Editing Human Embryos: So This Happened

Earlier this week, Chinese researchers reported that they edited the genes of human embryos using a new technique called CRISPR. While these embryos will not be growing up into genetically modified people, I suspect this week will go down as a pivotal moment in the history of medicine. David Cyranoski and Sara Reardon broke the news today at Nature News. Here I’ve put together a quick guide to the history behind this research, what the Chinese scientists did, and what it may signify.

There are thousands of genetic disorders that can occur if a mutation happens to strike an important piece of DNA. Hemophilia, sickle cell anemia, cystic fibrosis– the list goes on and on. As I wrote in the Atlantic in 2013, a particularly cruel genetic disorder, fibrodysplasia ossificans progressiva causes people to grow a second skeleton. It’s caused by a mutation that changes a single “letter” of a single gene, called ACVR1. The protein encoded by the gene doesn’t work properly, triggering a wave of changes in people’s bodies, with the result that when they heal from a bruise, they replace entire chunks of muscle with new bone.

In some cases, people can offset many of the symptoms of genetic disorders with simple changes, like watching what they eat. In other cases, like hemophilia, they have to take regular doses of drugs to remain healthy. In other cases, like fibrodysplasia ossificans progressiva, there’s no effective treatment yet.

For decades, scientists have tried to develop a new way to treat genetic disorders like these: to heal the patient, heal the gene.

This approach came to be known as gene therapy. As I wrote in Wired, gene therapy soared to heady heights of hype in the 1990s. Researchers developed viruses that they could load with working versions of people’s defective genes. They injected the viruses into their subjects, and the viruses delivered the genes to some cells–enough cells, in theory, to start doing the work required to make the people healthy again.

Gene therapy research crashed around 2000 when one volunteer died during a study due to an overwhelming immune response to the viruses he received. Since then, gene therapy researchers have found safer, more efficient viruses, and now gene therapy is starting to emerge in the clinic.

But the revival of gene therapy doesn’t necessarily mean that viruses are the best of all possible tools to fix broken genes. What if, for example, you could just remove the mutant DNA in a gene and replace it with the right sequence?

For a long time, that question was best left to late nights at bars and episodes of Star Trek. Nobody knew how to manipulate DNA with that kind of precision. But in just the past couple years, scientists have created exactly this kind of gene-editing tool, which is known as CRISPR.

As I wrote recently in Quanta, CRISPR didn’t spring fully formed from someone’s mind. It’s actually a collection of molecules that bacteria use to fight viruses. They can create molecules that can latch precisely to certain stretches of DNA and cut them apart. Shortly after scientists figured out how bacteria use CRISPR, they began to wonder if they could use it, too.

It soon became clear they could. They could easily synthesize “probe” molecules that would grab onto a specific stretch of DNA in just about any cell. Enzymes could then chop out that stretch. If the scientists supplied a different version of that stretch of DNA, the cell would incorporate it where the original stretch once was.

Delivering CRISPR into the bodies of people with genetic disorders could conceivably repair their genes. Of course, the success of this kind of treatment would depend on how efficiently the molecules could get inside the cells that needed repairing, and how accurately they cut the DNA. Still, some early experiments on animals suggest that the approach may someday work on people.

But what if you didn’t have to wait until so late in the game to repair a broken gene? If a fertilized egg ended up with a defective gene, you could conceivably use CRISPR to fix the mistake. That single cell could then give rise to an entire healthy human with trillions of cells that all had the correct version of the gene.

Last month, a team of leading scientists–including pioneers in both gene therapy and CRISPR–declared that this would be a bad idea. “At present, the potential safety and efficacy issues arising from the use of this technology must be thoroughly investigated and understood before any attempts at human engineering are sanctioned, if ever, for clinical testing,” they declared in a piece they published in Science.

But meanwhile, a team of researchers led by Junju Huang at Sun Yat-sen University were testing out CRISPR on human embryos. Huang told Nature that both Nature and Science rejected the paper based on ethical objections.  So they ended up publishing the results in the journal Protein & Cell (open access, by the way).

The scientists tested out CRISPR as a form of embryonic gene therapy. Imagine an embryo had a mutation in a gene called beta-globin involved in making hemoglobin. It would develop into a person with the blood disorder beta-thalassemia.  Would it be possible to cure the embryo by rewriting the gene?

The researchers set out to do the study on human embryos–but they didn’t want to use embryos that might ever actually be able to develop into a fully-formed human being. When fertility doctors fertilize eggs with in vitro fertilization, they sometimes end up with two sperm delivering their DNA into a single egg. These “tripronuclear zygotes” can start dividing as normal embryos do, but their abnormal collection of genes causes them to stop developing when they’re still just tiny clumps of cells. The researchers argue that this failure makes tripronuclear embryos “an ideal model system” for studying CRISPR therapy. (Bioethicists, start your engines!)

All told, the researchers injected 86 embryos, 71 of which survived long enough for them to study. CRISPR only managed to cut DNA in a fraction of the embryos, and in only a fraction of those embryos did cells manage to take up the new version of the target gene (called beta-globin).

Two big problems stick out from the results.

One is the fact that CRISPR sometimes missed its target and inserted DNA in the wrong places. Such a misfire wouldn’t just fail to fix a disease like beta-thalassemia. It could create a disease of its own.

The other big problem is that the embryos that did get edited correctly were actually a mix of edited cells and unedited cells–what’s known as a mosaic. Mosaics can give doctors a lot of headaches, as I’ve written in the New York Times. If fertility doctors used CRISPR to create healthy, hemophilia-free embryos, they’d need to make sure the embryos were repaired by picking off a cell and examining it up close. A cell from a mosaic embryo could give doctors the wrong picture of the embryo as a whole.

The authors conclude their paper by warning that these failures need to be “investigated thoroughly before any clinical application.”

Just because this experiment came out poorly doesn’t mean that future experiments will. There’s nothing in this study that’s a conceptual deal-breaker for CRISPR. It’s worth recalling the early days of cloning research. Cloned embryos often failed to develop, and animals that were born successfully often ended up with serious health problems. Cloning is much better now, and it’s even getting to be a business in the world of livestock and pets. We still don’t clone people, though–not because we can’t, but because we choose not to. We may need to make the same choice about editing embryos before too long.

Postscript 4/23 9:30 am: While I was hammering out this explainer yesterday, I got in touch with Jennifer Doudna, a CRISPR pioneer at Berkeley I wrote about in my Quanta piece, who co-authored the call for putting the brakes on human germline CRISPR research. She got back to me this morning with this to say:

Although it has attracted a lot of attention, the study simply underscores the point that the technology is not ready for clinical application in the human germline. And that application of the technology needs to be on hold pending a broader societal discussion of the scientific and ethical issues surrounding such use.

[Update: fixed the details on the beta-globin gene]

 

24 thoughts on “Editing Human Embryos: So This Happened

  1. As a CF patient who’s seen gene therapy treatments crash in popularity following that unexpected death, I’m actually happy they’re getting back on the horse. I think that gene therapy is a promising field, and it might not be able to help CF patients today, but future kids with CF will surely benefit.

  2. They could have just avoided the ethical issues by using the embryo of some other species.

    [CZ: That’s already a busy area of research (see this paper, for example). But humans are not mice.]

  3. They have done this in other animals, like mice. A lot of labs are now using CRISPR/Cas to develop animal models of disease. It fails a lot of the time, but if you do proper quality control and screening it works quite well.

    [CZ: The quality control for humans would have to be far, far higher than in research animals.]

  4. This is a critically important development. Thank you Carl, for highlighting it. One of my greatest worries is what advanced medical treatment is doing to the human gene pool. Not that I want others to experience the heartbreak of seeing a child of theirs suffer and die prematurely because medical treatment is withheld, you understand, but the survival of that child to adulthood can spread the genetic defect to still others. In prior generations, such individuals would have died, their parents would be in sorrow, but the familial line would not have propagated. With experiments such as you report, I hope that we are on the threshold of being able to have both fantastic modern medicine and the ability to keep from — pardon the expression — “contaminating” the gene pool. Genetic diseases (if “disease” is really the correct term) such as Duchane Muscular Dystrophy, Autism (YES! There may be an environmental element, but I see it as genetically linked. Prove me wrong — please!) and Niemann-Pick Type C, for example — and I’m just barely scratching the tip of the iceberg — are devastating and cost a fortune to deal with. If these can be cured by genetic engineering in vivo or in utero, for example, GO FOR IT. And award the discovers the Nobel prize.

  5. Fascinating and very informative. Thank you. I look forward to more breakthroughs in the future.
    Tiny typo:
    “These “tripronuclear zygotes” can start dividing as normal embryos do, but their abnormal collection of genes causes them [to*] stop developing when they’re still just tiny clumps of cells.”

    [CZ: Thanks! Fixed.]

  6. A fascinating account. The parallels to the early days of genetically modifying bacterial plasmids are pretty obvious. Then, as now, there are many calls to slow down and to think of the ethics. I happen to agree with that call for caution, but I expect that people will (cautiously) move forward anyway.

  7. Interesting article here, and thanks for the direct link to the original paper. As a science fiction writer, I’ve been interested in the possibilities of intentional human modification for a long time and included consideration of the personal, social, political, and economic effects in some of my books. Now that this cat is clawing its way out of the bag, it will be interesting to see if any of my projections are in the ballpark or not. Early days…needs more research, sure. But there is already a demand for such a technique, as well as opposition to it. The ethical issues are multiple, complex, and cultural diversity means a diverse interpretation.

  8. This is an interesting article. However, I hope that editing embryos doesn’t become the norm. I’m an identical triplet adolescent, and my embryo wasn’t edited or IVF’d. Just think of the consequences of altering embryos! There are too many genetic and ethical issues with this practice.

  9. As we all know throughout history, major technology breakthrough must ahead the knowledge structure of human society. The potential overweight of monumental impact on all aspect of routine life could cause a lot of discussion. Well, you know what’s interest? I am now right in China and non of the Chinese media have ever make a sound of this. The truth is that people always don’t have the access or possibility to obtain the huge information needed to process this kind of issue. Routine life do not come with up of the depth of knowledge or moral issue. And those who change the world will never be those who set back behind a reporter’s dest.

  10. Carl, this is a really great review of the science and the many pitfalls that await any technology as it tentatively moves from bench to clinic. As an advocate for publishing negative results, I was surprised by the ethical concerns offered by some journals as a reason not to publish, yet you have to wonder if their decision could have had even more terrifying ethical consequences. I’m glad this failure has been shared – and that a healthy debate on next steps will follow.

  11. If the first generation of such experiments succeds as planned and predicted, but how can the progeny of this experimental being be guarenteed. Perhaps the use may be limited to the growth of organs in lab. Else, the technique can be misused like nuclear technology.

  12. The biggest issue is not whether the science is advanced enough for use, it’s whether human consciousness is advanced enough. Really, would you trust other human beings with the future of humanity? If genetically modified seeds threaten the survival of non-modified species, imagine what modifying human genes could mean. As this example demonstrates, the opinions and declarations of bodies of scientists can’t control human behavior. If the science is developed, somebody somewhere will use it for their own purposes, for control and power.

  13. “For decades, scientists have tried to develop a new way to treat genetic disorders like these: to heal the patient, heal the gene.” Yup, you will hear more and more about Genes, Nano’s, and chips carrying your DNA. Sounds like lions, tigers and bears, oh my! No, it is the dawn of where we are. Welcome to the DNA revolution. I sure do wish I was in China this week @ the WDD. http://www.dnaday.com

  14. We should certainly make sure we can do this safety and consistently before we start actually using it on humans. However, I really disagree with the idea that we should put this research on hold “because of ethical issues”. This is a technology that’s going to improve the health and well-being of the next generation; delaying or preventing that from happening out of some vague fear about how it could be used is itself incredibly unethical.

    We should move ahead with research into this technology as quickly as we can, and as soon as we can do it safely, we should allow and encourage widespread use of the technology.

  15. We’ve always been able to clone humans, its called twins. If we keep screwing with genetics, it surely will come back an bite us in the butt.

  16. Jay L Stern, the thought behind this research is that people with genetic disorders would not spread them to others in the gene pool because they genetic disorder would be fixed. It’s like changing a flat tire with a new tire on your car – if tires were genes.

  17. Wait, stop, slow down, let’s look at this carefully for a long time.
    Wait let’s experiment only on animals, carefully, slowly.
    BS and blather, there is a big generation of us who the statistical tables, are dismally predicting death. So how about the ethics of survival, this is a generational demographically sinking ship, we need quick progress.
    We the Flower Power kid’s of the 60’s Need this potential Life Extension technology now. Should we band together once more, this time around selfishly for ourselves in a new revolution and promote, finance, and clear the Political. Social, road of obstructions. The cautions are appropriate and the ‘scientific and ethical leaders’ are right and yet totally WRONG, anyone over 50 should be hurrying toward this future, our new Omega point, the Singularity. So we should leave the babies alone for a while, experiment on us the old, the needy ones.
    The term limit defense of age, to retain the knowledge, we possess, and perhaps of necessity to ship us off planet as fast as you can.

  18. As a 35 year old, who survived a car accident where I lost half my blood supply through my face and it activated recessive gene’s that had skipped generations in my family ( Raynauds Disease, Hemiplegic Migraines that have now turned into Complicated Migraine Syndrome, Gastroparesis, and most recently Fat Necrosis in area’s that shouldn’t be prematurely dying), this concept is a fascinating idea, however, I believe that in order for it to work they need study the primary application and then use different binders that are genetically modified to keep the original application from slipping. The problem is finding such a binder that wouldn’t effectively work. Think of medications……an extra added component or multiple component is added to the medications to make them effective. Same concept! Only issue I see is using this technology on brain disorder’s……until this ever becomes reliable, the ethical issue’s remain on catastrophic consequences that are unforseeable. Yes, we had the polio vaccine work only because it’s maker went against everyone and tried it on himself first…..but is their someone in this real who will take that tremendous risk to do the same when ethics prevent it from going past an embryonic state??? I can only hope this evolves into a medical breakthrough before my time end’s. If it could not save my life it would be able to save countless other’s. I agree this discovery needs more research than what’s being given to other thing’s society is being exposed to with detrimental cost to our live’s. Because in the end, what is worth more…..life or death?

    1. I agree with you. Unless there are more proven safety measures to make sure that none of this is botched, the practice of editing embryos can’t be allowed.

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