4 ms·

I have two mutations of USH2A, causing blindness. It’s a big gene. This kind of tech can’t come soon enough.

freedomben 9y ago
I too have some bad genes that make life pretty challenging at times. This type of tech gives me great hope. I wish I were more qualified to work on it and advance it.
- guelo 9y ago
  I'm sorry to be trying to take away your hope but I just don't see the path from CRISPR to gene therapy that can cure diseases in adults. CRISPR allows scientists to modify DNA in individual cells in a lab setting. But it doesn't help with mass editing DNA in cells throughout the body. I've heard of experiments where they take white blood cells, edit their DNA, and then reinject them. But there's currently no way to modify the genes in-place in a person's retina for example.
  - freedomben 9y ago
    I appreciate the comment. It is certainly better to be realistic about hopes. I think my hope is really more into something like the Ray Kurzweil cellular-sized nano computers that can be injected into the body to perform various functions. As we understand what causes certain "bugs" in bodies, perhaps an effective solution can be developed.
    - freedomben 9y ago
      Forgot to add that I expect to see ads for "Company XYZ is hiring node developers to write robust and reliable javascript for our nano-computer platform" because of course the nano-bots will run javascript :-)
  - rflrob 9y ago
    Actually, the retina is one of the few places that gene therapy has been really successful. Adeno associated virus can be injected, and it has a fairly conservative safety profile (for instance, it doesn't normally integrate into the genome). https://en.wikipedia.org/wiki/Gene_therapy_of_the_human_retina https://en.wikipedia.org/wiki/Gene_therapy_of_the_human_reti... is a good place to start.
  - brianberns 9y ago
    CRISPR can be delivered by virus to many cells of the body at once, so it seems possible that this could lead to adult therapies. https://www.quora.com/How-does-the-CRISPR-Cas9-therapy-manage-to-enter-multiple-cells-of-the-body-when-injected https://www.quora.com/How-does-the-CRISPR-Cas9-therapy-manag...
    - raquo 9y ago
      Who needs nanobots when you can engineer viruses with such a payload. Amazing. Horrifying, but amazing.
      - s4vi0r 9y ago
        Viruses are the OG nanobots. Not only do they look robot-y, they also technically don't count as living IIRC
        0xJRS 9y ago
        There is actually a large controversy where one half of people who care think they are non living and the other half of people who care think they _are_ living.
        tormeh 9y ago
        Life, like free will, is just one of those words that mean less and less the closer you look. Whether they are alive or not doesn't matter.
  - adventured 9y ago
    That's extremely far from the truth. The entire CRISPR field is focused heavily on being able to mass edit genes in adults in fact. The three major CRISPR companies, Berkeley and Broad are all focused on pushing the technology there. It's not a question of if, it's inevitable. They already know it can be done, the challenge is scaling it up and constantly improving the accuracy and the overall command they have of what eg Cpf1 can do (in the case of Broad & Editas). A very large percentage of all disease occurs in adults after the age of ~30. That is, well after the person is an adult. Take a look at the disease targets that Editas, Intellia and Crispr Therapeutics are pursuing: they're going after adult diseases long-term, including targeting things such as diseases of the liver more near-term (next five years). Most of their initial targets are focused on easier (relative term) editing targets, the retina being a popular target due to the genes there. First they'll learn to crawl, then walk, then run. You don't have to edit all the genes in the body to cure most genetic diseases.
    - Gatsky 9y ago
      Yes, this is correct. We develop from a single cell, and many complex tissues ultimately derive from single cells. A single mammary stem cell can recapitulate the entire breast tissue for example. Bone marrow stem cells are able to produce the entire complement of red and white blood cells. If you can edit these stem cells, you will make a big difference to the patient.
    - nonbel 9y ago
      >"That's extremely far from the truth. The entire CRISPR field is focused heavily on being able to mass edit genes in adults in fact." It doesn't seem so to me. I've noticed less and less focus on toxicity lately, as if they've given up on that. For example, I took a look at one of the papers[1] from TFA. All they look at is percent of sequences from surviving cells that contained the A->G mutation. They don't report how many cells died during the process to get there. Also, they see these mutations in the control group too (figure 4 untreated A5 = 99.8), so it seems this may be yet another way to use crispr to select for pre-existing mutants. It's hard to say since no info is provided on the toxicity for this new strategy. On the other hand, the new strategy may be less toxic since it is only supposed to introduce a single strand break rather than double (ie as opposed to cas9). Reviewers should be on this, not sure why they so consistently drop the ball regarding the role of toxicity in these studies. [1] https://www.nature.com/nature/journal/vaap/ncurrent/full/nature24644.html https://www.nature.com/nature/journal/vaap/ncurrent/full/nat...
Geee 9y ago
Is it enough to edit the genes or is there a need to activate some kind of regenerative process? The body is regenerating all the time but larger changes might require rebuilding from the ground up?
- adventured 9y ago
  The very earliest targets are ideally large gene punch-out targets, using Cas9. For example that's what Editas is targeting with their first retina program. To deal with complex, higher order genetic diseases (which is also where the money will be in the field) you'll have to be able to do inserting of healthy replacement genes. Cas9 is not very good at that as of now, it's like using a mallet to tie a fishing line. There is an immense amount of effort going into trying to shoehorn Cas9 into being better at that. Other options such as Cpf1 (and possibly one day CasX/CasY from Berkeley) have been shown to be far superior at more advanced editing.
craftyguy 9y ago
How would this help you? I don't think they could edit all of the cells required to undo this genetic defect for good, right?
- est 9y ago
  cells in your body are being replaced every two weeks I think? There must be some way to spread the cure.
  - djur 9y ago
    It depends on when the gene normally expresses. Some genetic disorders result in incorrect development of organs, which means that gene therapy alone will never resolve the issue. Organ donation or surgery plus gene therapy might be a possible cure for some such disorders, though. But if a condition just results in producing too much of a hormone or something like that it could be addressed with just gene therapy.

I too have some bad genes that make life pretty challenging at times. This type of tech gives me great hope. I wish I were more qualified to work on it and advance it.

guelo 9y ago
I'm sorry to be trying to take away your hope but I just don't see the path from CRISPR to gene therapy that can cure diseases in adults. CRISPR allows scientists to modify DNA in individual cells in a lab setting. But it doesn't help with mass editing DNA in cells throughout the body. I've heard of experiments where they take white blood cells, edit their DNA, and then reinject them. But there's currently no way to modify the genes in-place in a person's retina for example.
- freedomben 9y ago
  I appreciate the comment. It is certainly better to be realistic about hopes. I think my hope is really more into something like the Ray Kurzweil cellular-sized nano computers that can be injected into the body to perform various functions. As we understand what causes certain "bugs" in bodies, perhaps an effective solution can be developed.
  - freedomben 9y ago
    Forgot to add that I expect to see ads for "Company XYZ is hiring node developers to write robust and reliable javascript for our nano-computer platform" because of course the nano-bots will run javascript :-)
- rflrob 9y ago
  Actually, the retina is one of the few places that gene therapy has been really successful. Adeno associated virus can be injected, and it has a fairly conservative safety profile (for instance, it doesn't normally integrate into the genome). https://en.wikipedia.org/wiki/Gene_therapy_of_the_human_retina https://en.wikipedia.org/wiki/Gene_therapy_of_the_human_reti... is a good place to start.
- brianberns 9y ago
  CRISPR can be delivered by virus to many cells of the body at once, so it seems possible that this could lead to adult therapies. https://www.quora.com/How-does-the-CRISPR-Cas9-therapy-manage-to-enter-multiple-cells-of-the-body-when-injected https://www.quora.com/How-does-the-CRISPR-Cas9-therapy-manag...
  - raquo 9y ago
    Who needs nanobots when you can engineer viruses with such a payload. Amazing. Horrifying, but amazing.
    - s4vi0r 9y ago
      Viruses are the OG nanobots. Not only do they look robot-y, they also technically don't count as living IIRC
      - 0xJRS 9y ago
        There is actually a large controversy where one half of people who care think they are non living and the other half of people who care think they _are_ living.
        tormeh 9y ago
        Life, like free will, is just one of those words that mean less and less the closer you look. Whether they are alive or not doesn't matter.
- adventured 9y ago
  That's extremely far from the truth. The entire CRISPR field is focused heavily on being able to mass edit genes in adults in fact. The three major CRISPR companies, Berkeley and Broad are all focused on pushing the technology there. It's not a question of if, it's inevitable. They already know it can be done, the challenge is scaling it up and constantly improving the accuracy and the overall command they have of what eg Cpf1 can do (in the case of Broad & Editas). A very large percentage of all disease occurs in adults after the age of ~30. That is, well after the person is an adult. Take a look at the disease targets that Editas, Intellia and Crispr Therapeutics are pursuing: they're going after adult diseases long-term, including targeting things such as diseases of the liver more near-term (next five years). Most of their initial targets are focused on easier (relative term) editing targets, the retina being a popular target due to the genes there. First they'll learn to crawl, then walk, then run. You don't have to edit all the genes in the body to cure most genetic diseases.
  - Gatsky 9y ago
    Yes, this is correct. We develop from a single cell, and many complex tissues ultimately derive from single cells. A single mammary stem cell can recapitulate the entire breast tissue for example. Bone marrow stem cells are able to produce the entire complement of red and white blood cells. If you can edit these stem cells, you will make a big difference to the patient.
  - nonbel 9y ago
    >"That's extremely far from the truth. The entire CRISPR field is focused heavily on being able to mass edit genes in adults in fact." It doesn't seem so to me. I've noticed less and less focus on toxicity lately, as if they've given up on that. For example, I took a look at one of the papers[1] from TFA. All they look at is percent of sequences from surviving cells that contained the A->G mutation. They don't report how many cells died during the process to get there. Also, they see these mutations in the control group too (figure 4 untreated A5 = 99.8), so it seems this may be yet another way to use crispr to select for pre-existing mutants. It's hard to say since no info is provided on the toxicity for this new strategy. On the other hand, the new strategy may be less toxic since it is only supposed to introduce a single strand break rather than double (ie as opposed to cas9). Reviewers should be on this, not sure why they so consistently drop the ball regarding the role of toxicity in these studies. [1] https://www.nature.com/nature/journal/vaap/ncurrent/full/nature24644.html https://www.nature.com/nature/journal/vaap/ncurrent/full/nat...

Geee 9y ago

Is it enough to edit the genes or is there a need to activate some kind of regenerative process? The body is regenerating all the time but larger changes might require rebuilding from the ground up?

adventured 9y ago
The very earliest targets are ideally large gene punch-out targets, using Cas9. For example that's what Editas is targeting with their first retina program. To deal with complex, higher order genetic diseases (which is also where the money will be in the field) you'll have to be able to do inserting of healthy replacement genes. Cas9 is not very good at that as of now, it's like using a mallet to tie a fishing line. There is an immense amount of effort going into trying to shoehorn Cas9 into being better at that. Other options such as Cpf1 (and possibly one day CasX/CasY from Berkeley) have been shown to be far superior at more advanced editing.

craftyguy 9y ago

How would this help you? I don't think they could edit all of the cells required to undo this genetic defect for good, right?

est 9y ago
cells in your body are being replaced every two weeks I think? There must be some way to spread the cure.
- djur 9y ago
  It depends on when the gene normally expresses. Some genetic disorders result in incorrect development of organs, which means that gene therapy alone will never resolve the issue. Organ donation or surgery plus gene therapy might be a possible cure for some such disorders, though. But if a condition just results in producing too much of a hormone or something like that it could be addressed with just gene therapy.