5 ms·

Since T cells do not reproduce by themselves, I presume the effects of modified T cells will only last until the cells exist in the body. This reminds me of a q

by maga 10y ago

Since T cells do not reproduce by themselves, I presume the effects of modified T cells will only last until the cells exist in the body. This reminds me of a question I was wondering about since I heard about Crispr: can we use this method to make permanent changes in the DNA of grown up humans, and if so, do we have clear understanding of how to do it? The thing that puzzles me most is that if we do it by creating some cells and injecting them, how do we guarantee that these cells replace their existing unmodified counterparts?

patall 10y ago
I would not be so sure about that. They do not state which kind (or state) of T cells they target but it is not unlikely that they do not draw them from the blood but from bone marrow. May also be memory T cells ... This should also answer your second question: You target some cells higher up in the hirachy like CMPs or even MPP and HSC (stem cells). Other tissue, other stem cell type. And ultimately obviously some lineage commited (cells aimed to become a certain cell type) iPS cells (which are stem cells generated from normal body cells). Thats all possible, the only thing really missing is good understand of epigenetics (only a question of time) and some way for reliable epigenetic programming/modification. (Sorry if thats too short too complicated but maybe it guides you in the right direction) Edit: And third question: I am not entirely sure why you would need to replace all the existing cells. Some additional functionality might be sufficent. Where this is not the case, you usually go for irradition (and full replacement).
- maga 10y ago
  Thanks for the detailed answer! >This should also answer your second question: You target some cells higher up in the hirachy like CMPs or even MPP and HSC (stem cells). Other tissue, other stem cell type. And ultimately obviously some lineage commited (cells aimed to become a certain cell type) iPS cells (which are stem cells generated from normal body cells). Thats all possible, the only thing really missing is good understand of epigenetics (only a question of time) and some way for reliable epigenetic programming/modification. (Sorry if thats too short too complicated but maybe it guides you in the right direction) If I understand you correctly, we can replace the cells in charge of producing other cells (stem cells) to make the changes lasting, but we are not yet certain how the changes will play with the rest of their environment (epigenetics). >I am not entirely sure why you would need to replace all the existing cells. Some additional functionality might be sufficent. Where this is not the case, you usually go for irradition (and full replacement). To make an example, let's say I'm a secret ginger carrying the mutation that makes me far more susceptible to skin cancer[1]. And let's say we know what exactly to change in DNA to fix my problem. Now, I don't know how the skin producing machinery works, but I guess replacing it in one go isn't an option. So, if we go with changing cells higher up in skin production, can we guarantee that in due time they will replace all (or most of) the skin with modified cells? As a bonus question, since we limit ourselves to targeting only particular cell types (skin in this case) that means the rest of the body is carrying unmodified DNA, hence, those changes are not hereditary, right? [1] http://www.telegraph.co.uk/science/2016/07/12/one-quarter-of-britons-carry-ginger-gene-which-raises-risk-of-sk/ http://www.telegraph.co.uk/science/2016/07/12/one-quarter-of...
  - patall 10y ago
    > If I understand you correctly, we can replace the cells in charge of producing other cells (stem cells) to make the changes lasting, but we are not yet certain how the changes will play with the rest of their environment (epigenetics). Not quite, we are not yet 100% certain what these changes are (or whether we even know all epigenetic marks). We know that epigenetics determines what cell type a particular cell is, but we do not know yet what all of these are. Slight analogy: What we have with the genome is the compiled code of the program, the sum over all epigenetic marks somewhat is the state at run time. >To make an example, let's say I'm a secret ginger carrying the mutation that makes me far more susceptible to skin cancer[1]. And let's say we know what exactly to change in DNA to fix my problem. Now, I don't know how the skin producing machinery works, but I guess replacing it in one go isn't an option. So, if we go with changing cells higher up in skin production, can we guarantee that in due time they will replace all (or most of) the skin with modified cells? As a bonus question, since we limit ourselves to targeting only particular cell types (skin in this case) that means the rest of the body is carrying unmodified DNA, hence, those changes are not hereditary, right? That is going to be hard, as you basically want to replace a whole organ with another. The (idealistic) idea there is rather to take a virus that performs the modification in the body in all cells. But that is still somewhat in the future as you have to make sure the virus does not spread to other persons, the changes are lasting etc. Note: What we did not cover here is the whole interplay with the immune system. It may well happen that some B or T cells recognize the modified cells as foreign (at least if the change is in a protein) and fight it, so you'd rather have the modified cells as nonessential. In the study here this is not that important as you still have other T cells and you'd be happy enough if they (the modified cells) fought the cancer for some time and then disappear.
    - maga 10y ago
      >Slight analogy: What we have with the genome is the compiled code of the program, the sum over all epigenetic marks somewhat is the state at run time. Now you're talking. That's a brilliant analogy, I'm stealing it for the next time I explain CS to biologists, thanks! >The (idealistic) idea there is rather to take a virus that performs the modification in the body in all cells. But that is still somewhat in the future as you have to make sure the virus does not spread to other persons, the changes are lasting etc. Indeed, I forgot about viruses. To sum up, to get to changing adult DNA we need a) more knowledge of the "runtime"/epigenetics to know what to change, b) ways to handle viruses if we go with them. That sounds reassuring, actually, at least we might not get stuck in Gattaca like future for too long.
rgejman 10y ago
T cells proliferate when they see their target antigen. This technology is being used without CRISPR in a number of clinical trials. See here: http://www.cancer.gov/about-cancer/treatment/research/car-t-cells http://www.cancer.gov/about-cancer/treatment/research/car-t-...
- maga 10y ago
  Thanks for the correction, I didn't know T cells multiply by themselves. Yet I assume they don't hang around permanently and will be sooner or later replaced by new, unmodified, cells produced by the body, hence, why I was asking about making permanent changes.
  - rgejman 10y ago
    Maybe. We haven't been doing this long enough to know. T cells can divide into a T "memory" type, but I'm not sure if CAR-T cells do this.

by maga 10y ago

patall 10y ago

I would not be so sure about that. They do not state which kind (or state) of T cells they target but it is not unlikely that they do not draw them from the blood but from bone marrow. May also be memory T cells ... This should also answer your second question: You target some cells higher up in the hirachy like CMPs or even MPP and HSC (stem cells). Other tissue, other stem cell type. And ultimately obviously some lineage commited (cells aimed to become a certain cell type) iPS cells (which are stem cells generated from normal body cells). Thats all possible, the only thing really missing is good understand of epigenetics (only a question of time) and some way for reliable epigenetic programming/modification. (Sorry if thats too short too complicated but maybe it guides you in the right direction) Edit: And third question: I am not entirely sure why you would need to replace all the existing cells. Some additional functionality might be sufficent. Where this is not the case, you usually go for irradition (and full replacement).

maga 10y ago
Thanks for the detailed answer! >This should also answer your second question: You target some cells higher up in the hirachy like CMPs or even MPP and HSC (stem cells). Other tissue, other stem cell type. And ultimately obviously some lineage commited (cells aimed to become a certain cell type) iPS cells (which are stem cells generated from normal body cells). Thats all possible, the only thing really missing is good understand of epigenetics (only a question of time) and some way for reliable epigenetic programming/modification. (Sorry if thats too short too complicated but maybe it guides you in the right direction) If I understand you correctly, we can replace the cells in charge of producing other cells (stem cells) to make the changes lasting, but we are not yet certain how the changes will play with the rest of their environment (epigenetics). >I am not entirely sure why you would need to replace all the existing cells. Some additional functionality might be sufficent. Where this is not the case, you usually go for irradition (and full replacement). To make an example, let's say I'm a secret ginger carrying the mutation that makes me far more susceptible to skin cancer[1]. And let's say we know what exactly to change in DNA to fix my problem. Now, I don't know how the skin producing machinery works, but I guess replacing it in one go isn't an option. So, if we go with changing cells higher up in skin production, can we guarantee that in due time they will replace all (or most of) the skin with modified cells? As a bonus question, since we limit ourselves to targeting only particular cell types (skin in this case) that means the rest of the body is carrying unmodified DNA, hence, those changes are not hereditary, right? [1] http://www.telegraph.co.uk/science/2016/07/12/one-quarter-of-britons-carry-ginger-gene-which-raises-risk-of-sk/ http://www.telegraph.co.uk/science/2016/07/12/one-quarter-of...
- patall 10y ago
  > If I understand you correctly, we can replace the cells in charge of producing other cells (stem cells) to make the changes lasting, but we are not yet certain how the changes will play with the rest of their environment (epigenetics). Not quite, we are not yet 100% certain what these changes are (or whether we even know all epigenetic marks). We know that epigenetics determines what cell type a particular cell is, but we do not know yet what all of these are. Slight analogy: What we have with the genome is the compiled code of the program, the sum over all epigenetic marks somewhat is the state at run time. >To make an example, let's say I'm a secret ginger carrying the mutation that makes me far more susceptible to skin cancer[1]. And let's say we know what exactly to change in DNA to fix my problem. Now, I don't know how the skin producing machinery works, but I guess replacing it in one go isn't an option. So, if we go with changing cells higher up in skin production, can we guarantee that in due time they will replace all (or most of) the skin with modified cells? As a bonus question, since we limit ourselves to targeting only particular cell types (skin in this case) that means the rest of the body is carrying unmodified DNA, hence, those changes are not hereditary, right? That is going to be hard, as you basically want to replace a whole organ with another. The (idealistic) idea there is rather to take a virus that performs the modification in the body in all cells. But that is still somewhat in the future as you have to make sure the virus does not spread to other persons, the changes are lasting etc. Note: What we did not cover here is the whole interplay with the immune system. It may well happen that some B or T cells recognize the modified cells as foreign (at least if the change is in a protein) and fight it, so you'd rather have the modified cells as nonessential. In the study here this is not that important as you still have other T cells and you'd be happy enough if they (the modified cells) fought the cancer for some time and then disappear.
  - maga 10y ago
    >Slight analogy: What we have with the genome is the compiled code of the program, the sum over all epigenetic marks somewhat is the state at run time. Now you're talking. That's a brilliant analogy, I'm stealing it for the next time I explain CS to biologists, thanks! >The (idealistic) idea there is rather to take a virus that performs the modification in the body in all cells. But that is still somewhat in the future as you have to make sure the virus does not spread to other persons, the changes are lasting etc. Indeed, I forgot about viruses. To sum up, to get to changing adult DNA we need a) more knowledge of the "runtime"/epigenetics to know what to change, b) ways to handle viruses if we go with them. That sounds reassuring, actually, at least we might not get stuck in Gattaca like future for too long.

rgejman 10y ago

T cells proliferate when they see their target antigen. This technology is being used without CRISPR in a number of clinical trials. See here: http://www.cancer.gov/about-cancer/treatment/research/car-t-cells http://www.cancer.gov/about-cancer/treatment/research/car-t-...

maga 10y ago
Thanks for the correction, I didn't know T cells multiply by themselves. Yet I assume they don't hang around permanently and will be sooner or later replaced by new, unmodified, cells produced by the body, hence, why I was asking about making permanent changes.
- rgejman 10y ago
  Maybe. We haven't been doing this long enough to know. T cells can divide into a T "memory" type, but I'm not sure if CAR-T cells do this.