actual cure in the foreseeable future; say, next 15 years)

How does the disease impact your life, if I may ask?

Mitochondrial disease is not a disease per se, but I broad category of all kinds of both nuclear and mitochondrial mutations. Some of them are fatal and kids die within days or years after birth and some are more like chronic conditions with a varying degrees of severity.

In my case, my genotype is a single, large-scale mtDNA deletion. It is heteroplasmic, meaning that some of my mitochondria are normal and some are mutant. In these type of mutations, heteroplasmy percentage drives disease severity.

Disease is also progressive. Mutant mitochondria have a replication advantage, so that the percentage of mutant mitochondria goes up as you age.

My phenotype is called CPEO (Chronic Progressive External Ophthalmoplegia), probably the most common and benign disease presentation. I have ptosis (droopy eyelids) and diplopia (double vision). Both corrected by surgery.

I have also some systemic symptoms, mostly a profound "fatigue" that hits me 2-3 days per month. I quote fatigue because it is a unique feeling not like normal fatigue. Malaise could be also a good definition.

I am lucky. I have a normal life with minor issues. A good diet and exercise made a huge difference. I also take some over the counter supplements that also help my body to cope with all the mutant mitochondria.

I wonder how you'd distribute these, therapeutically. Our bodies have mechanisms to let healthier mitochondria out compete less healthy mitochondria within a cell - the oxidative stress mitochondria are under basically requires that for us to stay healthy - but how do you get the mitochondria into your cells. Especially long lived cells like skeletal muscles much less neurons?

This sounds very complicated. Maybe the future of medicine is in simplifying the human biology and possibly even "upgrading" it to something that is less susceptible to illness and injury.

Interesting idea. I wonder if instead of requiring oxygen to hand off electrons to during respiration we could substitute a simpler system by dumping the excess charge via a wire? Anyone with domain expertise care to comment on whether this is possible?

Electroactive bacteria?

I do love refactoring!

And the current state of computing on a global scale is so ad-hoc it might as well have been evolved, so it probably wouldn't even feel that different.

Looks like the methods are already there but they’re not streamlined yet, as well as the research. You’d most likely go for an existing virus that targets cell mitochondria specifically, maybe you’d want mitochondria of a specific cell. The viral DNA can be altered in the ways you want and the virus can deliver the DNA to your cells. I’m not sure how specifically this would be done, usually they use viruses to deliver a small portion of a DNA that encodes a specific protein, so the main objective there is to make the cell produce that protein. Not sure how that would work with simply mortifying existing DNA.

I highly recommend ThoughtEmporium on YouTube btw. This guy literally does gene editing in his streams; not saying that he’s doing any breakthrough research but it’s at the very least inspiring and shows complex things in a very down to earth manner. See his videos on how he treated his lactose intolerance using a virus containing DNA that encodes lactase; or a recent video where he builds a plasmid DNA from genomes of Malaria + HIV for treating cancer developing antibodies against cancer and letting immune system do the hard work (might sound silly with all those HIV and malaria but there’s some actual research behind that)

Paper mirror: https://www.gwern.net/docs/genetics/editing/2020-mok.pdf

Could someone create a respiratory virus that spreads throughout the earth's population gene editing everyone into perfection?

What could possibly go wrong?

Or right

I would hope not, but I'm sure there's lots of science fiction predicated on similar ideas.

There's a pretty horrific short story about that

https://en.wikipedia.org/wiki/Blood_Music_(novel)

That's a great book, worth a read!

I'm afraid how this kind of stuff can be used to create some sort of DNA signature, lets say, for people of a giving country. A government could do it through vaccines for example.

This later could be use to spread biologic weapons that would be engineered to not attack hosts cells with that particular signature.. as everybody else that were not "marked" would die..

We need to advance a lot morally and ethically as a societies, because i'm pretty sure atomic bombs will look like child stuff compared to the harm we could do with the things being discovered.

And giving the current trends, im very pessimistic about our future prospects. We have too much corruption by design, embedded in our cultural systems.

Isn’t that he opening scene of I Am Legend?

How long until we can write DNA as easily as we do Python?

Reminds me of xkcd's "hottest editors"[0].

In all seriousness, if I'm reading this correctly, Ddd9 would resolve the challenge of using CRISPR-Cas9 to edit mitochondrial genomes. Could this be used for treatments of mitochondrial diseases in the future? Additionally, mitochondrial DNA is passed through the mother, so modification could potentially have a long lasting effect.

[0] https://xkcd.com/1823/

I think an electron app will beat both Vim and Emacs to it.

I would even happily suffer through Electron in this rare case

You flinched. Now the downvotes will never stop ;)

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