When applied to adult humans, this is many orders of magnitude more difficult than you claim.
Casgevy is not a standard gene edit, because although the mutation for sickle cell is known, the didn’t target that mutation! (I assume they have their reasons, they are activating fetal haemoglobin expression instead). Also, the treatment works by removing all the bone marrow from your body, editing it, and putting it back in, because they know exactly what cells haemoglobin is expressed in for it to do its mechanistic role.
Unless you’re planning to edit at the fertilized egg stage, with only a black box you have to edit every single cell in the human body, and these treatments, though the stuff of science fiction, doesn’t seem to have an easy answer. Once you know where the genes you’re editing are being expressed you can target them, but some places are easier to target than others (like the brain, or the bone marrow), and it’s likely some sites can only be accessed with a good surgery.
Wagner also mentions off-target errors which are an additional issue with current technologies.
You can probably do all the diabetes edits in the pancreas and get a good reduction in diabetes, but that’s because you have the mechanistic information on how it works.
Though at that point we can probably grow organs from single cells so we can edit them there.
And with Casgevy’s approach (turning on a gene, not editing), you probably want to know the mechanism, otherwise you get haemoglobin being expressed in your neurons and that’s probably not good for your health.
When applied to adult humans, this is many orders of magnitude more difficult than you claim.
I’m not suggesting getting a therapy like this working is easy. I think it will be quite hard.
(I assume they have their reasons, they are activating fetal haemoglobin expression instead)
They targeted fetal hemoglobin because reactivating it simultaneously treats sickle cell and beta thallasemia. Fetal hemoglobin doesn’t sickle and the symptoms of beta thallasemia ultimately arise from a lack of functional hemoglobin.
Also, the treatment works by removing all the bone marrow from your body, editing it, and putting it back in, because they know exactly what cells haemoglobin is expressed in for it to do its mechanistic role
I’m working on a post about this topic that goes into much more depth and addresses issues with delivery. But needless to say, I don’t think we will have many viable therapies if they rely on extracting bone marrow and then reinjecting it.
Unless you’re planning to edit at the fertilized egg stage, with only a black box you have to edit every single cell in the human body, and these treatments, though the stuff of science fiction, doesn’t seem to have an easy answer.
You don’t actually need to edit every cell. You just need to get enough edits in a large enough fraction of cells to affect the phenotype. Will there be issues with mosaicism?
Maybe. But long-lived cells in the human body already have about 1500 de novo mutations by the time you hit 40, so the body is clearly able to deal with some level of mosaicism already.
Wagner also mentions off-target errors which are an additional issue with current technologies.
Yes, you are correct. I will address this in my longer post.
You can probably do all the diabetes edits in the pancreas and get a good reduction in diabetes, but that’s because you have the mechanistic information on how it works.
We understand diabetes well enough but we don’t have a mechanistic understanding of all the genetic variants known to influence diabetes risk do so.
Though at that point we can probably grow organs from single cells so we can edit them there.
If they can get that to work then it will be amazing. But how would it work for organs like the brain?
When applied to adult humans, this is many orders of magnitude more difficult than you claim.
Casgevy is not a standard gene edit, because although the mutation for sickle cell is known, the didn’t target that mutation! (I assume they have their reasons, they are activating fetal haemoglobin expression instead). Also, the treatment works by removing all the bone marrow from your body, editing it, and putting it back in, because they know exactly what cells haemoglobin is expressed in for it to do its mechanistic role.
Unless you’re planning to edit at the fertilized egg stage, with only a black box you have to edit every single cell in the human body, and these treatments, though the stuff of science fiction, doesn’t seem to have an easy answer. Once you know where the genes you’re editing are being expressed you can target them, but some places are easier to target than others (like the brain, or the bone marrow), and it’s likely some sites can only be accessed with a good surgery.
Wagner also mentions off-target errors which are an additional issue with current technologies.
You can probably do all the diabetes edits in the pancreas and get a good reduction in diabetes, but that’s because you have the mechanistic information on how it works.
Though at that point we can probably grow organs from single cells so we can edit them there.
And with Casgevy’s approach (turning on a gene, not editing), you probably want to know the mechanism, otherwise you get haemoglobin being expressed in your neurons and that’s probably not good for your health.
I’m not suggesting getting a therapy like this working is easy. I think it will be quite hard.
They targeted fetal hemoglobin because reactivating it simultaneously treats sickle cell and beta thallasemia. Fetal hemoglobin doesn’t sickle and the symptoms of beta thallasemia ultimately arise from a lack of functional hemoglobin.
I’m working on a post about this topic that goes into much more depth and addresses issues with delivery. But needless to say, I don’t think we will have many viable therapies if they rely on extracting bone marrow and then reinjecting it.
You don’t actually need to edit every cell. You just need to get enough edits in a large enough fraction of cells to affect the phenotype. Will there be issues with mosaicism?
Maybe. But long-lived cells in the human body already have about 1500 de novo mutations by the time you hit 40, so the body is clearly able to deal with some level of mosaicism already.
Yes, you are correct. I will address this in my longer post.
We understand diabetes well enough but we don’t have a mechanistic understanding of all the genetic variants known to influence diabetes risk do so.
If they can get that to work then it will be amazing. But how would it work for organs like the brain?