I only attempted to address the factually incorrect part of what the AC said. AC made other valid points, which I did not contest. I don't have to explicitly address every single point in the comment in order to reply, and the fact that you think this "omission" (sarcasm quotes, FYI) indicates subtext speaks poorly of your ability to interpret what people are saying.
You know as well as I do (or you should, at least) that moderation here is chaotic. However, since you seem to need these things spelled out for you, the original "Good job" was sarcastic, and your appeal to authority via moderation is just silly.
AC said "Blocking prevents users from seeing official policy changes." which is factually wrong. I provided a solution for that, and made no attempt to solve any other problem.
What I said was not factually wrong; it didn't solve the problem you wanted it to, but that's not the same thing. Herp derp.
What are easy tissues to get? Adipose tissue and blood. Electroporation is easy for introducing stuff. Think about what you can you do with such a system.
You specified targets and a delivery method. Is that not "an approach"?
I didn't estimate any times.
One of your main points was that hackers/outsiders could speed things up and make the field progress faster than it currently is. You implied times would be shorter if outsiders got involved. I'm saying I don't think they would, because of the time it takes to know whether something is safe and effective.
You're jumping to unwarranted conclusions.
If you are an "insider" as you claim, it merely shows to what low intellectual standards our field has sunk.
I'll grant you that I made the conclusion that you weren't an insider, because I would have expected an insider to have a basic grasp on the underlying technology. As such, if you are an insider (as you're implying by saying "our"), then I'll have to agree the field has dropped its standards.
Not "no matter what". There's plenty you could do, if you knew what you were talking about. If YOU bring up short-lived blood cells and an immune stimulant, I'm going to point out why your approach won't work. But there definitely are things that *could* be done with blood, potentially even with basic medical supplies and less complicated reagents. You just haven't hit on any of them yet, because you lack basic knowledge about the things you're proposing.
My thinking is focused on genetic diseases, like DMD or Pompe's disease, because that's what I have experience in. There certainly are unique, cool ideas that I'm missing, and biotech is starting to get moving on those.
I think you're dramatically underestimating the time and effort required to actually show that something works, as well as the variability between individuals. Gene therapy has made slow progress for three reasons: one, we're still learning about what viral vectors work in which settings (and why), and working on non-viral vectors but they're mostly not good for anything you want to last more than a couple weeks. Two, there are a lot of diseases (including infections) for which there is no animal model or the animal model isn't effective at recapitulating the phenotype - and the researchers themselves don't have the disease or we don't know enough about it for them to be comfortable doing it to themselves. Three, with the focus being more on inherited genetic disorders, because that's often the major unmet need, there's understandably a lot of focus on making sure gene therapy lasts long enough and is safe.
All you've demonstrated is that outsiders coming in need to have even a basic understanding of what you're talking about, not that they'd be better or more effective at making progress.
Which cells in the blood do you want to target? Red cells and platelets don't have DNA, and the immune cells are a very mixed population. Immune cells also aren't always short-lived; memory T and B cells can last a super long time. You also can't electroporate blood in vivo, you'd have to take it out and then reintroduce it, which is beyond most people to do safely AND loses the immune stimulant part of the equation.
I'd argue that clinical trials for gene therapy, while they do take a long time (which you need if you're modifying genes anyway) cannot be said to "often" result in negligible gains in knowledge or safety. Most gene therapy clinical trials to date have been pretty informative.
That's true for some genes but not others. We know, definitively, that some genes are causative for specific diseases - Duchenne Muscular Dystrophy, for example. The dystrophin gene makes the dystrophin protein, which plays a key role in muscle cell force transduction and is lacking function in DMD patients. We know dystrophin's structure and we know, from looking at patients, a lot of ways it can get screwed up.
We can identify major splicing variants, so we generally know what portions of the gene actually code for protein, and some changes within that are clearly causative as well. An early stop codon, for instance, is a pretty good indication. Or if we can detect mRNA in cells of patients but no protein, then it's very likely a folding or processing defect, and we can probe the issue further with animal models. There are definitely some genes that aren't well-studied, but the ones that predominantly cause genetic diseases tend to get a lot of focus.
I'm not aware of any times when replacing a mutant allele with the "normal" one made things worse - it's certainly possible it could happen, but no result or an improvement are far more likely.
We know some parts of gene therapy appear to be safe in the reasonable long term - AAV directed to the liver, muscle, or retina hasn't had any major safety concerns (mostly efficacy, and that's improving dramatically) and they've been in some patients at least ten years.
I suspect there are a lot of researchers with HSV, HPV, HIV, and similar infections, which is what we're talking about here.
Much fewer than you'd think with HIV - the anti-retrovirals usually have some effects on your brain, and can interfere to some degree with your ability to reason. It's not impossible to do research when you're on those drugs, but it's definitely a lot harder. And if HIV was easily cured it would have been done by now.
Blood is easy to get, but the stem cells - which are what you'd need to target to treat diseases long-term - are in the bone marrow, and are much harder to get at. Electroporation dramatically increases the risk of an immune response - it's been used in some vaccine development because of that - which makes it pretty unsafe for in vivo work. Maybe adipose tissue would work, but then what can you do with it? Many diseases aren't caused by defects in adipose tissue.
Yeah, pretty obvious treatments, but much harder delivery. Also, gene editing with CRISPR isn't as easy as you're making it out to be - knocking out a gene is pretty easy, but the efficiency of recombination is still generally too low for in vivo use. And leveraging the results depends more on the controls and whether it replicates in others than how clear-cut the effects are. One of the advantages of a clinical trial (at least in gene therapy) is that dose and endpoints are examined in a systematic way. There will definitely be some of that sort of work in places with less oversight, you're right.
I think once systems get farther along in how well that's understood, that's often true, but has notably not been true in many areas that require expensive equipment (high energy physics, I think, and a lot of genomics).
As much as CRISPR is touted as an easily tunable/targetable system, that's mostly only true in relation to what we were using previously. It's a hell of a lot easier than TALENs or ZFNs, but even experts often need to screen different guide RNAs and make dramatic changes to their approach depending on the surrounding sequences.
It's certainly possible some amateur will discover a revolutionary approach to gene therapy in his garage, but given the current uncertainties about the system and the risks involved, I doubt it. When the basic science is better understood, I think that likelihood goes up by a substantial amount.
Not all, certainly, but a lot. DIY gene therapists often don't have access to good animal models, and generally can't run properly controlled experiments anyway (either lack of resources or lack of ability to create them, or both).
And it is their choice to take that risk.
I didn't say it wasn't.
More to the point, there's a huge issue of quality control - the process of actually making the stuff for gene therapy is not easy to replicate at home
Again, it's their choice to take that risk.
Again, I didn't say it wasn't.
There is the potential for human gene therapy to progress rapidly, but the much more likely outcome is that a bunch of people fuck it up royally, public trust goes to near-zero, and academic institutions and drug companies can't make progress because people aren't interested in it any more.
That is not a good argument for restricting people's right to control their own body.
Cool, good thing I wasn't arguing that there should be legal restrictions on self-experimentation then. I'm arguing it's generally a stupid and selfish idea to do so, because they don't have the tools or expertise needed to do it properly, and it could have dire consequences for others in similar situations.
"require" more testing before people should believe that it's both safe and effective to use. It requires more testing before we understand it well enough to say any therapy would be useful for widespread use, beyond the few people who would potentially have the skills, access to resources, and need to do this to themselves.
The lack of access to good animal models comes down to two things: 1) lack of facilities to keep them safe and in a controlled environment that also passes regulations against animal cruelty, and 2) lack of funding. It's not overregulation of drug development that hinders access to animal models.
You can argue that highly-qualified researchers want to do this themselves, but most places they work wouldn't let them use their facilities for a risky side project that has a pretty good chance of hurting the institution's image, and there aren't that many highly qualified scientists with genetic disorders amenable to gene therapy. As a side note, some of the more common delivery vectors out there have a habit of inducing immune responses in the researchers when they're exposed at very low levels, which would prevent the vectors from working. So self-experimentation has an additional hurdle there.
Shipping it off to China also has its own risks - and still isn't exactly cheap.
Generally, academic institutions would not allow use of their equipment or facilities for personal experimentation, partially due to liability reasons. If they sign off on the use of those facilities, then it's certainly much easier to do safely.
Existing delivery systems are very difficult to make yourself and most people working on specific diseases don't - they outsource it to core facilities that do it regularly.
Incurable doesn't necessarily mean untreatable though. Someone with a certainly lethal disease may well want to try their own hand at fixing it, and I don't think we should block that via legal means. I do think that whatever results a self-treater got would be very difficult for others to leverage in the search for a cure.
If he or she wanted to, yes. I would discourage it, given the substantial amount of personal effort and probable lack of translatability to others, but I think he or she should be allowed to.
There are a lot of human genes where we do know what they do specifically. Not all, certainly, but we know a lot about genes involved in specific genetic diseases, and we know what a functional copy looks like.
What's more worrying is the possibility of unintentionally changing other stuff and not knowing what we're changing or what the effects will be.
You can try a similar treatment in animals to what you intend to use in humans, but it's going to give you little useful safety data.
Well, that's just wrong. Delivery methods are certainly going to give you safety data. And you can see off-target effects if you use cultured human cells, which most people can't do at home.
CRISPR/Cas9 does not always make predictable changes to DNA. There's mounting evidence that there's a lot more off-target effects than we initially thought, and while people are certainly trying to fix that, those changes will also require more testing. In addition, the actual cell/vector modification and delivery are definitely not well understood.
Slashdot Mirror
What you assume the OP meant is up to you, but without that qualifier there, AC was wrong. Troll harder, dude.
I only attempted to address the factually incorrect part of what the AC said. AC made other valid points, which I did not contest. I don't have to explicitly address every single point in the comment in order to reply, and the fact that you think this "omission" (sarcasm quotes, FYI) indicates subtext speaks poorly of your ability to interpret what people are saying.
You know as well as I do (or you should, at least) that moderation here is chaotic. However, since you seem to need these things spelled out for you, the original "Good job" was sarcastic, and your appeal to authority via moderation is just silly.
AC said "Blocking prevents users from seeing official policy changes." which is factually wrong. I provided a solution for that, and made no attempt to solve any other problem.
What I said was not factually wrong; it didn't solve the problem you wanted it to, but that's not the same thing. Herp derp.
I didn't say it wasn't an issue; I said AC was factually wrong.
Which addresses exactly no part of what I said. Good job.
I just did when I was logged out. You can't go to "tweets and replies" but you can see replies below the original tweet.
Blocking doesn't prevent people from seeing what he posts. Just log out or use a different account.
Social safety net != socialism.
I didn't specify "an approach".
So we're just ignoring this then?
What are easy tissues to get? Adipose tissue and blood. Electroporation is easy for introducing stuff. Think about what you can you do with such a system.
You specified targets and a delivery method. Is that not "an approach"?
I didn't estimate any times.
One of your main points was that hackers/outsiders could speed things up and make the field progress faster than it currently is. You implied times would be shorter if outsiders got involved. I'm saying I don't think they would, because of the time it takes to know whether something is safe and effective.
You're jumping to unwarranted conclusions.
If you are an "insider" as you claim, it merely shows to what low intellectual standards our field has sunk.
I'll grant you that I made the conclusion that you weren't an insider, because I would have expected an insider to have a basic grasp on the underlying technology. As such, if you are an insider (as you're implying by saying "our"), then I'll have to agree the field has dropped its standards.
People of most political persuasions don't listen to science that contradicts their beliefs.
Not "no matter what". There's plenty you could do, if you knew what you were talking about. If YOU bring up short-lived blood cells and an immune stimulant, I'm going to point out why your approach won't work. But there definitely are things that *could* be done with blood, potentially even with basic medical supplies and less complicated reagents. You just haven't hit on any of them yet, because you lack basic knowledge about the things you're proposing.
My thinking is focused on genetic diseases, like DMD or Pompe's disease, because that's what I have experience in. There certainly are unique, cool ideas that I'm missing, and biotech is starting to get moving on those.
I think you're dramatically underestimating the time and effort required to actually show that something works, as well as the variability between individuals. Gene therapy has made slow progress for three reasons: one, we're still learning about what viral vectors work in which settings (and why), and working on non-viral vectors but they're mostly not good for anything you want to last more than a couple weeks. Two, there are a lot of diseases (including infections) for which there is no animal model or the animal model isn't effective at recapitulating the phenotype - and the researchers themselves don't have the disease or we don't know enough about it for them to be comfortable doing it to themselves. Three, with the focus being more on inherited genetic disorders, because that's often the major unmet need, there's understandably a lot of focus on making sure gene therapy lasts long enough and is safe.
All you've demonstrated is that outsiders coming in need to have even a basic understanding of what you're talking about, not that they'd be better or more effective at making progress.
Which cells in the blood do you want to target? Red cells and platelets don't have DNA, and the immune cells are a very mixed population. Immune cells also aren't always short-lived; memory T and B cells can last a super long time. You also can't electroporate blood in vivo, you'd have to take it out and then reintroduce it, which is beyond most people to do safely AND loses the immune stimulant part of the equation.
I'd argue that clinical trials for gene therapy, while they do take a long time (which you need if you're modifying genes anyway) cannot be said to "often" result in negligible gains in knowledge or safety. Most gene therapy clinical trials to date have been pretty informative.
That's true for some genes but not others. We know, definitively, that some genes are causative for specific diseases - Duchenne Muscular Dystrophy, for example. The dystrophin gene makes the dystrophin protein, which plays a key role in muscle cell force transduction and is lacking function in DMD patients. We know dystrophin's structure and we know, from looking at patients, a lot of ways it can get screwed up.
We can identify major splicing variants, so we generally know what portions of the gene actually code for protein, and some changes within that are clearly causative as well. An early stop codon, for instance, is a pretty good indication. Or if we can detect mRNA in cells of patients but no protein, then it's very likely a folding or processing defect, and we can probe the issue further with animal models. There are definitely some genes that aren't well-studied, but the ones that predominantly cause genetic diseases tend to get a lot of focus.
I'm not aware of any times when replacing a mutant allele with the "normal" one made things worse - it's certainly possible it could happen, but no result or an improvement are far more likely.
We know some parts of gene therapy appear to be safe in the reasonable long term - AAV directed to the liver, muscle, or retina hasn't had any major safety concerns (mostly efficacy, and that's improving dramatically) and they've been in some patients at least ten years.
I suspect there are a lot of researchers with HSV, HPV, HIV, and similar infections, which is what we're talking about here.
Much fewer than you'd think with HIV - the anti-retrovirals usually have some effects on your brain, and can interfere to some degree with your ability to reason. It's not impossible to do research when you're on those drugs, but it's definitely a lot harder. And if HIV was easily cured it would have been done by now.
Blood is easy to get, but the stem cells - which are what you'd need to target to treat diseases long-term - are in the bone marrow, and are much harder to get at. Electroporation dramatically increases the risk of an immune response - it's been used in some vaccine development because of that - which makes it pretty unsafe for in vivo work. Maybe adipose tissue would work, but then what can you do with it? Many diseases aren't caused by defects in adipose tissue.
Yeah, pretty obvious treatments, but much harder delivery. Also, gene editing with CRISPR isn't as easy as you're making it out to be - knocking out a gene is pretty easy, but the efficiency of recombination is still generally too low for in vivo use. And leveraging the results depends more on the controls and whether it replicates in others than how clear-cut the effects are. One of the advantages of a clinical trial (at least in gene therapy) is that dose and endpoints are examined in a systematic way. There will definitely be some of that sort of work in places with less oversight, you're right.
I think once systems get farther along in how well that's understood, that's often true, but has notably not been true in many areas that require expensive equipment (high energy physics, I think, and a lot of genomics).
As much as CRISPR is touted as an easily tunable/targetable system, that's mostly only true in relation to what we were using previously. It's a hell of a lot easier than TALENs or ZFNs, but even experts often need to screen different guide RNAs and make dramatic changes to their approach depending on the surrounding sequences.
It's certainly possible some amateur will discover a revolutionary approach to gene therapy in his garage, but given the current uncertainties about the system and the risks involved, I doubt it. When the basic science is better understood, I think that likelihood goes up by a substantial amount.
Not all, certainly, but a lot. DIY gene therapists often don't have access to good animal models, and generally can't run properly controlled experiments anyway (either lack of resources or lack of ability to create them, or both).
And it is their choice to take that risk.
I didn't say it wasn't.
More to the point, there's a huge issue of quality control - the process of actually making the stuff for gene therapy is not easy to replicate at home
Again, it's their choice to take that risk.
Again, I didn't say it wasn't.
There is the potential for human gene therapy to progress rapidly, but the much more likely outcome is that a bunch of people fuck it up royally, public trust goes to near-zero, and academic institutions and drug companies can't make progress because people aren't interested in it any more.
That is not a good argument for restricting people's right to control their own body.
Cool, good thing I wasn't arguing that there should be legal restrictions on self-experimentation then. I'm arguing it's generally a stupid and selfish idea to do so, because they don't have the tools or expertise needed to do it properly, and it could have dire consequences for others in similar situations.
"require" more testing before people should believe that it's both safe and effective to use. It requires more testing before we understand it well enough to say any therapy would be useful for widespread use, beyond the few people who would potentially have the skills, access to resources, and need to do this to themselves.
The lack of access to good animal models comes down to two things: 1) lack of facilities to keep them safe and in a controlled environment that also passes regulations against animal cruelty, and 2) lack of funding. It's not overregulation of drug development that hinders access to animal models.
You can argue that highly-qualified researchers want to do this themselves, but most places they work wouldn't let them use their facilities for a risky side project that has a pretty good chance of hurting the institution's image, and there aren't that many highly qualified scientists with genetic disorders amenable to gene therapy. As a side note, some of the more common delivery vectors out there have a habit of inducing immune responses in the researchers when they're exposed at very low levels, which would prevent the vectors from working. So self-experimentation has an additional hurdle there.
Shipping it off to China also has its own risks - and still isn't exactly cheap.
Generally, academic institutions would not allow use of their equipment or facilities for personal experimentation, partially due to liability reasons. If they sign off on the use of those facilities, then it's certainly much easier to do safely.
Existing delivery systems are very difficult to make yourself and most people working on specific diseases don't - they outsource it to core facilities that do it regularly.
Incurable doesn't necessarily mean untreatable though. Someone with a certainly lethal disease may well want to try their own hand at fixing it, and I don't think we should block that via legal means. I do think that whatever results a self-treater got would be very difficult for others to leverage in the search for a cure.
If he or she wanted to, yes. I would discourage it, given the substantial amount of personal effort and probable lack of translatability to others, but I think he or she should be allowed to.
There are a lot of human genes where we do know what they do specifically. Not all, certainly, but we know a lot about genes involved in specific genetic diseases, and we know what a functional copy looks like.
What's more worrying is the possibility of unintentionally changing other stuff and not knowing what we're changing or what the effects will be.
Medical doctors, often - but PhDs, on the other hand...
You can try a similar treatment in animals to what you intend to use in humans, but it's going to give you little useful safety data.
Well, that's just wrong. Delivery methods are certainly going to give you safety data. And you can see off-target effects if you use cultured human cells, which most people can't do at home.
CRISPR/Cas9 does not always make predictable changes to DNA. There's mounting evidence that there's a lot more off-target effects than we initially thought, and while people are certainly trying to fix that, those changes will also require more testing. In addition, the actual cell/vector modification and delivery are definitely not well understood.