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Born CRISPRed. Now What?

Are there CRISPR-modified human babies now or not? I was waiting to write about this story in hope that it might get a little more clear, but so far that doesn’t seem to be happening. So here we go. What we know so far is that He Jiankui, a researcher from Shenzhen’s Southern University of Science and Technology, claims to have used CRISPR to alter human embryos in vitro, and that these were later implanted and brought to term: twin girls with the CCR5 gene edited out.

No one was expecting this. Or rather, everyone was expecting something like it at some point, but the world was not expecting it on Monday morning. But perhaps some people were? This article by Antonio Regaldo in Technology Review (dated November 25th) had the rumblings of the work in it, and in hindsight is quite interesting indeed. A lot of people have known that something was up, apparently. According to Stat, He had given a talk last year in which he described human embryo CRISPR work, but with no mention of using it to produce human babies just yet. A Rice University researcher (Michael Deem) says that he was working with the Shenzhen team and was present when the people involved gave their consent. Here’s another news roundup as of Tuesday. Prof. He apparently had discussed the implications of such experiments with many people over the last couple of years.

The SUST people certainly are acting as if they’d been blindsided by the news, with a press release saying that they had no knowledge of such an experiment (which they call a serious violation of academic ethics), that Dr. He had been on leave without pay since last February (reasons unspecified), and that the work appears to have been conducted at some off-site location. Note, however, that this timing means that the human embryo implantation may well have occurred while he was still on the faculty; the twins are said to have been born several weeks ago. Meanwhile, at least 100 prominent Chinese researchers have signed a public statement against this work and condemning He for having tried it. There were initial reports of oddities about the consent and review-board paperwork on all this, with some saying that the people involved were only told that they were involved in a study of HIV vaccines or that signatures were forged, but I haven’t seen as much follow-up on those yet. At any rate, He is set to speak very soon in Hong Kong at the Second International Summit on Human Genome Editing, and won’t that be a circus?

At this point, though, I’d say odds are very much in favor of these genetically altered babies having been produced as described. George Church says that he has seen the data, including multiple sequencing runs, and believes that Dr. He has probably done what he says he’s done. This has been possible for some time; it’s just that no one has been foolhardy enough to try it. If Dr. He is expecting accolades as some sort of father of human genetic engineering, I hope he has a long wait. This is not a time for congratulations. Everyone has been standing around looking at this weapon; He Jiankui is just the guy who walked up and pulled the trigger before anyone was quite clear where the thing was aimed.

And let’s talk about that for a moment: CCR5? That’s a chemokine receptor of the immune system, well-known for its role in HIV’s infection mechanism. The report is that the twin girls were born to an HIV-positive father, but still – that doesn’t mean at all that the babies would have contracted the disease, and deletion of CCR5 itself may not be harmless either (greater susceptibility to other viral infections). So this is an odd choice. I’m pretty sure everyone expected the first human embryo modifications would correct something that would otherwise be fatal, an experiment that would seem ethically more defensible.

The problem is, for all we know about CRISPR technology, there are still plenty of things that we don’t know, and things that we don’t even know that we don’t know. The human genome is large, human embryonic development is complex, and CRISPR is not a magic knife of perfection (or certainly not yet). If these two girls have indeed been genetically altered and they grow up without some unexpected problems, it will simply mean that they (and Dr. He) got lucky, and that’s no way to handle the lives of innocent human beings.

So put me down on the side of those saying that this experiment should not have been done yet. We’re going to alter alter the human genome, of that I have no doubt. But there was no reason to alter it now, like this, under these conditions. He Jiankui has just made life more complicated for everyone working in the field, and for what?

 

43 comments on “Born CRISPRed. Now What?”

  1. Isidore says:

    I am curious, do you have in mind any specific milestones with regard to our understanding of CRISPR that would then make its use in embryonic human genome editing about as risky as, say, fetal surgery that is currently performed to address certain defects. In other words, what are we waiting for? Mind you, I am not arguing that we (well, Dr. He Jiankui, actually) shouldn’t have waited, but it would be good to know for what.

    1. Nesprin says:

      We need to collectively as a society decide that such an action is ethical.
      If so, under what circumstances- lethal mutations like Tay Sachs? Sub lethal but devastating chronic diseases like cystic fibrosis or li fraumeni? Or anything goes editing for height or attractiveness?

      1. Wavefunction says:

        Editing for height or “attractiveness” would be far more complicated than editing for Tay-Sachs or common inherited genetic diseases. One thing I find annoying is that people tend to make the jump from “We could prevent/cure well-defined genetic illnesses” to “We can breed more intelligent and attractive babies” in a heartbeat. Let’s separate the two aspects of the technology to have a prudent discussion.

        1. Nesprin says:

          Yes, getting a supermodel out of an embryo is not currently possible, but I’d argue that discussing whether such a decision would be ethical should happen before such a thing is possible. And I’d argue that eye color and skin tone are already on the list of single gene alterations which could alter perceived attractiveness and or racial presentation.

    2. anotherguy says:

      One important difference vs. fetal surgery is that the genetic changes will be inherited in the germline – any changes made will not only affect the individual, but also affect the genes they pass on to any children that they have as well. This obviously puts a high bar for our understanding of the safety of the edit, and the impact of any mis-editing or off-target editing that may be deleterious (and heritable as well).

    3. Jb says:

      When regenerative tissue engineering ideas came out, regulatory bodies were requiring 50 years, yes you read that right, of long term follow up to make sure there were no late onset toxicities. I think that’s a reasonable bar to start with for CRISPR. Gene editing in the lab is now pretty easy, but identifying and characterizing the risks are not. At least 20-30 years of follow-up to check to see if there are higher incidences of cancer, including being able to catch ones with late onset, in gene edited people must absolutely be done.

  2. Piet Skiet says:

    But they told me editing my genes was no more likely to kill me than being born was!

  3. John Wayne says:

    What are you going to do next, deliberately expose these kids to HIV (and other viruses) and see what happens? Even if you can set the shocking ethical implications of this aside (and you shouldn’t), this is a terribly designed experiment.

  4. Cato says:

    This was done for pure scientific hubris, to be “first”. I hope this guy is thrown in jail

    1. SV says:

      in Silicon Valley he’d be an entrepreneur of the year

      1. MoMo says:

        Or if He used his methods for ED or to grow hair. Instant hero instead of instant pariah.

        1. Ken says:

          According to Idiocracy, those will be the two main areas of medical research for the next 500 years.

    2. fajensen says:

      In China there are several options: They might give him a non-refundable ticket to the Organ Donor Bus or they might send him up north to work in the rice fields for “quiet contemplation concerning the errors of his thinking”. Basically a “cold storage” for people – in case that the state feels they may need his kind of thinking again at some point in the future.

      My bet (knowing nothing of China) would be “Rice Fields”.

  5. Tapio says:

    Not surprised that someone tried to do it and “succeeded”. It’s not super challenging to do, at least if you ignore safety. I’m just amazed that somebody would choose such a stupid first target as CCR5 – the effect is hard to read out (apart from just the sequencing data), there is no real reason to do it, as numerous alternatives exist and HIV is hardly a death sentence anymore.

    It will be interesting to see the future development of these children. If there are indeed no serious off-target effects, does that mean the girls were just super lucky or were all of those concerns about side effects just overblown? The experimental design won’t be able to tell us, but I strongly suspect the latter.

    This story could go several ways, but I see two main ones. It could demonstrate that CRISPR on humans is safe, accelerating work on more legitimate target genes. More likely is that the increased public pressure slows down more legitimate research, even more so if there are serious adverse effects.

    Overall, probably not a great idea to do it, but I’m strangely excited about what’s going to happen. Anyone willing to tacke a gamble and buy stock of companies heavily invested in CRISPR technology?

    1. a. nonymaus says:

      Indeed, the choice of CCR5 seems hype-driven. Wake me when someone uses Cas9 plus homology-directed DNA repair templates to restore gulonolactone oxidase function (in a guinea pig first!). Extra credit if they don’t wreck anything else in the process.
      On the other hand, CCR5 is a reasonable target given its penetrance in the human genome. For rare genetic diseases, the only worthwhile treatments are ones that can be applied after birth. If one knows that a fertilized ovum carries a rare disorder, why treat and then implant that ovum over one that doesn’t carry the defect? Either way, one practices eugenics with the question being whether it is at the genetic or whole-organism level.

      1. Scott says:

        I would argue that it is more ethical to edit out potentially fatal mutations in an affected embryo than it is to only implant healthy ones. Riskier, though, given the long-term effects potentially at play here.

        Though this experiment seems odd. I’m not a doc, but I would have knocked-in one of the HIV-immune variants of the CCR5 instead of knocking out CCR5 entirely. Seems to be much lower-risk to the children and grandchildren at first glance.

        So what am I missing? Why just knock out CCR5 entirely instead of putting in a known HIV-immune variant?

        1. Scott says:

          Blargh, should say “I would argue that it is more ethical to edit out potentially fatal mutations in an affected embryo than it is to only implant healthy *embryos*”

        2. Tapio says:

          Presumably just because knocking a gene out with CRISPR is easier and tends to work at higher efficiency than knocking a gene in (at least it was that way in the zebrafish I CRISPRed).

          1. Scott says:

            Thank you!

            Though I will note that since the CRISPR editing was done at the level of (presumably single-cell) embryo, I would imagine that would be much easier than editing a multicellular organism.

  6. CloneWars says:

    The experiments to worry about are the ones that will never be publicized…

  7. Chrispy says:

    If you’re going to KO stuff out of healthy embryos, myostatin and PCSK9 would both be better choices.

  8. Uncle Al says:

    Imagine the international furor if He Jiankui had gene-gineered male Chinese porn stars – and the lines. I would not mind having another 30 IQ points, or breeding an entire nation that could count to 1023 on its fingers

    1. Chris Phoenix says:

      Just wait – soon it’ll be 3^10, then 4^10….

  9. Anonymous says:

    On yesterday’s topic (Leukemia journal rejecting submission from industry), I wondered if the corresponding editor might have had a conflict of interest (financial or professional or both). Today, I am wondering if He has any financial interest in a Chinese or US company seeking to become a leader in embryo manipulation. It isn’t clear where He did the manipulations, implantation, and where the babies were born. I see nothing mentioned in the articles I’ve read other than that China wants to become a leader in CRISPR and funds a lot of research.

    Twins? My understanding is that IVF usually involves implantation of multiple zygotes, so I am guessing that these are fraternal twins and not identical twins from the splitting of a single embryo during development. I haven’t read any details of that (frat / ident), either. But that suggests that He CRISPRed a batch of eggs. Is that reasonable to assume? How variable is the technique? If you CRISPR a bunch of cells in the research lab, do they all respond the same way? Can’t your needle technique hit different parts of the membrane and lead to different outcomes? Suppose you disrupt a receptor rich portion of Cell-A and receptor deficient patch of Cell-B? Do you see different outcomes?

    Also assumed is that this is a CCR5 knockout? Or did He CRISPR/Cas9 in a mutant (HIV resistant) CCR5 variant (e.g., CCR5 Delta32)? From Derek’s wikipedia link to CCR5, there are all sorts of things that can occur in homozygous CCR5-Delta32s. Will similar risky side effects be expected in CCR5 knockouts?

    Since many are questioning the medical benefits of this choice of CRISPR manipulation, I’m thinking that there’s a money trail that will be uncovered.

    1. He says:

      Original article said one twin was homozygous deletion where as other heterozygous deletion

  10. Nick K says:

    Minor correction: the city in Southern China where the work was done is Shenzhen, not Shenzhan.

  11. Jb says:

    Now what? You get cancer, that’s what. We still have no friggin’ clue how precise gene editing technology needs to be so that errors won’t cause cancer, or that off target effects on the genome that are hot spots for cancer aren’t hit. How accurate do you have to be? 99%? 99.9%? 99.9999%? Even with a .01% occurrence of off target effects, that could represent a lot of cells out of the 10 trillion or so that will ultimately make up the body, which replicate over time and could increase over time.

    1. Tapio says:

      I doubt it would be as severe as “OMG, cancer everywhere”. We would most likely have seen such side effects in lab animals by now and from my experience they are (from the outside) as healthy as their non-CRISPRed relatives. We also had lots of fish lines created via ENU mutagenesis and those were generally not as robust or fecund. What is more interesting and likely in this case are very long term, mostly statistically noticeable defects. To really say anything about that, the sample size is waaaayyy to small. Let’s hope any off-target effects only hit non-essential parts of the genome. The only thing that is clear right now (assuming they were actually CRISPRed), is that no genes essential for normal gestation were affected…

  12. GD says:

    Jb: gene editing was performed at the single cell stage, to avoid mosaicism. Hence any off-target mutation will be present in every single cell of the body. Whole genome sequencing has been performed, so we may soon know the number of unintended mutations.
    CCR5 is really not a sensible target though, as some HIV strains use CXCR4 as entry receptor. Even homozygous inactivation of CCR5 does not fully protect against HIV.

    1. tangent says:

      > Even homozygous inactivation of CCR5 does not fully protect against HIV.

      So… this is kinda dumb then?

      I have a super-basic HIV 101 question too: why do any of this? Why would the children be at any risk from their father’s HIV+ in the first place? From the mother they would be, but from the father, even if his seminal fluid is crawling with viruses and dangerous to the mother, is there any risk to the zygote?

      I find rare (kinda gross) cases like this: “Shortly after his birth, his father was diagnosed with HIV. At the time, the father also had the chickenpox and syphilis, and was undergoing treatment for both. As a result of the father’s infections, the man developed large blisters all over his body that leaked fluid profusely, the report said.”
      https://www.livescience.com/63710-father-transmits-hiv-to-son-rare-case.html

      1. Isidore says:

        This is what JIankui He is reported to have said yesterday at a conference in Hong Kong during Q&A after his talk:
        “The first question was whether CCR5 is an unmet medical need. I actually believe that this is not just for this case, but for millions of children. They need this protection. HIV vaccine is not available. I personally experience with some people in AIDS where 30% of a village people are infected. They even have to give their children to relatives and uncles to raise just to prevent potential transmission. For this specific case, I feel proud. I feel proudest, because they had lost hope for life.”

        1. tangent says:

          Thanks, Isidore.

          “They even have to give their children to relatives and uncles to raise just to prevent potential transmission.”

          What is going on in this statement. Is there a belief in these villages that HIV is transmissible from parents to child by… touching toothbrushes or something?

          And that’s not even getting to GODDAMNIT it is unconscionable that these parents are not all on ART drug therapy, every one of them. Every HIV+ person on earth. I know the drugs cost money to manufacture but in any objective accounting the damage to patients’ lives, and their family, and THE ONGOING TRANSMISSION THAT COULD BE STOPPED has to outweigh that. God weeps.

          (Though I recently learned that the “undetectable viral load = untransmissible” statement does not apply to breastfeeding. Because breastmilk is a transferred immune tissue and carries retroviral DNA in live cells, probably.)

      2. another guy says:

        The clinical approach to preventing HIV transmission in this case would be to have the father take antiretrovirals and get his HIV viral load down to undetectable levels. The body of evidence shows that HIV+ patients with undetectable levels of virus in their blood cannot transmit the virus to another person (risk approaches zero). As an additional protective measure, “sperm-washing” can be done to further reduce the chances of transmitting HIV. If the pregnant mother were to somehow become infected with HIV she could take antiretrovirals and it is now very rare to give birth to an HIV+ baby if expert care is available. Even if the baby is born HIV+, it is now a chronic manageable condition. I agree with the consensus that the “CRISPR-babies” experiment was unneccessary, ethically very questionable, possibly could cause harm to the babies and is being done in a way that suggests the priority is self-promotion over putting the healthcare needs of the patients first.

  13. crni says:

    Hmmm maybe a bit out of left field, but wouldn’t an experiment on human gene editing actually be more ethical if it did not significantly alter the subjects health? Perhaps a cosmetic type of thing such as changing the hair color or eye color?

    1. fajensen says:

      One of the interesting things about applied genetics seems to be that “trivial things” like hair or eye colouring often are loosely coupled to wondrous complexities such as how the mind works.

      At least in dogs, the colouring of the coat seems to be connected to the personality of the dog so that darker coats means that the dog tends to be more stable and less excitable, whereas the lighter dogs (of the same race) tends to be more skittish and excitable.

  14. tangent says:

    > “My sense is that the groundwork for future self-justification is getting laid,” says Benjamin Hurlbut

    Well I have concluded that I totally, totally misinterpreted this here phrasing.

    https://www.technologyreview.com/s/612458/exclusive-chinese-scientists-are-creating-crispr-babies/

  15. Kling says:

    From what I understand, it is easier to eliminate heterozygous embryos that bear undesirable traits before implantation.

    For some odd reason I don’t seem to hear much controversy over that.

  16. Bertrand Jordan says:

    Correcting deleterious mutations is often quoted as the potential aim of embryo editing, but it does not make sense as a significant fraction (50%, 25%) of the embryos obtained after IVF are unaffected, so PGD is a proven and much safer alternative. This is a smoke screen used to justify the potential use of embryo editing by highlighting a very acceptable purpose. The real motivation for embryo editing is enhancement (for characters determined by a single gene, not height or intelligence!), so the choice of CCR5 inactivation does make sense: it is a kind of enhancement that can be dressed up as “prevention”.

  17. Kirito says:

    History is full of people criticizing scientist for remarkable discoveries and inventions. Why was CRISPR-Cas9 developed if not for human genome editing ? Everyone knew it was going to happen one day. What’s the real problem ? That he did it before everyone else ? He worked to solve a real world HIV problem. I feel rather proud too. Everyone is scared about super babies and stuff. As if that wasn’t going to happen anyway once CRISPR-Cas9 human genome editing is “approved” by the scientific community.

    Instead of taking a scientific observable approach everyone is just quick to criticize. If this is the reaction we will never conquer the frontiers of science. Elon Musk, please ask He to work for you.

    1. Derek Lowe says:

      This was not working to solve a real-world HIV problem – the idea of CRISPR/CCR5 to have any real-world impact on HIV is ridiculous now, and may well always be ridiculous compared to other modes of treatment. This is unfortunately obvious to anyone in the infectious disease field, which is why He’s statements about it did not go over very well in Hong King.

      And the real problem is not that he was first. It’s that anyone could have been first, if they were willing to take such unacceptable chances with human lives.

      1. He says:

        Cowards! Science is driven forward by those who take bold risks, not those who cower, sniveling, waiting for permission from the sheep to do what they are too frightened to contemplate!

        This is only the beginning! Soon, all the world will acknowledge my genius as I breed a race of superhumans! I will not be known as the father of human genetic engineering, I will be known as the father of the next evolution of man! I will be immortalized in legend as a god!

        HA HA HA HA HA

        HE HE HE HE HE

        He

        p.s. I’ve got a lair, superheroes, come @ me. The address is 1234 NOT TELLING AVENUE, HA HA HA HA

  18. Not the Null Hypothesis says:

    He probably won’t win an Alfred Nobel medal, but he might just win a Josef Mengele award.

  19. Scott says:

    Looks like the Chinese aren’t too happy about this, either!

    “HONG KONG (AP) — China’s government ordered a halt Thursday to work by a medical team that claimed to have helped make the world’s first gene-edited babies, as a group of leading scientists declared that it’s still too soon to try to make permanent changes to DNA that can be inherited by future generations.

    Chinese Vice Minister of Science and Technology Xu Nanping told state broadcaster CCTV that his ministry is strongly opposed to the efforts that reportedly produced twin girls born earlier this month. Xu called the team’s actions illegal and unacceptable and said an investigation had been ordered, but made no mention of specific actions taken.”

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