bcl05

I think there is far, far more variation in standings year-to-year in the NFL than the NBA. In the NBA, one can pretty much predict the contenders at the beginning of the year. It is far more likely that a team will surprise in the NFL than the NBA. That suggests to me that even a middling NFL front office might luck into some playoff success once a decade or so. It takes a pretty putrid effort to be as consistently hopeless as the Skins have been. In the NBA, a team can go from terrible to great fast with the acquisition of one or two great players, but how often does that really happen? It's not very common - mainly because there are not enough great players out there. All that is to say, I think Bruce is more incompetent. Though I wouldn't want either to watch my houseplants.

His fracture was compound (with bone piercing skin). Those nearly always get infected, and those infections can be awful. This is unsurprising, but bad.

Nats have more than half a billion in 3 starters. I think this makes the Gomes trade even better - his pitch framing data looks awesome.

Excellent. I'm ready for pitchers and catchers to report.

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

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?

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...

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.

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.

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.

This is one of my favorite photos from one of my medical mission trips to Uganda. I sent it home to my wife. She was not amused.

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.

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 a clinical geneticist, and am involved in the discovery, diagnosis and management of rare, severe genetic disease daily. I'm skeptical that CRISPR is really ready for prime time. There are still significant off-target effects, and I think using it in non-diseased embryos as a proof-of-concept (as is being described in the Chinese report) is absurd. There will almost certainly be unplanned off-target genetic variants introduced, which may lead to significant disease. I'd be very curious to see if and how the CCR5 variant was confirmed in the babies and how their genome was assessed for off-target effects. Until I see that stuff, I'm extremely skeptical. When I was in medical school in the mid-90's, I remember being told that broad-based gene therapy was "right around the corner." It's still right around the corner. We'll see... That isn't to say that CRISPR isn't very exciting technology. I do think we will see it used successfully to dramatically alter, and in some cases cure, certain genetic diseases. It is not a cure-all, but there will be some targeted fixes that will be extremely beneficial.

We have lost any ability to even pretend to be moral leaders in the world. I am so ashamed of our country. I wish we were better than this, but we clearly aren't. We are not a country of compassion.