Science AMA Series: I'm Paul Knoepfler, Professor at UC Davis. I do research with CRISPR on stem cells and brain tumors. CRISPR genetic modification of human embryos is making big news. Can we erase genetic diseases? Are designer babies or eugenics coming? I’d love to talk about stem cells too. AMA!



Hey! This may be a stupid question, so I apologize if it's a bit ridiculous. I have cystic fibrosis, and I hear over and over how CF is a prime candidate for CRISPR gene modification. It's very exciting stuff.

My question is, in the event that it becomes possible to erase this disease; this is purely at the embryonic stage, correct? I'm constantly having people forward me articles explaining how CF could be erased in the not so distant future using CRISPR. And I keep explaining that, as a 27 year old man, you can't just feed me in one end and have me come out the other free of disease.

So as ridiculous as this sounds, could you just confirm that for me so I have something to point at the next time I'm told to "just CRISPR myself".

Thanks! I'm a big fan of your work!


Hi coughycoffee, You are right and it's a great question, not a stupid one. Most scientists when talking about CF or Huntington's as candidate diseases to target with CRISPR are thinking about a future where the mutations causing these diseases are genetically "fixed" in 1-cell embryos so that the resulting person has no mutation in their cells. In an already living person like yourself with trillions of cells, such a broad fix isn't possible. However, it is possible that a gene therapy to fix the mutation in a large proportion of the very specific cells most tightly associated with the disease could have some beneficial effect in a person already facing the disease. That may be a long way off and it would have to be shown in preclinical studies to have a good probability of working and being safe, but it's not impossible. One of the hardest parts would be getting the genetic change into a high enough % of diseased cells to make a significant difference clinically.

For the people who don't understand genetics well: What do you think are the biggest misconceptions about CRISPR?


Hi teskimo, Great question. There are many misconceptions. One is that we already know CRISPR can safely be used in humans and human embryos. Nope. We don't know that yet. Especially in embryos there are going to be so many risks. Another misconception is that CRISPR is always precise. It often isn't very precise. It's fantastic for us scientists doing genetic research just in the lab and more precise than past tools but people are way too gung-ho about using it soon in the clinic. Another idea floating around is that CRISPR can fix any mutation. There are probably mutations that are unfixable and others that would be very tough to fix. There's debate over whether the discussion of designer babies and CRISPR is "worrying too soon and too much". I'm not so sure. A lot depends on what one means by "designer babies". If people think it'd be easy to make smarter, better looking, etc. people via CRISPR then that is a misconception about designer babies.

Hello professor,

About 5 years ago, I wrote my master's thesis on the role of subventricular CD133+ stem cells in the formation of glioblastoma. There seemed to be some excitement in the field of oncology, that cancer stem cells might be the quintessential driving force in most, if not all, tumors, including astrocytoma.

What is the current, updated view on the role of cancer stem cells in tumorigenesls in general, and the role of CD133+ stem cells in the formation of glioblastoma in particular?

Thank you


Hi Shaokim, There's still a great deal of excitement about cancer stem cells in general, even as the debate continues about how important they are for any given specific tumor. In some cancers they may play less of a role though. In other tumors it may be cancer precursor cells that are the main drivers rather than "cancer stem cells' exactly. In gliomas like glioblastoma there is good evidence for a role for stem and/or precursor cells, but I'd say the jury is out on the exact nature of the cells of origins of these tumors and they are likely to vary depending on the subtype of glioma and in each patient. Another interesting idea floating around is that when specific oncogenic mutations occur and/or epigenetic changes happen, a precursor or more differentiated cell may "dedifferentiate" or get reprogrammed into a more stem cell-like state. There's more plasticity than we all might have imagined originally years ago. I still favor the model where the key cell of origin is a precursor/stem cell to start with.

I think I get embryos, but how could an adult edit their genetic code? I feel like a shot or an IV just wouldn't do the trick.


Altering the adult genetic code is mostly going to be much harder because we have trillions of cells. In theory if you "edit" a 1-cell embryo all cells might have the genetic change once you get to a fully formed human, but even there we have worries of chimerism. In an adult how do you CRISPR enough of the cells of interest to make a meaningful impact? Gene therapy based approaches such as via viruses in certain tissues like blood cells might be able to achieve this. This is particularly true if combined with chemoablation (chemotherapy) to reduce the population first. Good question.

Thank you for doing this AMA!

I often hear this technology is "right around the corner" but it still seems distant to the average person like me. In your opinion how long will it be until we start to see the effects of CRISPR in our daily lives?


Great question. CRISPR is genuinely revolutionary and exciting with real clinical potential, but it is also sometimes hyped by some and there are many examples of statements suggesting its clinical impact will be very soon realized. In terms of impact on daily lives specifically via medical interventions, I'd imagine that is probably a decade or so away for gene therapy approaches, maybe longer for germline use of CRISPR which I see as far riskier. So it's not tomorrow or next year, etc. in that sense. In other ways or more specific instances, impact could come sooner such as via agriculture, advancing in scientific knowledge that transform our thinking achieved because of CRISPR, and such. Negative impacts could come sooner too such as if terrorists use it as a weapon or there are accidents via powerful technologies such as CRISPR-based gene drive. I hope those are unlikely but so much is going on in so many labs around the world and it is such a widespread technology that many things are possible both positively and negatively.

Hi Paul and thank you for doing this AMA.

I'll express a somewhat controversial opinion: CRISPR's future is much more likely to be confined to the laboratory than the clinic.

When it comes to gene therapy, especially a therapy that would require substantial changes to the genome (as opposed to simple CRISPR-mediated indels) I just don't think CRISPR is efficient enough.

NHEJ, unfortunately for CRISPR, dominates HR when it comes to efficiency of Double Strand Break repair pathways. Most cells in the body are non-dividing or slowly dividing, further giving an edge to NHEJ. In my experience, getting even 1% of target cells in an easy to modify organ (like the liver or the eye) to be successfully edited via CRISPR is a difficult task. Obviously, you can try to get fancy and use alternative CRISPR approaches (say hijack micro-homology mediated repair), but I still worry this will be inefficient. I just see so much more potential in the clinical gene therapy space for adeno associated vectors (see the work being done by Spark Therapeutics as an example). That said, I love CRISPR as a research tool - excellent for screening.

I'd love to hear your opinion on the translational potential of CRISPR. Do you think the efficiency problem is surmountable? Or will CRISPR only be limited to a few indications where hitting only a small subset of cells is sufficient for clinical benefit? What about challenges related to immunogenicity of the CRISPR proteins? Thanks!


Hi SirT6, You have some good points and you obviously know this technology really well. I agree that its potential clinical impact may be oversold at times. There some very tough hurdles like efficiency, making precision changes rather than NHEJ-mediated deleterious Indels at targets, clinical delivery, and more. These are not going to be easy, quick fixes. Some tissues like the hematopoietic system are going to be far more amenable to use of CRISPR for gene therapy and I imagine those hurdles can and are being addressed with research. The respiratory system might be more approachable than others too. But for other tissues it's much harder. In any given internal organ say with 500 billion cells, how do you CRISPR enough cells to make any difference? The immunogenicity issue may be transient if Cas9 is deployed within a protein-RNA complex transiently (rather than via a virus say) in patient cells, but it should be carefully examined.

Designer babies are often cited like a mantra as inherently evil. It is clear the technology could be abused, but that is true for just about any technology. Can you outline the ethical argument against "designer babies" and delineate what distinguishes eliminating genetic diseases in an embryo from making designer babies? What is the basis for deciding between allowed and forbidden genetic traits to be modified?


Some good answers below. I'll weigh in a bit too. Issues like cost, access, social justice, transgenerational issues (like CRISPR'ing a new person now via an embryo leads to a whole new branch of a family tree with genetic modifications if the new person has children), and more. Eugenics comes up too. When writing my GMO Sapiens book on potential use of CRISPR in humans I also learned a lot more about eugenics and that the US in the not so distant past had a very active eugenics movement, thousands of people deemed "less fit" were sterilized in the US, and more bad things happen. Then of course there could be all kinds of bad health outcomes since this is such a new technology.

What's your biggest fear regarding the future of this technology?


It's a good question. I don't want to say too much about it, but weaponization is a real concern. Misguided use of CRISPR in human embryos for heritable genetic change is a serious issue with huge risks. The hype on this tech could lead to all kinds of problems too such as over-regulation of its use even just for research. Long term I do think eugenics and designer babies are a real issue that should be discussed as a risk. What do you see as the biggest risks?


How has the struggle with the ethics behind things like using human embryos and "designer babies" affected your work?


I actually wish bioethicists would be more frequently invited into the discussions over CRISPR and meetings, etc. Human embryo use and modification needs a lot more discussion.


How has the struggle with the ethics behind things like using human embryos and "designer babies" affected your work?


There hasn't been a major effect at this point.

People are already talking about stem cell therapy fixing issues like shoulder and knee injuries in athletes. Joe Rogan talks about studies being done on regenerating brain and spinal cord tissue in people with head injuries and the like.

Could you "explain like im a complete layman" a brief synopsis on the research being done to regenerate tissue, especially brain and spinal tissue? What are the current scientifically confirmed limitations of tissue regeneration, as in, how close are we to fixing spinal cord injuries with stem cells? Do you see a day in the near future where insurance companies will cover stem cell therapy and it will become an affordable cure all for many injuries or is it mostly hopeful science fiction?


Hi LionsEatCake, So much depends on the types of stem cells and the specific health condition they are intended to help with. I'm an advocate for the stem cell field and I strongly believe in their potential, but after all these years I've seen so many examples of hype too and with stem cell clinics I've seen many patients be hurt and ripped off. So we need some common sense balance in how we talk about it. I'm a "data guy" so I like to see solid data to back up claims. There is probably real potential for stem cells to help ortho conditions, but it has to be proven safe and effective by science so I see some of what's out there already as jumping the gun. For neuro conditions, there is real hope but again some folks are getting way ahead of the science with their commercialization. You can't just squirt in a hodgepodge of stem cells into someones bloodstream, brain, or spinal cord and expect good things to happen. On the other hand, there are solid, legit clinical trials ongoing that are reason for real hope like a company Asterias using a stem cell product for spinal cord injury. It's early days in that trial but it's hopeful. Brain and CNS conditions more generally present challenges such as delivery of the stem cells, the mostly non-proliferative nature of the nervous system, it's tightly interconnected "wiring" and the spinal cord architecture makes it much harder to fix. My hope is that within a decade or two we'll have more proven therapies that are safe and effective for some of the most important health problems, but it's not going to be tomorrow or next year. Unfortunately these things take so much time and I know there are many people in need of help now.

First of all, thank you for being here! Here is my wuestion:

Do you think that gene editing is going to have an effect on human evolution on a greater scale? Right now we are looking at decisions like eye colour, removing congenital diseases etc, but what about simply using gene therapy to make us super strong, or heal faster, etc? What moral complications do you foresee arising from this?


It is quite possible over decades that gene editing will affect our evolution. It may be perceived by governments, for instance, to reduce health care costs leading to tax incentives to have a CRISPR'd baby. It could become fashionable to use CRISPR. Seismic changes in societal trends have to start somewhere and we can't always anticipate where they'll lead. I think that may be true with CRISPR if used in a heritable way in people.

One of the worries I hear is that this might set off a genetic arms race. Bill McKibben's "Enough" has a pretty good rundown of the concern. Essentially, we'll have a wave of babies that are smarter and stronger than everyone who isn't a designer baby. Parents who want to have "Natural" children will be disadvantaging their own children in favor of children who receive genetic enhancements. As the science improves, we'll see smarter and stronger people over time, assuming there's no maximum limit for human strength, intelligence, and stamina.

Scientists being who they are, and industry being what it is, those limits are likely to be pushed.

I don't necessarily agree with all of that, but how do we address and mitigate concerns like these?

Are we about to end up in a genetic arms race?

If not, how do we explain that to people?

If yes, how do we prevent social problems caused by it?


Great points and questions. I don't have all the answers, but see my TED talk (linked to at the top of this AMA) for some discussion of where we could find ourselves in 10-20 years.

On all your time researching the potential of CRISPR, do you feel it will lead to massive advances in life extension?


Good question, but I'm skeptical about life extension on a grand scale via CRISPR any time soon. It's hypothetically possible but then we have to consider quality of life, unintended consequences to individuals, and more. But, yeah, who doesn't want to live longer and healthier?

As someone who firmly backs CRISPR, what would be the best way to invest?


Someone already mentioned some companies in the answer thread below. Investment wise it's one of those uber risky areas that one is more likely to lose than make money. But you never know. One of the problems with CRISPR stocks is that clinical uses may mostly be far down the road, but gene therapy trials are ongoing, agricultural uses are exploding (at a recent CRISPR meeting at Berkeley the most common background of attendees was in agro), and eventually new applications and therapies will develop. How much risk are you willing to take on financially? You could also donate to a research foundation if you tend toward the philanthropic side too to invest in the future of the technology.

How far are we to start using crispr as a therapy? Is it possible to eliminate a proto-oncogene in a cluster of tumor cells from an adult individual using this technology?


It'd be super tough to use CRISPR effectively on an oncogene in cancer in vivo and hope for a big impact. Usually there are many mutations and it'd be near impossible to get it into most cells. Those cells that escaped would continue to grow.

Does crispr technology have the potential to be an actual cure for cancer? If so, how likely or soon do you see that happening?


As to a "cure" for cancer via CRISPR, I'm unfortunately skeptical of that being a direct way to go. Cancer is such a tough opponent and usually tumors have tons of different mutations. Where do you even start? Plus cancer cells love to evolve and fight back against treatments so you'd have to get the CRISPR into and working in 100% of the cancer cells. Tough hurdles. But the good news is that CRISPR research like we are doing in my lab on cancer has real potential to lead to new discoveries that could then be leveraged into new, better cancer drugs. That's our hope!

Are you a distant relative of Mark Knopfler or any other members of Dire Straits?


He might be a distant cousin of mine. We both have family from Hungary I think. Wish I could play the guitar like him.

My Mum passed away from a grade iv glioblastoma three weeks ago. I'd heard there was a possible gene therapy being offered privately in the uk but I didn't find much information about the benefits before Mum going downhill halted my research.

Do you envision a time when gene therapy shows marked results in treatment prognosis?


Gene therapy for glioblastoma, which is a particularly nasty tumor, is a real challenge. Tumors are very adaptable to whatever is thrown at them and since tumors start out being very diverse at the cellular level (every cell in a cancer is somewhat different), it'd be hard to use gene therapy as a cure for cancer. It'd be hard to get the gene therapy into all the cancer cells too and the ones we missed would thrive. But there may be ways gene therapy could be helpful for patients with cancer and we are using CRISPR in my lab to better understand glioblastoma. Many labs are using CRISPR to get to know how cancer works and what its vulnerabilities might be. That's another way CRISPR is going to help people.

But do you row for UC Davis


Nope...would be fun though!

Thank you for doing this AMA. I have several people in my family with a balanced translocation. They have a high risk of having a baby with an unbalanced translocation / trisomy / monosomy.

Is CRISPR something that could be used in the future to "repair" any future embryos? What about repairing eggs or sperm somehow?


Chromosome level interventions with CRISPR are possible in the lab and there have been a few papers on that. It can work in cells in the lab, but in human embryos it'd be highly risky. Is it possible to screen for the translocations that exist in your family? Embryo screening by PGD seems to me to be a far better way to go to avoid mutations as opposed to trying to "fix" them at this point. For many mutations, a few cells can be plucked off of say 8 embryos made by IVF in a dish, analyzed for the presence of mutations, and then only non-mutant embryos can be implanted into the mother-to-be. I worry that "repair" of embryo genomes could cause more problems.

As a middle school teacher who teaches the basics of genetics, I'm curious as to what new advances there are. I research a bit, but want to keep it understandable for students, but also keep interest high. Any suggestions?


My book GMO sapiens might be a good starting point on both potential risks and benefits of CRISPR use in humans. I wrote it for a general audience. Has a lot of cool diagrams and pictures of the people involved.

I'm an aspiring biologist who is interested in your line of work. I know it doesn't pertain specifically to the AMA, but what is the best kind of biology degree to obtain for this field? Or at least what focuses should there be?


You could get a Ph.D. in genetics or cell biology or related fields. Science can be a tough field, but if you are really passionate about it and work hard, you'll probably succeed and you can have a real impact on the world.

Given our lack of understanding of what genes do what in the human genome, how far are we from stopping all genetic diseases and having "designer babies"?


Very far. Decades at least. There could be many unintended consequences too. The genome is like a universe unto itself. Genes can perform somewhat different functions in different people. The on-off switch for one gene can be inside another genes. Then there are the societal issues and concerns.

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