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crispr

CRISPR as search term in Google

Remember interactive television? In the mid-1990s Microsoft was betting the farm on this new technology. As it happens they had to make a course correction. The Mosaic browser was the first “killer app” of the internet (sorry e-mail and usenet), creating the world wide web as we know it. The the rest is history. The lesson is that sometimes no one sees a technology coming. And when it does come, it disrupts the whole landscape. It can both create and destroy. This was clear in my recent post for the Genetics Society of America. The discipline is over 100 years old, and yet over the past 30 years we’ve seen genomics go from being invented as a term (in 1986), to revolutionizing the field, finally to a great extent becoming coextensive with the field. Similarly, the internet existed for two decades before the world wide web came along, but rather soon our conception of “the internet” became synonymous with the web (and e-mail and newsgroups have become absorbed into the web architecture as well).

Similarly, genetic engineering has been around for decades. Direct manipulation of DNA sequences emerged as a technique in the 1970s, and the Asilomar Conference on Recombinant DNA agreed upon a set of guidelines in terms of how the method would be deployed. Despite what you might have gathered from movies such as Gattaca genetic engineering was both difficult and limited in its power to effect change. Of course, despite public concern GMO crops have been moving into circulation for years in the United States, while medical research would be hampered without the access to engineered mice. But very few people would assert that genetic engineering is ubiquitous today.

The CRISPR/Cas system has the potential to change this. It is easy, cheap, and fast. It can take genetic engineering from a vital niche, to a pervasive aspect of human culture. CRISPR first began to gain some attention in scientific circles in 2012. As I write now, in 2015, its presence in discussions relating to genetics can seem ubiquitous, even cloying. Seminars with the word “CRISPR” in the title suddenly become standing room. If the world wide web is an analogy to what is going on, then we are in 1993. The implication is that we haven’t seen our first Netscape of CRISPR, nor the emergence of a whole economy built around the technology. Right now it is a scientific superstar, but we’ll known that it’s made the “big time” when we see it mentioned ubiquitously on CNBC.

So what’s holding us back? There are two primary things I can think of. First, fear and uncertainty. The regulatory environment is essential for the success of any technology today (well, except Uber!), and the framework is currently ad hoc rather than formalized. The Chinese scientists who modified embryos were only newsworthy because of the bioethical and regulatory consequences of their actions, not the science. It is certainly more significant that a British group is now asking for permission to do experiments on the developmental genetics of embryos using CRISPR technology. The outrage over the modifications last spring had as much to do with breaking the tacit social norm within science where everyone wants to establish some sort of agreed upon framework for novel human research, rather than concern about the the scientific implications. If the British group receives approval, it will set a precedent which could open the door for other reputable researchers.

But what about in concrete terms in a near term horizon? The ability to “edit DNA” sounds incredible in the abstract, and is almost certainly civilization changing in the long term. But over the next few years it seems likely that CRISPR/Cas will result the reemergence of gene therapies as a means by which Mendelian diseases may be treated. Gene therapy as a field suffered a major blow in the late 1990s due to a series of fatalities, arguably tied to unethical practices by one researcher. But the idea of curing someone of a genetic illness by modifying the gene reBut isponsible for that illness is straightforward in its logic.

Many diseases, such as diabetes or schizophrenia, are complex in their origins. There is no specific gene responsible for the cause in the vast majority of instances. The road to genetically engineer a “fix” would be long and the outcome not assured in these cases. Any risks would have to be weighed strongly. In contrast Mendelian diseases are often due to a single locus, and the cause is due to that precise biological malfunction. And their outcomes are often easy to quantify. Cystic fibrosis takes decades off your life expectancy, and entails hundreds of thousands of extra costs over the lifetime. There is some debate as the frequency of Mendelian disease within the population, but something on the order of ~10% of the American population seems likely using a very liberal definition of disease. If only a a percent or two of these have illnesses which are of some severity, that may still justify intervention if it is feasible and safe.

The feasibility of gene editing to cure Mendelian disease is conditional partly on mode of delivery, which is not a genetic concern per se. That is, how do you modify a sufficient number of cell’s in a living human’s body to result in a change in function? A second concern are “off target” changes. You may be attempting to modify one thing, but modify another, in which case you’ve gone from the frying pan to the fire. Both of these though seem to be soluble problems over the time scale of a decade (CRISPR precision has gotten better even in the past few years). And for diseases such as sickle cell and cystic fibrosis, which entail shortened lives and constant monitoring and treatment, the perfect can’t be the enemy of the good. In the near future the ethical mandate will not be if, but why not.

When that happens you will see a shift in the medical system in the United States. Instead of attempting to tackle symptoms of Mendelian diseases, physicians will plausibly offer up the possibility of eliminating the root cause. This will make some companies very rich, as health care is a growing sector of our economy. Sequencing will be ubiquitous, obligatory, with exemptions necessary, not elective. In a classic sense it will be a “win-win,” as medical costs per individual will decrease, and their lifetime earning power will increase due to greater health.

The effective utilization of genetic engineering to make lives better for a minority of Americans will also change perceptions in the public as to the implications of genetic engineering. Instead of a dystopian future, people will begin to see their own present, and the fear will give away to acceptance. And it is in the time horizon beyond 2025 that I think we may need to start thinking about tackling germ-line modifications and more radical ‘experiments’ in biological engineering….

 
• Category: Science • Tags: Genomics 
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  1. how do you modify a sufficient number of cell’s in a living human’s body to result in a change in function?

    seems to be just a part of the question – the other part being, how do you make the modification last? For CF, the “sufficient number” issue looks rosy at first, as it is presumed that even a modest percentage of the modified lung epithelial cells should bring some symptomatic relief … but these cells have a rapid turnover time, so a hypothetical aerosol delivery of a vector through the airways would have to happen again and again. Until the patient succumbs to pancreatic problems (which is the 2nd organ severely affected by the CTFR mutations).

    (Any hypothetical whole-body mod will probably fail approval because the modification would affect the gonads?)

    • Replies: @Razib Khan
    so i'm curious now more about this topic. is there a specific paper you think is of interest/note on this issue? i don't think in biomed terms often...
    , @cloudswrest
    FYI there are TONS of potential somatic cell *upgrades*, those where only a small fraction of cells upgraded would have a profound effect that ordinary people could have to improve their lives. Here is a short list off the top of my head.

    CCR5 fix Immunity to HIV. Preferably done *before* potential infection.
    Vit C fix to liver stem cells. Endogenous Vit C production. No more pills or OJ needed.
    apoA-I Milano upgrade to liver stem cells. Reduce/eliminate heart disease
    I’m sure there are many others I will think about.

    , @Randall Parker
    Making the modifications last: Isn't it just a matter of modifying the right cells? If the mods are integrated into mitotic cells then they'll get replicated when the cells replicate.

    There are lung epithelial progenitor cells that look like the ones to target for editing.
  2. @Dmitry Pruss
    how do you modify a sufficient number of cell’s in a living human’s body to result in a change in function?

    seems to be just a part of the question - the other part being, how do you make the modification last? For CF, the "sufficient number" issue looks rosy at first, as it is presumed that even a modest percentage of the modified lung epithelial cells should bring some symptomatic relief ... but these cells have a rapid turnover time, so a hypothetical aerosol delivery of a vector through the airways would have to happen again and again. Until the patient succumbs to pancreatic problems (which is the 2nd organ severely affected by the CTFR mutations).

    (Any hypothetical whole-body mod will probably fail approval because the modification would affect the gonads?)

    so i’m curious now more about this topic. is there a specific paper you think is of interest/note on this issue? i don’t think in biomed terms often…

    • Replies: @Dmitry Pruss
    Razib, first aerosol DNA delivery trials are well underway, and seem to work despite marginal vector efficiency - but only transiently. On Oct 10th, Dr. Alton will report on the outcomes of the UK gene therapy trial for cystic fibrosis relying on delivery of lipid-bound DNA directly into the lungs in an aerosol form.
    http://onlinelibrary.wiley.com/doi/10.1002/ppul.23105/pdf
  3. I appreciate this is more about serious medical issues etc but given how much money gets spent on this

    http://un-ruly.com/the-changing-business-of-black-hair/#.VgH1tMtViko

    someone could make a ton of money if there was an easy way to CRISPR straight hair – even more so if it only lasted a few months and had to be redone occasionally.

  4. Hokie says:

    Is there anyone looking to apply CRISPR to gut flora? Not my area of expertise, but my impression is that introducing “good” modified gut bacteria would go a long way to dealing with obesity, vitamin deficiencies, and allergies. If you know a paper/book about this, I’d be really interested in reading it.

  5. פון דיין ליפּס צו גאָט ‘ס אויערן (From your lips to God’s ears)

    I’m still waiting for electricity too cheap to meter. Nearly 60, I recall a field trip to 9 Mile Point in elementary school, but doubt that I will see it — i.e. EtCtM — in my lifetime (though who knows: maybe I’ll see it after).

    • Replies: @Drapetomaniac
    Advances in technology work to make things cheaper, interference from government works to make things more expensive. Currently, government is winning the battle.

    Not sure actual free markets would make electricity too cheap to meter but it would definitely be cheaper.
  6. @Razib Khan
    so i'm curious now more about this topic. is there a specific paper you think is of interest/note on this issue? i don't think in biomed terms often...

    Razib, first aerosol DNA delivery trials are well underway, and seem to work despite marginal vector efficiency – but only transiently. On Oct 10th, Dr. Alton will report on the outcomes of the UK gene therapy trial for cystic fibrosis relying on delivery of lipid-bound DNA directly into the lungs in an aerosol form.
    http://onlinelibrary.wiley.com/doi/10.1002/ppul.23105/pdf

  7. One major piece of the CRISPR puzzle will be figuring out which genes are worth editing.

    With Mendelian diseases like CF this will be obvious. But clear-cut cases like this are the exception, not the rule, as you note above. Peoples’ genomes are jungles, and it’s plausible that there are *lots* of sub-optimal things going on in each person’s body (i.e., genetic load), but how do we know what’s worth tinkering with?

    Let’s put it this way: CRISPR gives us a certain ‘editing budget’– how do we use it?

    I’d love to see an integrative approach that could combine multiple types of research and spit out, e.g., “The 10 genetic tweaks for Razib Khan’s genome with the most expected return”. Obviously this is hard to do well, but it wouldn’t need to be perfect to be useful.

  8. @Dmitry Pruss
    how do you modify a sufficient number of cell’s in a living human’s body to result in a change in function?

    seems to be just a part of the question - the other part being, how do you make the modification last? For CF, the "sufficient number" issue looks rosy at first, as it is presumed that even a modest percentage of the modified lung epithelial cells should bring some symptomatic relief ... but these cells have a rapid turnover time, so a hypothetical aerosol delivery of a vector through the airways would have to happen again and again. Until the patient succumbs to pancreatic problems (which is the 2nd organ severely affected by the CTFR mutations).

    (Any hypothetical whole-body mod will probably fail approval because the modification would affect the gonads?)

    FYI there are TONS of potential somatic cell *upgrades*, those where only a small fraction of cells upgraded would have a profound effect that ordinary people could have to improve their lives. Here is a short list off the top of my head.

    CCR5 fix Immunity to HIV. Preferably done *before* potential infection.
    Vit C fix to liver stem cells. Endogenous Vit C production. No more pills or OJ needed.
    apoA-I Milano upgrade to liver stem cells. Reduce/eliminate heart disease
    I’m sure there are many others I will think about.

    • Replies: @jackson
    We've known about CCR5 forever. Which biotech is making a killing having capitalized on that idea?
  9. Delivery in vivo is a bigger hurdle than fear and uncertainty. The gene therapy field has been struggling with the delivery problem for 25 years. Lots of great therapeutic strategies and techniques (like CRISPR), but no way to get them with adequate efficiency into their targets.

    I’d chalk a lot of the hype up to a desire for hype-able funding applications.

  10. @cloudswrest
    FYI there are TONS of potential somatic cell *upgrades*, those where only a small fraction of cells upgraded would have a profound effect that ordinary people could have to improve their lives. Here is a short list off the top of my head.

    CCR5 fix Immunity to HIV. Preferably done *before* potential infection.
    Vit C fix to liver stem cells. Endogenous Vit C production. No more pills or OJ needed.
    apoA-I Milano upgrade to liver stem cells. Reduce/eliminate heart disease
    I’m sure there are many others I will think about.

    We’ve known about CCR5 forever. Which biotech is making a killing having capitalized on that idea?

    • Replies: @Cloudswrest

    We’ve known about CCR5 forever. Which biotech is making a killing having capitalized on that idea?
     
    Whether or not somebody has exploited a "ccr5 upgrade" is irrelevant. Proof of principle has already been achieved with the "Berlin Patient" https://en.wikipedia.org/wiki/The_Berlin_Patient. Upgrading your bone marrow with your own upgraded bone marrow stem cells instead of from a donor should be much better as you drastically lower the risk of rejection or graft versus host disease. This probably would only work with your own bone marrow stem cells only if you do it before you are infected. HIV is a retrovirus and if all your source stem cells are already infected it's like closing the barn door after the horse has escaped. So in this regard it's functionally more like immunization.

    Exogenous injection of Apolipoprotein A-1 Milano (https://en.wikipedia.org/wiki/ApoA-1_Milano) clears arteries of plaque. So it stands to reason that merely introducing a small cohort of upgraded stem cells to make enough of "the product" should be sufficient. One doesn't need to upgrade all the cells in the body. Similarly for Vitamin C.
  11. Sorry but to think that genetic engineering of humans is going to be anything more than a niche activity for a handful of serious Mendelian disorders in our lifetimes is a fantasy.

    CRISPR makes genetic engineering easier, not easy. To deploy it to fix something in the germline with the necessary quality controls would be obscenely expensive. And for recessive genetic diseases there is already a pre-existing technology that would have all the same benefits and none of the risks– pre-implantation genetic diagnosis.

    Unless two CF patients were trying to conceive with one another and the number of good alleles of CFTR in the couple were zero there would be no reason to fix things with CRISPR. It’s way too hard, unproven, and you might introduce off-target effects or other weird side effects.

    As for therapy of Mendelian diseases in somatic tissues, the issue is still delivery. If you could truly deliver genetic material to all the lung epithelium in a CF patient or all the breast epithelium in a person with a BRCA mutation why would you try to use CRISPR to fix the bad allele instead of just delivering a transgene? The latter is going to be a lot more efficient than the former. The reason why neither is a great idea is because delivering any genetic material to a large fraction of somatic cells is too difficult and risky using existing technologies.

    So what compelling reason is left to use CRISPR? To introduce alleles that the parents don’t have. I.e., GATTACA style genetic engineering. Dream on. Imagine trying to tell a fertility center at an academic medical center that you wanted to just screen a few alleles in addition to one you were doing pre-implantation genetic diagnosis on. Say, OCA2 for blue eyes or some height allele. They’d never do it! And that’s so much less radical than using CRISPR.

    So maybe there are a handful of compelling reasons why people will want to CRISPR things in human genomes but this is still hugely complicated, expensive and risky, and in biotech, particularly when it comes to human biotech, regulatory agencies and researchers are risk averse. It’s never going to be something that is routinely done for complicated multigenic diseases like schizophrenia, obesity, autism etc. etc.

    • Replies: @Razib Khan
    your comment is a little assholish since i pretty much allude to a lot of what you said in the post. but i guess you just wanted to comment.

    (p.s., i moderate, so don't be a dick in any follow ups)
    , @notanon

    Imagine trying to tell a fertility center at an academic medical center that you wanted to just screen a few alleles in addition to one you were doing pre-implantation genetic diagnosis on. Say, OCA2 for blue eyes or some height allele. They’d never do it!
     
    Sure they would - just not in the West.

    It's probably being attempted already - which is sad for the Tibetans.

    Most people are ignorant of their carrier status for serious genetic diseases unless they have an affected relative, and even if they are aware that they are a carrier many probably would opt not to use this technology because it is costly in both time and money.
     
    So billionaires then - in clinics outside the West.
  12. @415 reasons
    Sorry but to think that genetic engineering of humans is going to be anything more than a niche activity for a handful of serious Mendelian disorders in our lifetimes is a fantasy.

    CRISPR makes genetic engineering easier, not easy. To deploy it to fix something in the germline with the necessary quality controls would be obscenely expensive. And for recessive genetic diseases there is already a pre-existing technology that would have all the same benefits and none of the risks-- pre-implantation genetic diagnosis.

    Unless two CF patients were trying to conceive with one another and the number of good alleles of CFTR in the couple were zero there would be no reason to fix things with CRISPR. It's way too hard, unproven, and you might introduce off-target effects or other weird side effects.

    As for therapy of Mendelian diseases in somatic tissues, the issue is still delivery. If you could truly deliver genetic material to all the lung epithelium in a CF patient or all the breast epithelium in a person with a BRCA mutation why would you try to use CRISPR to fix the bad allele instead of just delivering a transgene? The latter is going to be a lot more efficient than the former. The reason why neither is a great idea is because delivering any genetic material to a large fraction of somatic cells is too difficult and risky using existing technologies.

    So what compelling reason is left to use CRISPR? To introduce alleles that the parents don't have. I.e., GATTACA style genetic engineering. Dream on. Imagine trying to tell a fertility center at an academic medical center that you wanted to just screen a few alleles in addition to one you were doing pre-implantation genetic diagnosis on. Say, OCA2 for blue eyes or some height allele. They'd never do it! And that's so much less radical than using CRISPR.

    So maybe there are a handful of compelling reasons why people will want to CRISPR things in human genomes but this is still hugely complicated, expensive and risky, and in biotech, particularly when it comes to human biotech, regulatory agencies and researchers are risk averse. It's never going to be something that is routinely done for complicated multigenic diseases like schizophrenia, obesity, autism etc. etc.

    your comment is a little assholish since i pretty much allude to a lot of what you said in the post. but i guess you just wanted to comment.

    (p.s., i moderate, so don’t be a dick in any follow ups)

    • Replies: @415 reasons
    Sorry... didn't mean to be an asshole. I just have seen a lot of commentary online and talked to people IRL who don't understand the field who just read the news reports which don't explain how CRISPR works in technical detail, and these non-technical explanations often overstate the case for how CRISPR will be used.

    And to be fair, your post is, in my opinion, a bit overexuberant:


    Instead of attempting to tackle symptoms of Mendelian diseases, physicians will plausibly offer up the possibility of eliminating the root cause.
     
    This is arguably achievable nowadays in most cases with pre-implantation genetic diagnosis, yet is is infrequently done. Most people are ignorant of their carrier status for serious genetic diseases unless they have an affected relative, and even if they are aware that they are a carrier many probably would opt not to use this technology because it is costly in both time and money. The invention of CRISPR-Cas genome editing doesn't greatly alter this dynamic or push genetic engineering from a topic with relevance to a small number of people to a ubiquitous technology.
  13. @Razib Khan
    your comment is a little assholish since i pretty much allude to a lot of what you said in the post. but i guess you just wanted to comment.

    (p.s., i moderate, so don't be a dick in any follow ups)

    Sorry… didn’t mean to be an asshole. I just have seen a lot of commentary online and talked to people IRL who don’t understand the field who just read the news reports which don’t explain how CRISPR works in technical detail, and these non-technical explanations often overstate the case for how CRISPR will be used.

    And to be fair, your post is, in my opinion, a bit overexuberant:

    Instead of attempting to tackle symptoms of Mendelian diseases, physicians will plausibly offer up the possibility of eliminating the root cause.

    This is arguably achievable nowadays in most cases with pre-implantation genetic diagnosis, yet is is infrequently done. Most people are ignorant of their carrier status for serious genetic diseases unless they have an affected relative, and even if they are aware that they are a carrier many probably would opt not to use this technology because it is costly in both time and money. The invention of CRISPR-Cas genome editing doesn’t greatly alter this dynamic or push genetic engineering from a topic with relevance to a small number of people to a ubiquitous technology.

  14. @415 reasons
    Sorry but to think that genetic engineering of humans is going to be anything more than a niche activity for a handful of serious Mendelian disorders in our lifetimes is a fantasy.

    CRISPR makes genetic engineering easier, not easy. To deploy it to fix something in the germline with the necessary quality controls would be obscenely expensive. And for recessive genetic diseases there is already a pre-existing technology that would have all the same benefits and none of the risks-- pre-implantation genetic diagnosis.

    Unless two CF patients were trying to conceive with one another and the number of good alleles of CFTR in the couple were zero there would be no reason to fix things with CRISPR. It's way too hard, unproven, and you might introduce off-target effects or other weird side effects.

    As for therapy of Mendelian diseases in somatic tissues, the issue is still delivery. If you could truly deliver genetic material to all the lung epithelium in a CF patient or all the breast epithelium in a person with a BRCA mutation why would you try to use CRISPR to fix the bad allele instead of just delivering a transgene? The latter is going to be a lot more efficient than the former. The reason why neither is a great idea is because delivering any genetic material to a large fraction of somatic cells is too difficult and risky using existing technologies.

    So what compelling reason is left to use CRISPR? To introduce alleles that the parents don't have. I.e., GATTACA style genetic engineering. Dream on. Imagine trying to tell a fertility center at an academic medical center that you wanted to just screen a few alleles in addition to one you were doing pre-implantation genetic diagnosis on. Say, OCA2 for blue eyes or some height allele. They'd never do it! And that's so much less radical than using CRISPR.

    So maybe there are a handful of compelling reasons why people will want to CRISPR things in human genomes but this is still hugely complicated, expensive and risky, and in biotech, particularly when it comes to human biotech, regulatory agencies and researchers are risk averse. It's never going to be something that is routinely done for complicated multigenic diseases like schizophrenia, obesity, autism etc. etc.

    Imagine trying to tell a fertility center at an academic medical center that you wanted to just screen a few alleles in addition to one you were doing pre-implantation genetic diagnosis on. Say, OCA2 for blue eyes or some height allele. They’d never do it!

    Sure they would – just not in the West.

    It’s probably being attempted already – which is sad for the Tibetans.

    Most people are ignorant of their carrier status for serious genetic diseases unless they have an affected relative, and even if they are aware that they are a carrier many probably would opt not to use this technology because it is costly in both time and money.

    So billionaires then – in clinics outside the West.

    • Replies: @415 reasons
    I don't know about you but I wouldn't trust my germline to the questionable QC standards of Chinese biotechs.
  15. @jackson
    We've known about CCR5 forever. Which biotech is making a killing having capitalized on that idea?

    We’ve known about CCR5 forever. Which biotech is making a killing having capitalized on that idea?

    Whether or not somebody has exploited a “ccr5 upgrade” is irrelevant. Proof of principle has already been achieved with the “Berlin Patient” https://en.wikipedia.org/wiki/The_Berlin_Patient. Upgrading your bone marrow with your own upgraded bone marrow stem cells instead of from a donor should be much better as you drastically lower the risk of rejection or graft versus host disease. This probably would only work with your own bone marrow stem cells only if you do it before you are infected. HIV is a retrovirus and if all your source stem cells are already infected it’s like closing the barn door after the horse has escaped. So in this regard it’s functionally more like immunization.

    Exogenous injection of Apolipoprotein A-1 Milano (https://en.wikipedia.org/wiki/ApoA-1_Milano) clears arteries of plaque. So it stands to reason that merely introducing a small cohort of upgraded stem cells to make enough of “the product” should be sufficient. One doesn’t need to upgrade all the cells in the body. Similarly for Vitamin C.

    • Replies: @415 reasons
    Right so this works as prevention. Anyone up for lymphoablative chemo and bone marrow transplant to prevent getting HIV? It's a case of a metric ton of prevention not being as good as a pound of cure.
    , @jackson
    We've had "proof of principle" gene or cell therapy studies coming out the wazoo since forever. Point is, why so little execution in the clinic? Answer: can't deliver the payloads (genes or gene-modified cells) into people with sufficient efficiency. This is why we are still talking about the legendary "Berlin patient" from almost a decade ago.
  16. @marcel proust
    פון דיין ליפּס צו גאָט 'ס אויערן (From your lips to God's ears)

    I'm still waiting for electricity too cheap to meter. Nearly 60, I recall a field trip to 9 Mile Point in elementary school, but doubt that I will see it -- i.e. EtCtM -- in my lifetime (though who knows: maybe I'll see it after).

    Advances in technology work to make things cheaper, interference from government works to make things more expensive. Currently, government is winning the battle.

    Not sure actual free markets would make electricity too cheap to meter but it would definitely be cheaper.

  17. Apart from the vast cost of large scale gene therapy, isn’t it likely to cause a dire increase in such undesirable genes in the population? Government will restrict its use except to groups with a lot of political influence, e.g. sickle cell anemia.

  18. @Cloudswrest

    We’ve known about CCR5 forever. Which biotech is making a killing having capitalized on that idea?
     
    Whether or not somebody has exploited a "ccr5 upgrade" is irrelevant. Proof of principle has already been achieved with the "Berlin Patient" https://en.wikipedia.org/wiki/The_Berlin_Patient. Upgrading your bone marrow with your own upgraded bone marrow stem cells instead of from a donor should be much better as you drastically lower the risk of rejection or graft versus host disease. This probably would only work with your own bone marrow stem cells only if you do it before you are infected. HIV is a retrovirus and if all your source stem cells are already infected it's like closing the barn door after the horse has escaped. So in this regard it's functionally more like immunization.

    Exogenous injection of Apolipoprotein A-1 Milano (https://en.wikipedia.org/wiki/ApoA-1_Milano) clears arteries of plaque. So it stands to reason that merely introducing a small cohort of upgraded stem cells to make enough of "the product" should be sufficient. One doesn't need to upgrade all the cells in the body. Similarly for Vitamin C.

    Right so this works as prevention. Anyone up for lymphoablative chemo and bone marrow transplant to prevent getting HIV? It’s a case of a metric ton of prevention not being as good as a pound of cure.

    • Replies: @Cloudswrest
    Sounds like a straw man here. Nobody is talking about destroying/eliminating your "old" immune system. Just supplementing it with upgraded cells. The "lymphoablative chemo" was to eliminate the leukemia, not cure HIV, which was a side benefit for the Berlin Patient.
  19. @notanon

    Imagine trying to tell a fertility center at an academic medical center that you wanted to just screen a few alleles in addition to one you were doing pre-implantation genetic diagnosis on. Say, OCA2 for blue eyes or some height allele. They’d never do it!
     
    Sure they would - just not in the West.

    It's probably being attempted already - which is sad for the Tibetans.

    Most people are ignorant of their carrier status for serious genetic diseases unless they have an affected relative, and even if they are aware that they are a carrier many probably would opt not to use this technology because it is costly in both time and money.
     
    So billionaires then - in clinics outside the West.

    I don’t know about you but I wouldn’t trust my germline to the questionable QC standards of Chinese biotechs.

    • Replies: @notanon
    So if the only barrier is whether or not some people would risk it then you'd accept it's probably already happening somewhere?

    And if it's already happening among the very rich and/or some states then it wouldn't be at all surprising if they were keeping it secret.

    Also - people underestimate vanity and cosmetic changes. I've read (and would believe from experience) that height is the number one thing men lie about online. Would a 5' 6" billionaire risk it to be 6'?

    Some would imo.

    (No idea if that is feasible, it's just an example of a vanity change.)
  20. @Cloudswrest

    We’ve known about CCR5 forever. Which biotech is making a killing having capitalized on that idea?
     
    Whether or not somebody has exploited a "ccr5 upgrade" is irrelevant. Proof of principle has already been achieved with the "Berlin Patient" https://en.wikipedia.org/wiki/The_Berlin_Patient. Upgrading your bone marrow with your own upgraded bone marrow stem cells instead of from a donor should be much better as you drastically lower the risk of rejection or graft versus host disease. This probably would only work with your own bone marrow stem cells only if you do it before you are infected. HIV is a retrovirus and if all your source stem cells are already infected it's like closing the barn door after the horse has escaped. So in this regard it's functionally more like immunization.

    Exogenous injection of Apolipoprotein A-1 Milano (https://en.wikipedia.org/wiki/ApoA-1_Milano) clears arteries of plaque. So it stands to reason that merely introducing a small cohort of upgraded stem cells to make enough of "the product" should be sufficient. One doesn't need to upgrade all the cells in the body. Similarly for Vitamin C.

    We’ve had “proof of principle” gene or cell therapy studies coming out the wazoo since forever. Point is, why so little execution in the clinic? Answer: can’t deliver the payloads (genes or gene-modified cells) into people with sufficient efficiency. This is why we are still talking about the legendary “Berlin patient” from almost a decade ago.

    • Replies: @Cloudswrest

    We’ve had “proof of principle” gene or cell therapy studies coming out the wazoo since forever. Point is, why so little execution in the clinic? Answer: can’t deliver the payloads (genes or gene-modified cells) into people with sufficient efficiency.
     
    Perhaps for curing a systemic genetic diseases. But making modest somatic enhancements to an already healthy body is a much more modest goal, and one with a lot more ideological resistance. Try asking your traditional doctor for a prescription for provigil or some supplemental "T" (even if you're over 50) and see how far you get.
  21. @415 reasons
    Right so this works as prevention. Anyone up for lymphoablative chemo and bone marrow transplant to prevent getting HIV? It's a case of a metric ton of prevention not being as good as a pound of cure.

    Sounds like a straw man here. Nobody is talking about destroying/eliminating your “old” immune system. Just supplementing it with upgraded cells. The “lymphoablative chemo” was to eliminate the leukemia, not cure HIV, which was a side benefit for the Berlin Patient.

  22. @jackson
    We've had "proof of principle" gene or cell therapy studies coming out the wazoo since forever. Point is, why so little execution in the clinic? Answer: can't deliver the payloads (genes or gene-modified cells) into people with sufficient efficiency. This is why we are still talking about the legendary "Berlin patient" from almost a decade ago.

    We’ve had “proof of principle” gene or cell therapy studies coming out the wazoo since forever. Point is, why so little execution in the clinic? Answer: can’t deliver the payloads (genes or gene-modified cells) into people with sufficient efficiency.

    Perhaps for curing a systemic genetic diseases. But making modest somatic enhancements to an already healthy body is a much more modest goal, and one with a lot more ideological resistance. Try asking your traditional doctor for a prescription for provigil or some supplemental “T” (even if you’re over 50) and see how far you get.

  23. @415 reasons
    I don't know about you but I wouldn't trust my germline to the questionable QC standards of Chinese biotechs.

    So if the only barrier is whether or not some people would risk it then you’d accept it’s probably already happening somewhere?

    And if it’s already happening among the very rich and/or some states then it wouldn’t be at all surprising if they were keeping it secret.

    Also – people underestimate vanity and cosmetic changes. I’ve read (and would believe from experience) that height is the number one thing men lie about online. Would a 5′ 6″ billionaire risk it to be 6′?

    Some would imo.

    (No idea if that is feasible, it’s just an example of a vanity change.)

  24. @Dmitry Pruss
    how do you modify a sufficient number of cell’s in a living human’s body to result in a change in function?

    seems to be just a part of the question - the other part being, how do you make the modification last? For CF, the "sufficient number" issue looks rosy at first, as it is presumed that even a modest percentage of the modified lung epithelial cells should bring some symptomatic relief ... but these cells have a rapid turnover time, so a hypothetical aerosol delivery of a vector through the airways would have to happen again and again. Until the patient succumbs to pancreatic problems (which is the 2nd organ severely affected by the CTFR mutations).

    (Any hypothetical whole-body mod will probably fail approval because the modification would affect the gonads?)

    Making the modifications last: Isn’t it just a matter of modifying the right cells? If the mods are integrated into mitotic cells then they’ll get replicated when the cells replicate.

    There are lung epithelial progenitor cells that look like the ones to target for editing.

  25. […] brings you right up to date with current topics like GM foods, the origins of life, and the CRISPR techniques for editing the genome.  He is firm and clear on the very restricted scope of […]

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