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This was the immediate concern shared by me and several genomics researchers - gene variants that are often shown to be good for one thing may be bad for anothe

This was the immediate concern shared by me and several genomics researchers - gene variants that are often shown to be good for one thing may be bad for another. However, the way genome wide association studies (GWAS) currently works, is that gene variants are identified that have unexpectedly high frequencies in 'case' group compared to a control group; but follow-ups to see what other phenotypes are associated with those variants are rarely done.

trashE 8y ago
The same thing happens with IVF babies. It shakes up their epigenetics and causes a wide range of health problems which are less common in natural born populations.
- im3w1l 8y ago
  People get IVF babies because they can't get normal babies. Wonder if it would happen the same if you did IVF with normally fertile people.
- daxorid 8y ago
  Do you have a source for this? My understanding is that IVF babies have more problems because you are scraping the proverbial bottom of the barrel in terms of egg (or sperm) quality to begin with.
nordsieck 8y ago
> This was the immediate concern shared by me and several genomics researchers - gene variants that are often shown to be good for one thing may be bad for another. I think it's certainly possible to get mixed or even bad results with gene editing by trying to push the technology farther than we really understand. That being said, the basic priority for gene editing is probably to prevent/reverse bad genetic conditions that we understand well. No more downs syndrome. That seems to be an unmitigated win to me.
- Valmar 8y ago
  One thing that worries me is, that by attempting to prevent and/or reverse one set of conditions, other issues may pop up because of adding/removing/changing something we don't understand the full functionality of and how it interacts with other parts of DNA. DNA looks mightily like an extreme and profoundly complicated, complex piece of programming, with unnecessary redundancies removed, and useful redundancies left in, as well pieces of code that call lots of other pieces, as well as being called by others. If the genome is analogous to a computer binary... we don't understand the file format, and how it is read and interpreted. Nature knows far-and-away better than we do how to make it all work 99.99% of the time, with occasional errors due to radiation, poisoning, interbreeding being accounted for so that things don't get out of hand. Well, these assumptions held... until we intelligently stupid creatures came along, using our intelligence to create dangerous tools that are most abused by those least worthy to wield them...
  - Retric 8y ago
    We understand a lot of about the DNA ‘file format’ and how it works. That’s been a major priority of research. Nature does not ‘know how’ to make it work 99.99% of the time. Nature very frequently aborts pregnancy’s when any number of things go wrong. Getting all the way to birth is a huge checksum that validates the majority of critical DNA. Which gets it the larger point. Evolution focuses more on species propagation than individuals.
    - TheSpiceIsLife 8y ago
      It could be argued that miscarriages due to genetics that are incompatible with life to whatever degree are nature getting it right.
      - Retric 8y ago
        That’s a near tautology. Cell division is one of those things you need or get right or you don’t get a pregnancy. It’s not like the mother needs or do anything at that point, the result is just death by default.
im3w1l 8y ago
So uh how ethical would it be to hypothetically know all that but do it anyway for the knowledge it will provide us for the next iteration.
- subroutine 8y ago
  If the goal was to prove that CRISPR can be performed safely and reliably in humans I think the first edit should have been in a non-coding segment somewhere far away from genes and gene-regulatory elements; a locus with enough uniqueness (e.g. not a CpG repeat island) to make it extremely improbable that the guide RNA would match another locus resulting in off-target mutations. Why even risk messing around with genes in the very first attempt in humans?? And naturally, like Jiankui, I could be completely off-base (no pun intended), so my biggest qualm was that the decision on where/when/how to edit should have been made by a team of seasoned (perhaps the world's top) geneticists and molecular biologists so they could pool their expertise and come to a consensus. Many people are interested in seeing CRISPR push forward, and mention something like you have: but what about the "knowledge it will provide us for the next iteration". Trust me, I'm just as eager as anyone. However, if this mavrick experiment fails, and something is remotely off about these little girls (u can bet they will be under a constant magnifying glass), this will end up being a huge setback. It will spook the public, and the legislation factory will churn out regulatory policy that nobody wants.
  - Valmar 8y ago
    If there are issues, then it is very important to abort the experiment, and go back to studying DNA. Altering something so crucial to life, and its life-long health, is fraught with many-faceted issues. It's dangerous to tinker without a truly full knowledge of what one is doing.
    - subroutine 8y ago
      "Abort the experiment"? Yeah... since we're working with humans now, you can't exactly "abort" the experiment unless the mother has an actual abortion. This plays-off what I just mentioned above; there are a heap of politics to consider now. If tomorrow's headlines read: CRISPR Twins Aborted ...it's suddenly a political issue. An issue that could result in ~half the US population calling for regulation due to safety concerns and the other half demanding regulation from an ethical pretext (so, religious reasons).
carbocation 8y ago
Follow-ups to see what other phenotypes are associated with GWAS hits have occupied a meaningful fraction of the mindshare of statistical genetics over the past few years: GREML, BOLT-LMM’s REML, and MTAG are examples of tools for evaluation and exploitation of the genetic correlation between traits. I would add that PheWAS is often performed with specific genetic instruments of interest, and can be performed with aggregate measures such as a genetic risk score. This lets you see association across a slew of traits at once.
- subroutine 8y ago
  I was aware of the Broad tools, but point taken. There's also databases like GeneCards (e.g. bit.ly/APOE_genecards ) or just the NIH genome viewer: (e.g. bit.ly/APOE_NCBI ) which have SNP accession numbers, and annotations for disease-linked variants. And it's good we are sharing this info. But we are far from having high-powered GWAS for all of human's traits and diseases. And often what we do know is from a single demographic (fwiw mostly caucasian, not chinese). How gene variants influence outcomes in different genetic backgrounds, or within certain environments (think developmental nutrition in africa vs asia) is typically a big questionmark. So IMO performing CRISPR edits to mitigate a problem that was completely avoidable by other means was unethical at best.
  - carbocation 8y ago
    We are in violent agreement about the ethics. For UK Biobank, there is a GWAS of ~everything: http://www.nealelab.is/uk-biobank/ http://www.nealelab.is/uk-biobank/ The lack of diversity in genetic studies is a huge problem. This one isn't just moral, either: we're ignoring the richness of allelic diversity that is found in people throughout the world (particularly in Africa, which has the most genetic diversity because of its pre-bottleneck status). There is an awareness and I think you'll see big changes here in the next few years.

trashE 8y ago

The same thing happens with IVF babies. It shakes up their epigenetics and causes a wide range of health problems which are less common in natural born populations.

im3w1l 8y ago
People get IVF babies because they can't get normal babies. Wonder if it would happen the same if you did IVF with normally fertile people.
daxorid 8y ago
Do you have a source for this? My understanding is that IVF babies have more problems because you are scraping the proverbial bottom of the barrel in terms of egg (or sperm) quality to begin with.

nordsieck 8y ago

> This was the immediate concern shared by me and several genomics researchers - gene variants that are often shown to be good for one thing may be bad for another. I think it's certainly possible to get mixed or even bad results with gene editing by trying to push the technology farther than we really understand. That being said, the basic priority for gene editing is probably to prevent/reverse bad genetic conditions that we understand well. No more downs syndrome. That seems to be an unmitigated win to me.

Valmar 8y ago
One thing that worries me is, that by attempting to prevent and/or reverse one set of conditions, other issues may pop up because of adding/removing/changing something we don't understand the full functionality of and how it interacts with other parts of DNA. DNA looks mightily like an extreme and profoundly complicated, complex piece of programming, with unnecessary redundancies removed, and useful redundancies left in, as well pieces of code that call lots of other pieces, as well as being called by others. If the genome is analogous to a computer binary... we don't understand the file format, and how it is read and interpreted. Nature knows far-and-away better than we do how to make it all work 99.99% of the time, with occasional errors due to radiation, poisoning, interbreeding being accounted for so that things don't get out of hand. Well, these assumptions held... until we intelligently stupid creatures came along, using our intelligence to create dangerous tools that are most abused by those least worthy to wield them...
- Retric 8y ago
  We understand a lot of about the DNA ‘file format’ and how it works. That’s been a major priority of research. Nature does not ‘know how’ to make it work 99.99% of the time. Nature very frequently aborts pregnancy’s when any number of things go wrong. Getting all the way to birth is a huge checksum that validates the majority of critical DNA. Which gets it the larger point. Evolution focuses more on species propagation than individuals.
  - TheSpiceIsLife 8y ago
    It could be argued that miscarriages due to genetics that are incompatible with life to whatever degree are nature getting it right.
    - Retric 8y ago
      That’s a near tautology. Cell division is one of those things you need or get right or you don’t get a pregnancy. It’s not like the mother needs or do anything at that point, the result is just death by default.

im3w1l 8y ago

So uh how ethical would it be to hypothetically know all that but do it anyway for the knowledge it will provide us for the next iteration.

subroutine 8y ago
If the goal was to prove that CRISPR can be performed safely and reliably in humans I think the first edit should have been in a non-coding segment somewhere far away from genes and gene-regulatory elements; a locus with enough uniqueness (e.g. not a CpG repeat island) to make it extremely improbable that the guide RNA would match another locus resulting in off-target mutations. Why even risk messing around with genes in the very first attempt in humans?? And naturally, like Jiankui, I could be completely off-base (no pun intended), so my biggest qualm was that the decision on where/when/how to edit should have been made by a team of seasoned (perhaps the world's top) geneticists and molecular biologists so they could pool their expertise and come to a consensus. Many people are interested in seeing CRISPR push forward, and mention something like you have: but what about the "knowledge it will provide us for the next iteration". Trust me, I'm just as eager as anyone. However, if this mavrick experiment fails, and something is remotely off about these little girls (u can bet they will be under a constant magnifying glass), this will end up being a huge setback. It will spook the public, and the legislation factory will churn out regulatory policy that nobody wants.
- Valmar 8y ago
  If there are issues, then it is very important to abort the experiment, and go back to studying DNA. Altering something so crucial to life, and its life-long health, is fraught with many-faceted issues. It's dangerous to tinker without a truly full knowledge of what one is doing.
  - subroutine 8y ago
    "Abort the experiment"? Yeah... since we're working with humans now, you can't exactly "abort" the experiment unless the mother has an actual abortion. This plays-off what I just mentioned above; there are a heap of politics to consider now. If tomorrow's headlines read: CRISPR Twins Aborted ...it's suddenly a political issue. An issue that could result in ~half the US population calling for regulation due to safety concerns and the other half demanding regulation from an ethical pretext (so, religious reasons).

carbocation 8y ago

Follow-ups to see what other phenotypes are associated with GWAS hits have occupied a meaningful fraction of the mindshare of statistical genetics over the past few years: GREML, BOLT-LMM’s REML, and MTAG are examples of tools for evaluation and exploitation of the genetic correlation between traits. I would add that PheWAS is often performed with specific genetic instruments of interest, and can be performed with aggregate measures such as a genetic risk score. This lets you see association across a slew of traits at once.

subroutine 8y ago
I was aware of the Broad tools, but point taken. There's also databases like GeneCards (e.g. bit.ly/APOE_genecards ) or just the NIH genome viewer: (e.g. bit.ly/APOE_NCBI ) which have SNP accession numbers, and annotations for disease-linked variants. And it's good we are sharing this info. But we are far from having high-powered GWAS for all of human's traits and diseases. And often what we do know is from a single demographic (fwiw mostly caucasian, not chinese). How gene variants influence outcomes in different genetic backgrounds, or within certain environments (think developmental nutrition in africa vs asia) is typically a big questionmark. So IMO performing CRISPR edits to mitigate a problem that was completely avoidable by other means was unethical at best.
- carbocation 8y ago
  We are in violent agreement about the ethics. For UK Biobank, there is a GWAS of ~everything: http://www.nealelab.is/uk-biobank/ http://www.nealelab.is/uk-biobank/ The lack of diversity in genetic studies is a huge problem. This one isn't just moral, either: we're ignoring the richness of allelic diversity that is found in people throughout the world (particularly in Africa, which has the most genetic diversity because of its pre-bottleneck status). There is an awareness and I think you'll see big changes here in the next few years.