9 ms·

Unexpected Risks Found in Editing Genes to Prevent Inherited Disorders

Karunamon 10y ago
tl;dr: Earlier this month, a study published in Nature by Shoukhrat Mitalipov, head of the Center for Embryonic Cell and Gene Therapy at the Oregon Health and Science University in Portland, suggested that in roughly 15 percent of cases, the mitochondrial replacement could fail and allow fatal defects to return, or even increase a child's vulnerability to new ailments. It's not a risk of editing the genes so much as a risk of the treatment failing.
reasonattlm 10y ago
This isn't about editing genes, it is about replacing mitochondria. Not the same thing at all. Mitochondria are like bacteria in the way they replicate. There are hundreds of them in a cell. They can pass components around between one another, can split and fuse. They are integrated with quality control mechanisms that cull the herd. It is a complicated picture. As the article notes the procedure isn't effectively clearing out all of the old mitochondria, and dynamics can favor them in the future. It is known that variations in mitochondrial DNA produce radical differences in competition between mitochondrial strains in the cell. That is how deletions affecting OXPHOS machinery cause one mutant to take over the whole population very quickly - some differences produce mitochondria that either replicate better or resist quality control more effectively. That one is one of the causes of aging, but the same principle exists for other differences between mitochondrial genomes. If you put two or more in a cell and let them fight it out, hard to say in advance what the outcome will be given present knowledge. So, basically, the people working on mitochondrial replacement need to make their tools for cleaning out the old mitochondria more efficient. If 100% success is achieved, that genome isn't coming back. Alternatively, actual gene therapy might be a better approach - though challenging if you want to edit mitochondrial genomes, as you have the same problem of coverage and competition. There is allotopic expression, moving mitochondrial genes to the cell nucleus, which is feasible via today's gene therapy. Given the amount of work needed to copy mitochondrial genes into the nucleus, however, the challenge being how to alter them so as to get the proteins produced back to the mitochondria, something that has been achieved for three genes so far, it might be more cost-effective to work on better clearance and replacement technologies for the near term of assisted reproduction needs.
gioele 10y ago
Unexpected Risks Found in Editing Binary Code to Fix Bugs in Legacy Codebase. Genetic engineering has exactly the same problems that modifying binary-only code. After some very complex observation of the system you may spot the point that is responsible for a certain problem, but you will never be sure (as in provably sure) that the "fix" you put in place: 1. is going to stop all the occurrences of the behavior you want to fix; 2. will only affect the behavior you want to fix; 3. will have no effect on other systems that you did not modify. (The article is mostly about 1 and a bit about 2 and 3.) Modifying legacy code is hard enough when the uncommented source code is around. Changing directly the binary is both a great engineering feat and something to be scared of.
- pasbesoin 10y ago
  http://www.catb.org/jargon/html/story-of-mel.html http://www.catb.org/jargon/html/story-of-mel.html It's not always fully apparent what's going on.
- quotemstr 10y ago
  People modify old binary-only console game ROMs all the time, usually with useful and reliable results.
  - Natsu 10y ago
    Problem is that we might only get one try to get the edits right in a person. And we don't have much ability to 'debug' our modifications, either.
- Moshe_Silnorin 10y ago
  If we replace degenerate alleles with the most-common version of that allele, isn't that pretty safe? It would have been tested on billions of people naturally.
  - static_noise 10y ago
    Not if the people with the degenerate version also have another mutation that interacts. If you only fix one, you run into a third kind of bug.
marchenko 10y ago
The nuclear/mitochondrial mismatch theory is interesting. Communities with a long history of admixture often have a significant number of individuals with mitochondrial DNA and nuclear DNA of divergent geographic origins, but I have not seen it observed that they are subject to any deleterious mtDNA/nucDNA 'mismatch' effects. I wonder what the threshold for this effect is.
- jcoffland 10y ago
  How would you know which defects in a population were thus caused?
- a_bonobo 10y ago
  Maybe survivor bias? An embryo without mitochondrial/nuclear genes matching up may not survive long enough for a pregnancy to be visible
  - marchenko 10y ago
    This is probably the he case https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4614761/#s4title https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4614761/#s4titl...
lngnmn 10y ago
A single gene could be responsible for more than one trait? This is genetics 101.
damon_c 10y ago
Unexpected by whom? Wouldn't risks be the first thing one would expect when editing genes?
- jcoffland 10y ago
  Did you expect these specific risks?
deleted 10y ago
[deleted]
majkinetor 10y ago
Given that this is symbiotic relationship, this probably works in both ways but given that number of genes coded in mitos is low its probably way harder to notice the effect. So it might happen that even if 100% of 'old mitochondria' is cleared the new symbiosis will also be defective as some of the 40 genes required by the hosting cell might be missing with new mito lineage replacing the original one.
anigbrowl 10y ago
The article is good but the headline is terrible, falsely implying some surprising new discovery rather than the sobering actuality that we lack a good theory of genetic development. A better one would be 'Gene Editing's Risks Are Hard to Manage.'
jcoffland 10y ago
Seeking out and using so called super mitochondria for this therapy could have it's own problems. If future generations only had such mitochondria they could become immune to future therapies. By selecting and actively promoting "healthy" mitochondria we could limit mitochondrial diversity which could lead to diseases which affect huge swathes of the population. Obviously we are not there yet but these are some of the dangers of applying gene therapy to broad populations.
tormeh 10y ago
What I've thought about is replacing the DNA in cells of adults with an average of multiple samples of their DNA, to correct for the mutations in our DNA that accumulates as we age. I think I've heard something about progress in this area, but I don't know what to google for. Does anyone know if there's any news in this area?
ufmace 10y ago
Anyone else noticing this site to be broken in Chrome? Seems that the CSS files aren't loading due to some sort of security error from their CDN site.
- anchpop 10y ago
  Looks fine to me. Windows 10, latest version of Chrome
mirimir 10y ago
> Some research suggests that nuclear genes evolve to sync well with a mitochondrial haplotype, and that when the pairing is suddenly switched, health might be compromised. Normally, eggs provide all mitochondria. The sperm's mitochondrion gets left outside during fertilization. So in most zygotes, there's a new pairing between the father's nuclear genes and the mother's mitochondrial haplotype. I wonder what that entails. I do understand that most zygotes fail to implant, or get terminated very early in development. Maybe this is one of the causes. Anyone know?
dekhn 10y ago
This isn't gene editing, it's genome/organelle transfer. We have no science to explain the effects of organelle transfer. Also, none of these risks were "unexpected", except to people with very limited imaginations. Those of us who have followed advanced biomedicine for decades are rarely surprised when genomes behave "unexpectedly". They're not passive storage mechanisms made of just DNA that is accessed; they're complex, dynamic systems with a lot of behavior determined by the proteins that bind them. Some days I feel like people should just go back and study Barbara Mcclintock until they "get it".

tl;dr: Earlier this month, a study published in Nature by Shoukhrat Mitalipov, head of the Center for Embryonic Cell and Gene Therapy at the Oregon Health and Science University in Portland, suggested that in roughly 15 percent of cases, the mitochondrial replacement could fail and allow fatal defects to return, or even increase a child's vulnerability to new ailments. It's not a risk of editing the genes so much as a risk of the treatment failing.

reasonattlm 10y ago

This isn't about editing genes, it is about replacing mitochondria. Not the same thing at all. Mitochondria are like bacteria in the way they replicate. There are hundreds of them in a cell. They can pass components around between one another, can split and fuse. They are integrated with quality control mechanisms that cull the herd. It is a complicated picture. As the article notes the procedure isn't effectively clearing out all of the old mitochondria, and dynamics can favor them in the future. It is known that variations in mitochondrial DNA produce radical differences in competition between mitochondrial strains in the cell. That is how deletions affecting OXPHOS machinery cause one mutant to take over the whole population very quickly - some differences produce mitochondria that either replicate better or resist quality control more effectively. That one is one of the causes of aging, but the same principle exists for other differences between mitochondrial genomes. If you put two or more in a cell and let them fight it out, hard to say in advance what the outcome will be given present knowledge. So, basically, the people working on mitochondrial replacement need to make their tools for cleaning out the old mitochondria more efficient. If 100% success is achieved, that genome isn't coming back. Alternatively, actual gene therapy might be a better approach - though challenging if you want to edit mitochondrial genomes, as you have the same problem of coverage and competition. There is allotopic expression, moving mitochondrial genes to the cell nucleus, which is feasible via today's gene therapy. Given the amount of work needed to copy mitochondrial genes into the nucleus, however, the challenge being how to alter them so as to get the proteins produced back to the mitochondria, something that has been achieved for three genes so far, it might be more cost-effective to work on better clearance and replacement technologies for the near term of assisted reproduction needs.

gioele 10y ago

Unexpected Risks Found in Editing Binary Code to Fix Bugs in Legacy Codebase. Genetic engineering has exactly the same problems that modifying binary-only code. After some very complex observation of the system you may spot the point that is responsible for a certain problem, but you will never be sure (as in provably sure) that the "fix" you put in place: 1. is going to stop all the occurrences of the behavior you want to fix; 2. will only affect the behavior you want to fix; 3. will have no effect on other systems that you did not modify. (The article is mostly about 1 and a bit about 2 and 3.) Modifying legacy code is hard enough when the uncommented source code is around. Changing directly the binary is both a great engineering feat and something to be scared of.

pasbesoin 10y ago
http://www.catb.org/jargon/html/story-of-mel.html http://www.catb.org/jargon/html/story-of-mel.html It's not always fully apparent what's going on.
quotemstr 10y ago
People modify old binary-only console game ROMs all the time, usually with useful and reliable results.
- Natsu 10y ago
  Problem is that we might only get one try to get the edits right in a person. And we don't have much ability to 'debug' our modifications, either.
Moshe_Silnorin 10y ago
If we replace degenerate alleles with the most-common version of that allele, isn't that pretty safe? It would have been tested on billions of people naturally.
- static_noise 10y ago
  Not if the people with the degenerate version also have another mutation that interacts. If you only fix one, you run into a third kind of bug.

marchenko 10y ago

The nuclear/mitochondrial mismatch theory is interesting. Communities with a long history of admixture often have a significant number of individuals with mitochondrial DNA and nuclear DNA of divergent geographic origins, but I have not seen it observed that they are subject to any deleterious mtDNA/nucDNA 'mismatch' effects. I wonder what the threshold for this effect is.

jcoffland 10y ago
How would you know which defects in a population were thus caused?
a_bonobo 10y ago
Maybe survivor bias? An embryo without mitochondrial/nuclear genes matching up may not survive long enough for a pregnancy to be visible
- marchenko 10y ago
  This is probably the he case https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4614761/#s4title https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4614761/#s4titl...

lngnmn 10y ago

A single gene could be responsible for more than one trait? This is genetics 101.

damon_c 10y ago

Unexpected by whom? Wouldn't risks be the first thing one would expect when editing genes?

jcoffland 10y ago
Did you expect these specific risks?

deleted 10y ago

[deleted]

majkinetor 10y ago

Given that this is symbiotic relationship, this probably works in both ways but given that number of genes coded in mitos is low its probably way harder to notice the effect. So it might happen that even if 100% of 'old mitochondria' is cleared the new symbiosis will also be defective as some of the 40 genes required by the hosting cell might be missing with new mito lineage replacing the original one.

anigbrowl 10y ago

The article is good but the headline is terrible, falsely implying some surprising new discovery rather than the sobering actuality that we lack a good theory of genetic development. A better one would be 'Gene Editing's Risks Are Hard to Manage.'

jcoffland 10y ago

Seeking out and using so called super mitochondria for this therapy could have it's own problems. If future generations only had such mitochondria they could become immune to future therapies. By selecting and actively promoting "healthy" mitochondria we could limit mitochondrial diversity which could lead to diseases which affect huge swathes of the population. Obviously we are not there yet but these are some of the dangers of applying gene therapy to broad populations.

tormeh 10y ago

What I've thought about is replacing the DNA in cells of adults with an average of multiple samples of their DNA, to correct for the mutations in our DNA that accumulates as we age. I think I've heard something about progress in this area, but I don't know what to google for. Does anyone know if there's any news in this area?

ufmace 10y ago

Anyone else noticing this site to be broken in Chrome? Seems that the CSS files aren't loading due to some sort of security error from their CDN site.

anchpop 10y ago
Looks fine to me. Windows 10, latest version of Chrome

mirimir 10y ago

> Some research suggests that nuclear genes evolve to sync well with a mitochondrial haplotype, and that when the pairing is suddenly switched, health might be compromised. Normally, eggs provide all mitochondria. The sperm's mitochondrion gets left outside during fertilization. So in most zygotes, there's a new pairing between the father's nuclear genes and the mother's mitochondrial haplotype. I wonder what that entails. I do understand that most zygotes fail to implant, or get terminated very early in development. Maybe this is one of the causes. Anyone know?

dekhn 10y ago

This isn't gene editing, it's genome/organelle transfer. We have no science to explain the effects of organelle transfer. Also, none of these risks were "unexpected", except to people with very limited imaginations. Those of us who have followed advanced biomedicine for decades are rarely surprised when genomes behave "unexpectedly". They're not passive storage mechanisms made of just DNA that is accessed; they're complex, dynamic systems with a lot of behavior determined by the proteins that bind them. Some days I feel like people should just go back and study Barbara Mcclintock until they "get it".