MIT Tech Review: Chinese scientists are creating CRISPR babies

[Gibbit]

I only read the first post....but can we clone football players yet? I mean we need to get on this immediately, because.....(does the math) in 20 years if all our clones were born today....another superbowl before I die hopefully!

[PeterMP]

 

2 hours ago, No Excuses said:

 

None of this really changes the fact that the policy on stem cells was driven not by any science based policy but bogus ethical arguments. Science policy not based on facts or a proper understanding of the tech is nonsense, regardless of the outcomes. And even then, the major breakthrough of induced pluripotent stem cells came from a lab in Japan. But we had no way of knowing this when the initial ban was introduced. Ultimately it's hard to quantify or fully understand what was lost due to bad science policy and it's much easier to make revisionist arguments. Even the paper you links understands that it's hard to examine the impact and it is only their belief:

 

To this day, it remains bad science policy.

 

I am going to link George Church's interview on this issue today (there are few in the world who have more authority than Church on genetic engineering😞

 

https://www.sciencemag.org/news/2018/11/i-feel-obligation-be-balanced-noted-biologist-comes-defense-gene-editing-babies

 

Even the first US study on human germline editing with CRISPR last year found no off-site targets of consequence in their work.

 

It's not just experts. Ever year Congress asks for input from federal agencies and independent organizations on major areas of science and technology where the US needs to maintain global dominance. They do it because policy and funding priorities driven by these goals is necessary to maintain the elite position of our academies and institutes, and to create a vibrant private sector. They do it because it keeps our military far advanced than any other nations. 

 

You can think that it's silly. But it is the reality of our science policy in the US and it's worked for decades.

 

1.  I didn't say it was.  My point is it appears to be another case where people claimed vast consequences that never appeared.  Yes, it is hard to know what would have happened if Bush hadn't banned funding, but we certainly didn't seem to fall behind on anything overly important.

 

2.  You'll notice that I haven't once mentioned off target affects, and I'll point out, his comments do not address a single question that I raised before.  However, I think the science on that issue is not as straight forward as you and Church have suggested.  For example:

 

https://www.nature.com/articles/nbt.4192

 

"Repair of double-strand breaks induced by CRISPR–Cas9 leads to large deletions and complex rearrangements"

 

"Furthermore, lesions distal to the cut site and crossover events were identified. The observed genomic damage in mitotically active cells caused by CRISPR–Cas9 editing may have pathogenic consequences."

 

and:

 

"CRISPR–Cas9 genome editing induces a p53-mediated DNA damage response"

 

https://www.nature.com/articles/s41591-018-0049-z.epdf

 

Let's face it.  Church is heavily economically tied to this debate through his company eGenesis.  Have their pigs been analyzed by any independent entity with respect to their health or their genome?  Has he released a full genome sequence of the pigs?

 

3.  I'm not saying maintaining a lead in science isn't important.  I'm not advocating that we not work hard to maintain a lead in science.  I am questioning specifically how important is it that we maintain a lead in specific areas of USING technology (in this case CRISPR gene editing).  (and note, using technology isn't really science).  However, I also think you are mistaken about what has "worked" in our policy as to the effect of targeted funding and if experts in their field are actually good at predicting how important their field and even sub-area of their fields are (for example, I seriously doubt the experts in genomic editing would have favored funding the initial studies on that lead to the discovery of the CRISPR/CAS system) vs. the importance or extent of funding in general.  So you missed my point (and in doing so didn't actually address the question that I specifically asked).

[bcl05]

Speaking as an actual practicing clinical geneticist, I think I can accurately say that George Church is generally viewed as both a brilliant scientist and a seriously fringey thinker when it comes to practical applications of genetics.  I would take everything he says about actual applicability of new technology with a massive grain of salt.

 

The off target effects with CRISPR are better and more predictable than with previous technologies, but are still a massive, enormous problem that needs to be addressed and measured.  These will be overcomeable for targeted fixes for tissue-specific disorders (think correcting sickle-cell disease in bone marrow), but will make its use for germline treatment very limited for all but the most devastating diseases.

 

This is not to say that CRISPR isn't exciting and promising.  Its just to say that we are a long, long way from "designer babies," as its used in the popular parlance.

 

I remain skeptical that the chinese team has actually done what they said.  I'd like to see some actual genetic data from those babies addressing both the CCR5 variant and any testing for off-target effects.

[bearrock]

4 hours ago, Gibbit said:

I only read the first post....but can we clone football players yet? I mean we need to get on this immediately, because.....(does the math) in 20 years if all our clones were born today....another superbowl before I die hopefully!

You forgot that it'll still be Bruce and Dan picking the players to clone 

[twa]

China shuts it down and starts investigation.

 

https://www.apnews.com/0be63430c5914f09a124b968c844d994

 

 

 

[PeterMP]

12 hours ago, bcl05 said:

Speaking as an actual practicing clinical geneticist, I think I can accurately say that George Church is generally viewed as both a brilliant scientist and a seriously fringey thinker when it comes to practical applications of genetics.  I would take everything he says about actual applicability of new technology with a massive grain of salt.

 

The off target effects with CRISPR are better and more predictable than with previous technologies, but are still a massive, enormous problem that needs to be addressed and measured.  These will be overcomeable for targeted fixes for tissue-specific disorders (think correcting sickle-cell disease in bone marrow), but will make its use for germline treatment very limited for all but the most devastating diseases.

 

This is not to say that CRISPR isn't exciting and promising.  Its just to say that we are a long, long way from "designer babies," as its used in the popular parlance.

 

I remain skeptical that the chinese team has actually done what they said.  I'd like to see some actual genetic data from those babies addressing both the CCR5 variant and any testing for off-target effects.

 

I'm going to be blunt.

 

We know that the in vitro handling of human cells causes epigenetic changes.  That's essentially a given.

 

From there, there is good evidence that IVF increases the risks of some diseases (either very slightly or of things not very important so that the its use is not "apocalyptic"), and in  some cases the increased risks seem to be caused by epigenetic changes.

 

e.g.:

https://www.sciencedirect.com/science/article/pii/S1521693417301153?via%3Dihub

https://link.springer.com/article/10.1007%2Fs10815-018-1161-1

 

From there, it is completely reasonable to ask if further and new in vitro manipulations required for germ line or embryonic genomic editing makes the situation worse.  Will there be more/new/different epigenetic changes that compound the current apparent problems?  That's an obvious scientific question to ask.

 

Anybody that works in that field and addresses the safety of CRISPR genome editing by only talking about off target effects in the context of changes in the DNA sequence (which is what Church is addressing and was addressed in that post and you see being addressed by lots of other people out there) is either not a brilliant scientist, but is actually a bad scientist, or is being (intellectually) dishonest.  I don't work directly in that field and nobody has ever called me a brilliant anything, and I can see that's an issue.

 

Further, if I have a drug that was approved by the FDA, that had some known negative effect, and I wanted to change it somehow (even add in another molecule that was part of another drug that also had been approved by the FDA), I would have to directly address whether that change affected the known negative consequences in in vitro studies and in animal models before entering into any human clinical studies.

 

That is not a standard that a lot of people are talking about holding CRISPR editing too and if anything, CRISPR genome editing should be held to a higher standard because we are pretty much guaranteed that any negative consequences will have life time implications and likely even generational affects (i.e. traits, even epigenetic ones, will likely be passed down to offspring).

 

More fundamentally, if you have a technology that appears to have some issues, it seems to me that it makes sense to spend a lot of resources on improving that technology vs.spending resources on building a new technology that is dependent on the old one.

[bcl05]

George Church's contributions to technological developments in genetic sequencing are undeniable and were critical to major advancements.  He is not clinically relevant, and does not speak for clinical geneticists.  I know many clinical geneticists who roll their eyes every time he opens his mouth.   I think he is both a hugely important scientist and a fringe weirdo who should not be taken very seriously when he talks about clinical applications of new technology.  

 

You are right that both genetic and epigenetic changes are presumed after any germline manipulation.  The actual risks associated with IVF are very small, and are mostly reported around ICSI (intracytoplasmic sperm injection), and have been documented for a few disorders with imprinting abnormalities (Angleman syndrome, Prader-Willi syndrome, Beckwith-Wiedemann syndrome, Russell-Silver syndrome, etc).  

 

CRISPR studies in animal models have been pretty encouraging that the off target effects are much less than they were with traditional "gene therapy" models, including various viral vectors used to introduce new genes.  Still, they are not absent.

 

I think CRISPR has a place in our medical future, and initial efforts should (and generally are) being put towards awful, incurable diseases without other options.  

 

Again, I'm very skeptical that what the Chinese team reported was actually done.  It's one thing to say you've done this kind of thing, its an entirely different issue to prove it.  I'll believe it when I see it.  

 

 

[PeterMP]

4 hours ago, bcl05 said:

George Church's contributions to technological developments in genetic sequencing are undeniable and were critical to major advancements.  He is not clinically relevant, and does not speak for clinical geneticists.  I know many clinical geneticists who roll their eyes every time he opens his mouth.   I think he is both a hugely important scientist and a fringe weirdo who should not be taken very seriously when he talks about clinical applications of new technology.  

 

You are right that both genetic and epigenetic changes are presumed after any germline manipulation.  The actual risks associated with IVF are very small, and are mostly reported around ICSI (intracytoplasmic sperm injection), and have been documented for a few disorders with imprinting abnormalities (Angleman syndrome, Prader-Willi syndrome, Beckwith-Wiedemann syndrome, Russell-Silver syndrome, etc).  

 

CRISPR studies in animal models have been pretty encouraging that the off target effects are much less than they were with traditional "gene therapy" models, including various viral vectors used to introduce new genes.  Still, they are not absent.

 

I think CRISPR has a place in our medical future, and initial efforts should (and generally are) being put towards awful, incurable diseases without other options.  

 

Again, I'm very skeptical that what the Chinese team reported was actually done.  It's one thing to say you've done this kind of thing, its an entirely different issue to prove it.  I'll believe it when I see it.  

 

1.  Even clinicians will be (subconsciously) affected by societal pressure and comments by the like of Church contribute that. In addition, one thing that New Excuses has right is the economic incentive to push forward with this.  Somebody is going to go forward.  It looks like China might come down hard on this guy, but, I suspect, that's partly because he does not appear to have had the support of the government.  (Assuming he's done what he said), if everything looks okay for these 2 babies now, I would not be surprised to see China authorize future work.  And depending on where it is being done, there is a some chance we will not get accurate reporting of the negative consequences (e.g. China).

 

Also some people, including clinicians, are just heavily (emotionally, intellectually, and financially) invested in this technology.  Clinicians were involved in this:

 

https://www.nytimes.com/1999/11/28/magazine/the-biotech-death-of-jesse-gelsinger.html

 

2.  Out of curiosity, how do you do that determination in terms of IVF and these diseases?  I understand that the odds of any one of them are very very low, and even summed up they are still very low (seems to me it must be much less than 1%), but I also understand the odds are still much greater than natural births.

 

It might be something like 0.05% of IVF births suffer from one of these diseases even summing up all of the diseases, but that's still 5,000X more than non-IVF births (some numbers that seem like they might be in the ball park based on the almost nothing I know about the topic at a quantitative level).

 

I mean with somebody that's living, the process becomes a little more clear to me.  As a healthy adult, the odds of a negative consequence from having the flu vaccine are not 0, but are very very low.  However, the odds of getting the flu and suffering serious consequences are also very very low, but not 0.  Acting (getting the flu vaccine) and not acting (getting the flu vaccine) will have consequences and in terms of serious negative consequences they are somewhat close so you get the flu vaccine because it is unlikely it is really going to hurt you as compared to not acting.

 

In other cases, you have people that are very sick and acting (doing some gene therapy on bone marrow cells and then implanting them in the person) has a possible negative consequence, but not acting has likely negative consequences so even if the odds of negative consequences for acting are high, they still balance out.

 

For IVF and these diseases, even if you got to 0.5% that's still a small number independently, but it is also 50,000X more likely than non-IVF births.  There is no comparison in terms of not acting the odds.  If you don't act, no baby is born and no baby can't be born with one of these disorders.

 

At what point do you say, no that's not something I'm comfortable with and so I'm not going to be involved in that even.  If you want to do that, you'll have to find somebody else.

[bcl05]

The risks with IVF and imprinting diseases are far less significant than you are suggesting.  Those diseases have a cumulative incidence of about ~1/2-3000 in the general population, and the risk is, in the most alarmist of publications, ~1/1000 with IVF.  Other publications have found no evidence of risk.  So, maybe, these procedures increase risk at most about 3-fold, but still to a very small number.  

 

Finding evidence of risk with IVF is actually quite hard.  There have been some reports of increased risk of cerebral palsy, but others have not confirmed it.  

 

It makes sense to me, from a biological processes standpoint, that there would be a chance of imprinting errors with ICSI.  It speaks to the robustness and coolness of biology that these things work as well as they do.  

[PeterMP]

13 hours ago, bcl05 said:

The risks with IVF and imprinting diseases are far less significant than you are suggesting.  Those diseases have a cumulative incidence of about ~1/2-3000 in the general population, and the risk is, in the most alarmist of publications, ~1/1000 with IVF.  Other publications have found no evidence of risk.  So, maybe, these procedures increase risk at most about 3-fold, but still to a very small number.  

 

Finding evidence of risk with IVF is actually quite hard.  There have been some reports of increased risk of cerebral palsy, but others have not confirmed it.  

 

It makes sense to me, from a biological processes standpoint, that there would be a chance of imprinting errors with ICSI.  It speaks to the robustness and coolness of biology that these things work as well as they do.  

 

Okay, I don't really want to quibble over numbers that I said were maybe ballpark based on knowing essentially nothing quantitative on the topic.  I was really more interested in the thought process.

 

But the study in the link I posted earlier put the odds at Angelman syndrome at about ~1/10,000 to 1/20,000 in the general population, and in looking 949 IVF pregnancies they found 1 so less than 1/1000 (now n=1 so that's about meaningless in terms of statistics), but that still puts you at over a 10 fold difference.

 

Now to make it worse AS can apparently be caused by different things and in natural cases the odds of being due to an imprinting defect is 1 in 200,000 (again from the link I posted before), and the one they found in the IVF case was in imprinting error (again n = 1 so take it with a grain of salt), but that suggest your looking at like a factor 200.

 

And then as far as I know, the 1/10,000 and 1/200,000 number from the past didn't take into IVF births vs. non-IVF births (they are just everybody numbers IVF and non-IVF) so the real number from non-IVF cases is even lower (and I honestly didn't look, but I'm guessing that imprinting number must be from newer studies so that they knew what imprinting was and could test for it and so was after there were IVF births to cause AS), and you pretty quickly get even much larger numbers (i.e. every one of those 1/200,000 is actually the result of an IVF birth and AS essentially never happens due to imprinting errors in non-IVF births) and you get numbers that are hundreds to thousands of fold higher.

 

(Again, n = 1 so take with a grain and salt).

 

And AS is the only one I really know anything about so maybe it's really the outlier, and the others are much more common in the general population and appear much more rare in IVF births.  But given what I know, it seems odd to me to so conclusively state that it is at most 3 fold.

 

So now I'm curious where do you get at most 3-fold from so conclusively?

 

(Again, I don't want to argue my numbers are right.  As near as I can tell, there isn't enough good data to even start to put a number on it.)

[bcl05]

There are literally hundreds of studies looking for an association between assisted reproductive technology and various health outcomes in offspring, with dozens specifically assessing for imprinting/epigenetic disorders.  

 

This is a reasonably well-designed study that found an odds ratio of 2.9 for epigenetic disorders with ART.

https://www.ncbi.nlm.nih.gov/pubmed/29775803

 

This is a large meta-analysis that found an association but no significant evidence for increased risk for disease.

https://www.ncbi.nlm.nih.gov/pubmed/24961233

 

There are many others that come to some ballpark-similar conclusions. 

 

Where I work (the mayo clinic), we counsel prospective families considering these options with numbers informed by these studies, erring on the side of conservative estimates of risk.    

 

 

This is a massive (but interesting) derail of the original topic.  Happy to take it up in a new thread or PMs.  Also, happy to chat about clinical genetics at any time.  My line of work is endlessly interesting.

 

[bcl05]

Also - its far more complicated than that...

 

This study analyzed methylation patterns in spermatozoa from sub fertile men and found a higher than normal incidence of methylation abnormalities.

https://www.ncbi.nlm.nih.gov/pubmed/30270743

 

So it's not clear if methylation variants in offspring conceived through IVF are due to the IVF itself or due to pre-existing variants in the sperm themselves. Frankly, it's probably both.   

[PeterMP]

12 hours ago, bcl05 said:

There are literally hundreds of studies looking for an association between assisted reproductive technology and various health outcomes in offspring, with dozens specifically assessing for imprinting/epigenetic disorders.  

 

This is a reasonably well-designed study that found an odds ratio of 2.9 for epigenetic disorders with ART.

https://www.ncbi.nlm.nih.gov/pubmed/29775803

 

This is a large meta-analysis that found an association but no significant evidence for increased risk for disease.

https://www.ncbi.nlm.nih.gov/pubmed/24961233

 

There are many others that come to some ballpark-similar conclusions. 

 

Where I work (the mayo clinic), we counsel prospective families considering these options with numbers informed by these studies, erring on the side of conservative estimates of risk.    

 

 

This is a massive (but interesting) derail of the original topic.  Happy to take it up in a new thread or PMs.  Also, happy to chat about clinical genetics at any time.  My line of work is endlessly interesting.

 

 

I think we are OnT enough because the underlying issue is really the ethics of these situation (and I'll bring it back around to CRISPR).

 

The meta-analysis is not very helpful because they give you no idea how high the odds would have to be before they see a significant affect, and it is older.  It is possible that a 3 fold change would be a significant result in the meta-analysis when it was done.

 

(In my experience this is what you sort of see.  You get a bunch of older studies that show mixed results, meta-analysis based on them show no significant result, then a bunch of new studies come out and show a more clear result, and it takes a few years for the meta-analysis to catch up, and it seems to me here the newer studies are leaning towards there are effects.)

 

And the newer (French based) study puts the 95% confidence interval at over 8 fold.  The mean is under 3 fold, but to say the odds are at most 3 fold based on that study, seems odd.  There's a reasonable (~40%), they are over 3 fold.

 

(Looking more recent meta-analysis for this set of diseases finds significant positive results for all of them, with for all of them at least the upper limit of the CI is over 3 fold and for some of them the mean is over 3 fold so in totality, it seems the mean has to be greater than 3 fold.  Just adding up the means gets you to 24, and then obviously, ti could be higher than the sum of the means based on the 95% CI.)

 

https://link.springer.com/article/10.1007%2Fs10815-018-1173-x

 

And this recent paper for BWS alone puts it at about 20 for BWS, which is even higher (and presumably wasn't part of any of these meta-analysis).

 

https://www.ncbi.nlm.nih.gov/pubmed/29936652

 

Add in the paper that I originally cited that is also newer and certainly wasn't part of the meta-analysis that you linked and wasn't probably part of the above meta-analysis, and the expected OR even go up more.)

 

I did not know about the sperm, but I guess that is not surprising.  I did know that autism is more common in IVF babies, but IVF babies also tend to be born to older parents so when taking into account things like the age of the parents it is hard to say there is a significant effect.

 

But from a purely ethical stand point, I'm not sure that matters.  If the people aren't likely to have a baby without IVF, then the odds of them having an autistic baby are essentially 0 without IVF so whatever the odds are from IVF are essentially the odds due to IVF.

 

Which circles me back to the question I have been asking (and not really arguing over numbers).  As an involved individual, when/how do you say the odds are likely to high?  Or do you never?  Is the job of the clinician to simply present the best information we have and let the people decide?  Is there a point where the institution says no?  To your knowledge has the Mayo Clinic ever said, this is a case of IVF we do not want to be involved in for ethical concerns?

 

If parents came to you and said we know there are risks with IVF and there are risks that aren't really knowable with CRISPR, but we want to try this, would you (or the Mayo Clinic) say no?

 

One interesting thing here to me is that it might turn out that a key to preventing these issues is actually CRISPR.  IF the risks to CRISPR are low, then at least in some cases, CRISPR should be able to be used to edit the DNA that has been epigenetic changed and fix it.

 

CRISPR might actually be a key component to making IVF safer (once we better understand the risks from IVF).

 

The 2nd thing that it appears to me is this again a case where we seem to be treating these procedures different than drugs.  There's almost no way that the FDA would approve a drug like this without requiring post market studies, and what seems to be the case here is there is no organized collection of data that resulted from post market studies.

 

And again, IVF and CRISPR editing are much more likely to have life time and even generational affects than drugs and so I think they should be being treated even more rigorously than most drugs.

 

(Now, this isn't to say that post market drug studies are a panacea because they do miss things even when done well/correctly and sometimes the drug companies do out and out lie about the results of their post market studies.)

[bcl05]

10 hours ago, PeterMP said:

 

Which circles me back to the question I have been asking (and not really arguing over numbers).  As an involved individual, when/how do you say the odds are likely to high?  Or do you never?  Is the job of the clinician to simply present the best information we have and let the people decide?  Is there a point where the institution says no?  To your knowledge has the Mayo Clinic ever said, this is a case of IVF we do not want to be involved in for ethical concerns?

 

If parents came to you and said we know there are risks with IVF and there are risks that aren't really knowable with CRISPR, but we want to try this, would you (or the Mayo Clinic) say no?

 

 

Well, there is a lot to respond to here.

 

As a broad generalization, I don't think it is my place to say when/where risks are too high.  Fundamentally, the process of having children is inherently risky.  About 3% of all children will be born with a significant congenital anomaly.  A comparable percentage will have intellectual disability.  Depending on definitions, a percentage in the same ballpark will have an autism spectrum disorder.  Current assisted reproductive technology probably adds a marginal amount of risk, but not in a way that dramatically changes these calculations.  

 

My primary role as a geneticist is in the diagnosis and management of rare genetic diseases.  I see a lot of children with devastating autosomal recessive diseases.  Some of these are untreatable, and lead to painful, short lives.  Some have treatments and outcomes can be optimistic.  There is a huge range of severity.  In those families, the recurrence risk is 25%, meaning that there is a 1/4 chance of each subsequent pregnancy having the same disorder.  We can offer prenatal testing (with either CVS or amniocentesis), which brings a small amount of risk (likely less than 1/1000) of miscarriage, but can diagnose these diseases in a fetus with certainty.   We also offer pre-implantation genetic diagnosis, where we generate embryos with ART, test the embryos when they are still microscopic (and only a few cells), and implant only those without the disease in the mother.  It is remarkable and humbling to me, having had these conversations literally thousands of times, how variably different reasonable people approach these risks.  I've seen some couples who see the 25% recurrence risk and feel like the 75% chance of a healthy child is worth it, and get pregnant the old fashioned way.  I've seen others in whom even the miniscule risk of inaccurate testing with pre-implantation diagnostics is too high, and choose to either not have additional children, or to adopt, or to use sperm/egg donation, or whatever.  I think these questions about comfort with risk are about as personal as we get.  We have a whole cadre of geneticists and genetic counselors who work with families to consider these decisions and to provide them with the best information possible.  We make every effort to be non-directive, and to not allow our personal feelings about the disease or process to influence the patients (though that likely does happen some).  

 

I'm not aware of any family that was turned away from IVF for ethical reasons, though I only interact with a relatively small subset of all IVF patients.  We do have an active and engaged ethics board, and I have been involved in multiple cases where patients or families are requesting/demanding particular treatments that we deem are outside the bounds of responsible medical practice and outside our ethical boundaries.  Examples might be futile and painful surgeries/treatments in a patient at the end of life, requests for fetal surgical intervention (placing the mother at significant risk) for a fetal diagnosis where the outcome will not be altered, etc.  We have a process by which the ethics board gets engaged and helps mediate these conflicts.  I think every reasonable medical center has an ethics board.  Ours may have gotten involved with an IVF situation, but not in any cases I've been involved with.  

 

Back to CRISPR - I can certainly imagine a future where CRISPR plays a significant role in this practice.  One of the struggles with pre-natal testing is that once the pregnancy is established, even if we confirm a genetic diagnosis, there is little we can offer other than the option to continue or not continue a pregnancy.  For many families, that conversation is simply a non-starter.  Similarly, some families are not comfortable with pre-implantation diagnostics as there will inevitably be some embryos produced that are not implanted and are destroyed.  Some families are not comfortable with that at all.  If we could offer a treatment of some type that could allow the fetus to be born with less effects from whatever disease is found, that would dramatically change the risk/benefit calculation of prenatal and pre-implantation testing. 

 

I don't think CRISPR is ready to be broadly utilized in that way yet.  I hope it will be, but I don't think it is happening any time soon.  I'd love to be wrong - having more effective options to offer to my patients and their families would be great...

[PeterMP]

 

1 hour ago, bcl05 said:

 

Well, there is a lot to respond to here.

 

So in your personal/practical experience/knowledge when it comes to medical/scientific procedures carried out on embryos or germline cells as part of assisted reproductive practices or the conception process there has been no ethical oversight at the level of individual clinicians or the institution.  Right?  The ethical decisions are totally left up to the "parents" of the embryo/germ line cells?

 

Can I throw a hypothetical at you?

 

Let's say there is an infant that has no apparent issues, and the parents came to you and said there was something they wanted to give their child that would increase the odds ratio of their child having some significant anomaly (like the diseases we're talking about)  (let's say an 8-fold odds ratio increase as compared to not doing it) because it would make the parents happier.

 

(Let's say the parents always wanted to have a red head and they knew their infant was going to grow up to have brown hair, but they had found someway to make their child a red head, but it would increase the odds ratio of their child getting a rare disease that causes affects like some of these disease by like 8 fold.  I'm not sure what a good disease would be.  Maybe you know of something.  GBS isn't quite right, but something like that where it is a rare disease and so not many people get it and 8 fold increase in the odds ratio is still a very small number of people will get it.)

 

But they need your help.  Is your response the same (i.e. the ethical considerations are not really your concern)?

 

@No Excuses  (Do you want to give an opinion?)

[bcl05]

I think you're putting a lot of words into my mouth here, or maybe just misunderstanding me...

 

I would say that I have very rarely had any ethical concerns about the decisions made by the parents I care for.  Ethicists were very involved when we set up our ART clinic and our fetal medicine program, but are not as involved in the day to day operations, mainly because these kinds of ethical conflicts rarely arise.

 

Now, a big part of that is that many of these practices have been in place for many years, and have a good track record with many good outcomes.  If we were to propose some novel procedure (CRISPR manipulation of embryos, for example), we would absolutely have ethicists (and others) involved in the setup and monitoring of the program.  This is not unusual - we have an active fetal intervention program where our surgeons are operating on fetuses in the uterus to help ameliorate devastating congenital anomalies.  These procedures carry risk for both the mothers and the fetuses.  Our ethicists review each new procedure proposal and are involved in some of the difficult case decisions.  

 

The hypothetical situation you pose is very far from any medical experience I can relate to.  I have not had any parents request interventions that induce risk due for some perceived cosmetic (or non-medical) benefit.   I would have significant problems with your hypothetical situation, and that would be a case where our ethics board would certainly be involved. 

 

I may be misunderstanding you, but are you suggesting that because ART may increase the risk for certain, extremely rare diseases by (at most) 8-fold, we shouldn't be offering this treatment?  

[PeterMP]

1 hour ago, bcl05 said:

I think you're putting a lot of words into my mouth here, or maybe just misunderstanding me...

 

I would say that I have very rarely had any ethical concerns about the decisions made by the parents I care for.  Ethicists were very involved when we set up our ART clinic and our fetal medicine program, but are not as involved in the day to day operations, mainly because these kinds of ethical conflicts rarely arise.

 

Now, a big part of that is that many of these practices have been in place for many years, and have a good track record with many good outcomes.  If we were to propose some novel procedure (CRISPR manipulation of embryos, for example), we would absolutely have ethicists (and others) involved in the setup and monitoring of the program.  This is not unusual - we have an active fetal intervention program where our surgeons are operating on fetuses in the uterus to help ameliorate devastating congenital anomalies.  These procedures carry risk for both the mothers and the fetuses.  Our ethicists review each new procedure proposal and are involved in some of the difficult case decisions.  

 

The hypothetical situation you pose is very far from any medical experience I can relate to.  I have not had any parents request interventions that induce risk due for some perceived cosmetic (or non-medical) benefit.   I would have significant problems with your hypothetical situation, and that would be a case where our ethics board would certainly be involved. 

 

I may be misunderstanding you, but are you suggesting that because ART may increase the risk for certain, extremely rare diseases by (at most) 8-fold, we shouldn't be offering this treatment?  

 

First, I think I misunderstood you, which is why I asked the question.  I wanted to be sure that I was understanding what you were saying, and we were on the same page. (and sorry from my point.)

 

Second, I think 8-fold is probably low.  That's the upper range of the 95% CI based on the one study that you posted, but the newer studies appear to me be putting higher numbers on it, and the newer meta-study I posted puts the mean of the sum of the diseases at 24 fold (and that's just for those few diseases).  (The 8-fold number also comes from a study based on France so the difference might also be the result of some population difference/IVF practices in France and in the US.)

 

Lastly, I'd say it is a conversation that should be had at a larger societal level that was never really had because nobody ever really understood the risks.

 

Obviously, my hypothetical is not perfect, but at some level that appears to be what is happening.  We (as a society) appear to be increasing the risks of having children that have significant abnormalities to make (would be) parents happy.  Yes, it appears to be a small number of children because the base line level of the diseases are so low, but it appears to be a significant increase over what would happen naturally.

 

And when you look at the comments made by the likes of George Church (and in this thread @No Excuses), it looks to me like something we are (likely) to repeat again with CRISPR.

 

And you didn't answer the question!

 

What do you do?  Are the ethics not your concern?

 

(At what level of risks do we as a society so no to (potential) parents?  Does it matter if the child is born or the child is not born yet?  

 

(and right now, it seems to matter a whole lot if the child is born or not.  There is no way the FDA is approving a drug like I described if the risks are clear.  And that doesn't seem to me to be at all logical.)

[PeterMP]

More details reading about this today:

 

1.  I knew the one girl didn't have deletions in both genes, but it sounds like even in the other gene, the deletion is not complete enough to stop the production of functional protein so she likely has 0 protection from HIV.

 

2.  For the other girl, it appears she might be mosaic where some cells got changed, but not all of them and some cells would still be susceptible to HIV infection and others are not.  If that's the case, in terms of her practical level of protection, it will really come down to whether the cells that become the immune system got the change.  So again, it is possible that she really got 0 protection.

 

His reason for going forward with implantation even though they knew there issues (e.g. the one girl likely had no protection from HIV)- The parents wanted to.  (the ethical decisions were left to the parents.)

 

3.  It is being claimed that he didn't do deep enough DNA sequencing to identify large deletions that might have been made during the process.  In some animal cases, it has been reported that CRISPR editing has resulted in large deletions (even far from the edited site) (which relates to the problem of having a good/valid reference genome).  (Doing high quality DNA sequencing is still not a trivial thing).  Based on what seems to be the case for CRISPR, it isn't enough to do "normal" DNA sequencing.

 

He really made a mess of things (I guess the upside here might be, if they don't have any significant deletions, the change might not have been enough to negatively affect them in terms of making them more susceptible to other viruses.  They might have essentially no HIV protection, but they also don't have the negative affects associated with CCR5 deletion.)  

[Fresh8686]

https://www.theatlantic.com/science/archive/2018/12/15-worrying-things-about-crispr-babies-scandal/577234/

[bcl05]

1 hour ago, Fresh8686 said:

https://www.theatlantic.com/science/archive/2018/12/15-worrying-things-about-crispr-babies-scandal/577234/

 

That's a very good article, and I think it accurately reflects the community of clinical geneticists.  

[China]

China’s CRISPR twins might have had their brains inadvertently enhanced

 

The brains of two genetically edited girls born in China last year may have been changed in ways that enhance cognition and memory, scientists say.

 

The twins, called Lulu and Nana, reportedly had their genes modified before birth by a Chinese scientific team using the new editing tool CRISPR. The goal was to make the girls immune to infection by HIV, the virus that causes AIDS.

 

Now, new research shows that the same alteration introduced into the girls’ DNA, deletion of a gene called CCR5, not only makes mice smarter but also improves human brain recovery after stroke, and could be linked to greater success in school.

 

“The answer is likely yes, it did affect their brains,” says Alcino J. Silva, a neurobiologist at the University of California, Los Angeles, whose lab uncovered a major new role for the CCR5 gene in memory and the brain’s ability to form new connections. 

 

“The simplest interpretation is that those mutations will probably have an impact on cognitive function in the twins,” says Silva. He says the exact effect on the girls’ cognition is impossible to predict, and “that is why it should not be done.” 

 

Click on the link for the full article

[China]

China convicts 3 researchers involved in gene-edited babies

 

BEIJING (AP) — A Chinese scientist who set off an ethical debate with claims that he had made the world’s first genetically edited babies was sentenced Monday to three years in prison because of his research, state media said.

 

He Jiankui, who was convicted of practicing medicine without a license, was also fined 3 million yuan ($430,000) by a court in the southern city of Shenzhen, China’s official Xinhua News Agency reported. Two other researchers involved in the project received lesser sentences and fines.

 

The verdict said the three defendants had not obtained qualification as doctors, pursued fame and profits, deliberately violated Chinese regulations on scientific research, and crossed an ethical line in both scientific research and medicine, according to Xinhua. It also said they had fabricated ethical review documents.

 

The court also confirmed a third birth, saying the researchers were involved in the births of three gene-edited babies to two women. It said all three scientists pleaded guilty during the trial, which Xinhua reported was closed to the public because of privacy concerns.

 

He, the lead researcher, shocked the scientific world when he announced in November 2018 that he had altered the embryos of twin girls who had been born the same month. He described his work in exclusive interviews with The Associated Press.

 

Click on the link for the full article

[Cooked Crack]