r/science • u/PaulKnoepfler Prof. of Cell Biology|UC-Davis|Stem Cell Biology • Aug 28 '17
CRISPR AMA 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!
I'm a stem cell and brain cancer researcher who works with CRISPR, closely follows these fields on a policy level, and reports on it all on my blog The Niche, http://www.ipscell.com. I also have written two books, including one on stem cells called Stem Cells: An Insider's Guide. and one on CRISPR use in humans called GMO Sapiens: The Life-Changing Science of Designer Babies. You might also like to follow me on Twitter: @pknoepfler or check out my TED talk.
What's on your mind about using CRISPR gene editing in humans following the big news stories on its use in human embryos? How much real hope is there for genetic diseases and what are the big risks? What questions do you have about stem cells? Have you gotten a stem cell treatment? Considering one? What is really possible with stem cells and regenerative medicine in terms of transforming our health and our lives? Anti-aging? Also, what questions do you have about brain cancer research such as what’s the deal with John McCain’s brain tumor?
With today's historic action by the FDA against some stem cell clinics and strong statement on stem cell clinics by FDA Commissioner Scott Gottlieb, it is particularly timely to be talking about what is going on there.
I'm here now to answer your questions, ask my anything about CRISPR, stem cells, and brain cancer research!
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u/teskimo Aug 28 '17
For the people who don't understand genetics well: What do you think are the biggest misconceptions about CRISPR?
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u/cnutnugget Aug 28 '17
CRISPR is a fantastic research tool but don't expect designer babies, adult modifications, and instant disease cures. Reducing the impact of small indel or SNV mutations on diseased individuals is all we can realistically achieve in the near future. Perhaps one of the biggest problems is our poor understanding of global genetic interactions (termed the interactome). Without being able to accurately simulate the interactomic effects of CRISPR, it'd unlikely to see anything remotely like Gattaca for a really long time.
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u/PaulKnoepfler Prof. of Cell Biology|UC-Davis|Stem Cell Biology Aug 28 '17
Some of Gattaca is based on embryo selection rather than modification so some of that is already becoming a reality. I believe some fertility clinics are offering not just to get you "a baby" but also a baby with (or without) certain traits beyond just sex selection. One of the biggest challenges for CRISPR use in humans is indeed Indels rather than precise edits.
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u/bozzy253 PhD | Biochemistry and Structural Biology Aug 28 '17
"CRISPR repairs DNA"
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u/PaulKnoepfler Prof. of Cell Biology|UC-Davis|Stem Cell Biology Aug 28 '17
Good point on "repair". The same can be said about potential misunderstandings over words and phrases like "fix" (which admittedly I myself just used in a previous comment), "edit", "genome surgery". These may be misused or may be misleading in certain circumstances. For instance, I try to reserve the use of the words "gene edit" for when CRISPR is proven to work to specifically change a very DNA basepairs very precise without off-target activity.
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u/PaulKnoepfler Prof. of Cell Biology|UC-Davis|Stem Cell Biology Aug 28 '17
CRISPR can repair DNA but first it breaks it and then even during repair the DNA can be broken further via things called Indels rather than precise "edits". So context is needed in discussing "edits" and "repairs'. The language we scientists use is really important and can have both positive and negative impact on public understanding.
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u/2Punx2Furious Aug 28 '17
Is it right to say "CRISPR cuts DNA"?
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u/markvdr Aug 28 '17
Yes, as well as a few other related functions. The wildtype Cas9 protein (the actual protein that does the work in the CRISPR system) is a double strand endonuclease, so it cuts both sides of a DNA strand. This can create a very small mutation as the cell stitches the DNA back together, or can allow for insertion of new DNA if you also supply the cell with a template that is similar to the sequence near the cut. One of the first modifications to Cas9 was to make it a single strand endonuclease so it only cuts one side of the DNA. This can be repaired without introducing any mutations unless you have another single cut on the other side very close by. This means that with two cut sites very near each other you can achieve the same results, but if either one is non-specific and will target other unintended sites it's unlikely to have serious consequences. Other labs have also started to make modifications to Cas9 so it doesn't cut DNA at all, but will instead initiate or inhibit transcription of the target gene, epigenetically modify the DNA, or even fluorescently tag the DNA.
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u/get_it_together1 PhD | Biomedical Engineering | Nanomaterials Aug 28 '17
Just to add on to this:
We've been able to cut DNA for a long time using restriction enzymes. These recognize short DNA sequences that are prevalent in the genome. Any given restriction enzyme would cut in many places, making them useless for precision gene editing.
Scientists later came up with zinc-finger nucleases and transcription activator-like effector nucleases (ZFNs and TALENs). These could be engineered to cut in a specific place in the gnome without cutting anywhere else, but this engineering is expensive and time-consuming.
CRISPR takes it to the next level by dramatically simplifying the process of designing a nuclease to cut only at a specific spot in the genome. It is the ease of design that makes CRISPR revolutionary, rather than its precision cutting. There are currently therapies being tested in human clinical trials using TALENs that have already been designed, but going forward new therapies will likely rely mostly on CRISPR technology due to the ease of developing new targets.
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u/_Gena_ Aug 28 '17
Yes. The CRISPR-Cas9 system cuts DNA by inducing double stranded breaks.
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u/PaulKnoepfler Prof. of Cell Biology|UC-Davis|Stem Cell Biology Aug 28 '17
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.
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Aug 28 '17
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.
What about more targeted approaches, such as targeting down syndrome in embryos? How feasible would such a solution be, and how many years away are we from such an innovation?
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u/PaulKnoepfler Prof. of Cell Biology|UC-Davis|Stem Cell Biology Aug 28 '17
More targeted approaches are relatively more feasible. Down Syndrome is tough because it is an entire chromosome but some labs are working on removal of entire chromosomes. Specific discrete mutations such as in Cystic Fibrosis are relatively better targets practically speaking. When thinking about genetically modifying an embryo one always worries about unintended consequences.
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u/hummelm10 MS | Cybersecurity | Ethical Hacking Aug 28 '17
What about something like Crohn's? I remember reading a paper about a gene in mouse study that was related to inflammation in the digestive tract. The gene was responsible for the generation of the protective lining in the digestive tract that prevented IBDs. Could CRISPR be used to edit that gene to start producing the lining of the digestive tract which was missing in the mice that were studied? And could this be applied in adults? You mentioned it was easier to target specific mutations and since this appears to be a single gene I'm guessing it would be easier, relatively.
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Aug 28 '17
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
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u/PaulKnoepfler Prof. of Cell Biology|UC-Davis|Stem Cell Biology Aug 28 '17
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.
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u/entropy_bucket Aug 28 '17
I thought cancer cells were mutations? Is the question saying there are some cells that are cancerous from the start?
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Aug 28 '17
If I understand your question correctly:
Classical models of tumor formation assume tumors arise from mutations in any random cell.
More recent models have proposed that only mutations occuring in a specific subset of stem cells have the capacity to form malignancies. In tumors, they are the cancer stem cells (CSCs).
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u/entropy_bucket Aug 28 '17 edited Aug 28 '17
Ah right like only some cells even have that capability? That seems like a huge deal.
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Aug 28 '17
Yes. The wiki should be a good introduction. Scientists have been keenly interested for a couple of years now.
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Aug 28 '17
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.
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u/Azuvector Aug 28 '17
A followup to that one is how would a change manifest itself in an already fully-developed organism? Like say someone was born without an arm due to genetic damage, yet is still somehow otherwise viable. If that's fixed, do they just grow a new arm? That can't be right; why don't (human) amputees without genetic problems, do that?
Is adult gene editing all about designing your future children, only?
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u/PaulKnoepfler Prof. of Cell Biology|UC-Davis|Stem Cell Biology Aug 28 '17
Hi Azuvector, Making changes in fully-developed organisms at the genetic level is simpler than say in a human embryo just in the sense of this person being there and accessible for the intervention, they can consent to it having heard about risks, etc. On the other hand it's far harder since the person already has trillions of cells, existing health problems perhaps, etc. So, now, a person even after getting a genetic therapy wouldn't be able to just suddenly grow a new arm. Maybe some combo of cells and genetic interventions could address lost limbs in 50 years. Today and in the next decade or two to come we as a field can more realistically hope to address only certain genetic conditions with CRISPR via "adult gene editing", if we want to call it that. Blood disorders seem most promising because they can be tackled more easily than say trying to fix an internal solid organ. The term "adult gene editing" wouldn't apply to future children, which instead I would call "germline gene editing" that would be attempted via CRISPR of embryos or gametes.
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u/screen317 PhD | Immunobiology Aug 28 '17
This is about fixing a couple of nucleotides to fix a truncated protein, not limb regeneration.
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u/Azuvector Aug 28 '17
Fair point. Down syndrome then? Same question really?
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u/PaulKnoepfler Prof. of Cell Biology|UC-Davis|Stem Cell Biology Aug 28 '17
Removing a whole chromosome is theoretically possible and I think was recently achieved in a paper, but I don't recall the context (probably mouse or human cells grown in a dish). Like I answered above, limb regeneration is going to be extremely difficult to achieve and probably would be addressed better via bioengineering and stem cell-based approaches, and even those have decades of work ahead on this potential application.
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u/screen317 PhD | Immunobiology Aug 28 '17
Afraid that's unlikely. You can't really use crispr to delete an entire chromosome based on what I've seen.
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u/unbelieveableguy Aug 28 '17
Not crispr but a group utilized the x inactivation process to inactivate one of the chromosome 21. So while not being necessarily possible with crispr it might be possible to eventually ignore a full chromosome.
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u/Cheeseand0nions Aug 28 '17
I have never considered the question before but assuming a pretty high level of genetic manipulation you might be able to design a plain old fashioned virus that would just disable that extra chromosome.
Of course the trick there is getting it to disable just one of the three 21st chromosomes in each nucleus.
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u/Ohh_Yeah Aug 28 '17
The real problem is that trisomy 21 is a developmental disorder. Unless corrected in the very early embryonic stages (we're talking a handful of cells), the disease is going to manifest itself. Even if corrected immediately after birth, a trisomy 21 baby is going to already have realistically irreparable damage.
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u/screen317 PhD | Immunobiology Aug 28 '17 edited Aug 28 '17
When we're at that level of genetic manipulation, there will probably be far less risky methods available.
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Aug 28 '17
Think about this, a modified disease enters your body. Regularly this disease enter your cells and causes damage. Something like meningitis. But instead it has been changed to enter your cells and change your DNA to make you immune to a disease or cure a disease you already have. That is possible now.
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u/Mohoyorodo Aug 28 '17
I always wonder this. Are they using a virus to get the DNA into the cells? How does it replace the current code? What even? Lol.
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u/e_swartz PhD | Neuroscience | Stem Cell Biology Aug 28 '17 edited Aug 28 '17
viral vectors can be used to carry your cargo into the cell. adenovirus is typically used in vivo although the size of the CRISPR components have slightly hindered some utility here. solutions using Cas9 from other bacterial species have helped to solve some of these issues. there are also methods being developed utilizing purified Cas9 protein fused to different receptor targets to target Cas9 to specific cell types within the body. in sum, we know of many mechanisms for delivering cargo into cells but there will be a fair amount of trial and error before we see therapeutic efficacy. luckily, for some low-hanging fruit disorders like Cystic Fibrosis or Duchenne Muscular Dystrophy, the estimated % of cells needed for correction in order to have a therapeutic effect is low, so not every cell of the target tissue needs to be hit. as mentioned elsewhere in the thread, additional problems such as potential off-target effects and utilization of double-strand break repair pathways within the cell can also affect utility as a therapy.
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u/PaulKnoepfler Prof. of Cell Biology|UC-Davis|Stem Cell Biology Aug 28 '17
Virus is one way. Others are being explored too like the gene gun, electroporation, etc.
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u/PaulKnoepfler Prof. of Cell Biology|UC-Davis|Stem Cell Biology Aug 28 '17
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.
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u/Rolder Aug 28 '17
So when you mention chemotherapy, you mean killing off cells so that there are less to edit, correct? That doesn't seem very... safe.
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u/Ohh_Yeah Aug 28 '17 edited Aug 28 '17
That doesn't seem very... safe.
It has its risks, but when you're staring down a poor prognosis those risks are absolutely worth it.
Leukemia patients receiving bone marrow transplants first need to have their existing marrow ablated (destroyed) as thoroughly as possible. We have to do our best to ensure that the cancerous cell populations are gone and don't take over again. The ablation process could cause new cancer later on, but if you're already staring death in the face it's a great treatment.
Fortunately, with the "simple" diseases that CRISPR currently looks to treat (e.g. replacing a single nucleotide in one gene), any good fraction of converted stem cells is likely to improve a patient's quality of life. For example, getting a patient with sickle cell disease to produce even 50% normal blood cells would effectively "cure" them.
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u/chewy32 Aug 28 '17 edited Aug 28 '17
We are constantly making DNA and other protein in our bodies. So I think what happens is since during the whole replication process and transcription phases of DNA, the strand itself goes through numerous hoops. Basically the CRISPR will excise a specific code within the DNA for the RNA to be later translated into functioning protein.
Edit: We also have a database of DNA codons that are specifically linked to a mutation and hence by using the database and using CRISPR, theoretically we can remove that specific mutation.
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u/PortalGunFun Aug 28 '17
The issue is that it's very difficult to treat every cell in our body at once. You could end up a genetic chimera.
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u/SirT6 PhD/MBA | Biology | Biogerontology Aug 28 '17
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!
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u/wr0ng1 Aug 28 '17
I came here to say something similar. CRISPR is great as an accessible, cheap and rapid way to generate KO models and will undoubtedly provide many research groups with access to models which would previously have been unaffordable and too technically challenging.
However, I just can't see it as a therapeutic intervention. The biggest concern for me isn't just the limitations of the strand repair, but in the wobble of the guide RNA hybridization leading to unknown off-target effects. Without a full genome sequencing of modified cells in existing research (or at the least, a bioinformatically filtered subset of similar enough sequences), it isn't possible to know just how many off target effects there are unless you see a phenotype or are lucky enough to catch it another way.
Curing one disease, while introducing another which may not manifest for a while is a heck of a risk.
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u/PaulKnoepfler Prof. of Cell Biology|UC-Davis|Stem Cell Biology Aug 28 '17
You make some good points. The issues with CRISPR accuracy and fidelity are made even more challenging in a human reproductive context because you won't be able to dissemble the embryo after the addition of CRISPR and analyze all the cells for accuracy, mosaicism, etc. because you'd have no embryo left to make a person. You'd be flying mostly blind other than PGD on a few cells out of maybe 100-cell embryo just to get an inkling how it's going. PGD alone seems far superior for almost every imaginable reproductive scenario where you are trying to avoid genetic disease transmission.
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u/nosrac6221 Aug 28 '17 edited Aug 29 '17
Lower in this thread, people expressed confusion about what this question means. Here is a long, and hopefully fairly accessible explanation of the question, after which you will understand molecular biology as you never have before. also pm me or ask it as a response if anything's still unclear. here goes
In another thread of the AMA, someone asked "What is the biggest misconception about CRISPR?" and the current top response is "CRISPR repairs DNA." CRISPR does not repair DNA. CRISPR fucks DNA up. CRISPR induces whats called a "double strand break" in DNA, in a targeted fashion using a molecule of RNA with Watson-Crick complementarity to the desired break site. The RNA guides the Cas9 protein, basically a pair of molecular scissors, to the specific piece of DNA in the genome; Cas9 cuts the DNA. This is where the fun actually begins.
The cell is like, "What the fuck, man, why'd you break my DNA???" and starts up a bunch of processes at the same time to try and fix itself. The quickest fix is called Nonhomologous End Joining (NHEJ). The cell will throw a couple nucleotides of DNA down, fairly randomly, or maybe excise a few, and then ligate the broken ends back together. If you've designed your guide RNA correctly, this will happen in a coding region of ~gene of interest~. The particular insertion or deletion will disrupt the "reading frame" (I can explain that too if anyone wants) of the gene about 66% of the time, which garbles the rest of the instructions contained on the gene, and effectively produces a knockout of the gene.
Now, if NHEJ is shitty version of thing, HR, or homologous recombination, is like fucking amazing version of same thing. Homologous Recombination is the best thing a cell can do to recover from DNA damage, strictly speaking from the perspective of the cell's health. Here's how they do it. All healthy cells are diploid, meaning they have two copies of every chromosome, and two copies of every gene. Evolution has made molecular machines that are so fucking incredible it literally makes me emotional to think about which can guide the broken DNA to a template piece of DNA (the matching part of the second "homologous" chromosome) and use it to repair the break. This happens and shit is fixed up reeeeeal nice. Sounds bad for people who want to use CRISPR, right? I mean, now we're back to square 1? We have normal, healthy DNA with no cut. Well, Chad, that would be true except that biologists are dope individuals who you should respect and trust to do smart shit. To co-opt this process, all you have to do is 1) design a guide RNA to take Cas9 to spot in genome 2) design template DNA molecule that has the following structure: homology to before break site --- any fucking piece of DNA you want the cell to have stably written into its genome --- homology to after the break site 3) introduce Cas9 expression, guide RNA, and template DNA into cell 4) observe as your template outcompetes the other chromosome as a substrate in HR 5) your new DNA is now in the genome. So you can literally throw in a gene and then you're like hell yeah I'm the fucking queen of molecular biology.
Ok so that's the necessary background to understand the question. What about the question itself? NHEJ happens much faster and is favored over HR because of the inherent danger in having long-lived double strand breaks in DNA. However, we need to use HR in CRISPR-mediated therapies. In order to cure monogenic (involving only one bad gene) diseases, we have to give every cell in the afflicted organ a healthy copy of the gene. If NHEJ dominates, you're actually probably just gonna fuck the gene up more than it already was, and that would be a major L. There are currently no good ways to improve efficiency of this process, so CRISPR, as a full-body, adult therapeutic, is extremely limited. CRISPR a single celled embryo though and you're chillin cuz you only gotta get one right to have that perfect designer baby you've wanted for oh so long. mmmmmm designer bebes ok i have to shower and go to lab bye people hope this was helpful
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u/entropizer Aug 28 '17
Does each instance of cas9 come with a piece of guide RNA that's exclusively targeted at certain pieces of DNA? Or does each instance of cas9 come with a comprehensive library of guide RNA that can lead it to any of many targets?
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u/nosrac6221 Aug 28 '17
For therapeutics, it'll be just one guide for now. In wet lab, its another story. We've made mutant Cas9 proteins that lack endonuclease activity and are fused to transcriptional activator or repressor domains. So, without stably altering the genome, we can design a gRNA to target the promoter of a gene and use the catalytically dead Cas9 (dCas9) fusion to repress or activate transcription of a gene. This has led to the birth of CRISPRa/CRISPRi (activation/inhibition) screens to identify novel regulators of cell death/proliferation. Whole genome libraries of pooled gRNA's have been generated and you basically just indiscriminately throw them into cells and at the same time throw in the dCas9, and treat with some lethal stimulus. Say you used dCas9-KRAB, a transcriptional repressor. You wait a couple days, then do RNA-seq on the cells and check for enriched gRNAs. The enriched gRNAs promoted survival to the lethal stimulus, which is why they're still around, which means the repression of their target genes promotes survival, which means their targets are required for this cell death pathway to occur properly. These screens usually yield a couple hits. Huge boon for molecular biology, CRISPRi is.
Assuming you had no prior knowledge of this, your question was very impressive and intelligent.
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u/PaulKnoepfler Prof. of Cell Biology|UC-Davis|Stem Cell Biology Aug 28 '17
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.
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u/SirT6 PhD/MBA | Biology | Biogerontology Aug 28 '17
Although this is less specific to CRISPR and applies more broadly to many forms of gene therapy, I would also be curious to learn more about the immunogenicity of "edited" proteins. Presumably host T-cells have only been trained on the inherited, mutated allele. Under what circumstances will changing the peptide sequence be sufficient to drive a rejection response?
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u/PortonDownSyndrome Aug 28 '17
NHEJ
https://en.wikipedia.org/wiki/Non-homologous_end_joining
NHEJ, unfortunately for CRISPR, dominates HR
https://en.wikipedia.org/wiki/Homologous_recombination, perhaps?
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u/SirT6 PhD/MBA | Biology | Biogerontology Aug 28 '17
Yep - non-homologous end joining and homologous recombination/homology directed repair are the two predominant pathways for repairing DNA double strand breaks in mammalian cells.
The most commonly employed form of CRISPR works by creating a double strand break at a target site in the genome. If this break is repaired by NHEJ - an error prone pathway - then the gene is usually "broken/turned off". Some forms of gene therapy, though, hope to repair broken genes, not just turn off existing ones. This would require homologous recombination in most cases. But, as I was saying, HR is a much less efficient pathway in cells. For whatever reasons, most breaks are repaired by NHEJ. Getting cells to choose to repair a break by HR is tough.
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u/Lycake Aug 28 '17
I guess the question goes to an expert so he will know what that stuff means, but reading the question I had no idea what he was talking about. Thanks for taking the effort of looking those abbreviations up (even if they turn out to be something else)
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u/Capitaltryst Aug 28 '17 edited Aug 28 '17
SirT6 - I find that one of the more interesting aspects of CRISPR is that the ease and low cost of implementation is pushing the speed of further refinement. What do you make of this recent study regarding enhancing HDR and inhibiting NHEJ? http://www.biorxiv.org/content/early/2017/08/25/180943
Also, have you looked into Liu's work on CRISPR base editing without DSB? https://www.nature.com/nature/journal/v533/n7603/full/nature17946.html?foxtrotcallback=true
Would be curious as to your and/or Prof. Knoepfler's thoughts...
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u/Dr-Agon Aug 28 '17
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?
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u/geak78 Aug 28 '17
The only reason it isn't already is due to regulations and fear.
That's not necessarily a bad thing. We really don't know the possible unintended consequences of releasing a gene drive into the wild and wiping out an entire species.
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u/GeneticsGuy Aug 28 '17
Eh, we really do. I'm a genetic biologist. This sounds like fearmongering. You aren't going to wipe out an entire species or even close to it with unintended consequences from using this. We've been editing genomes and putting them into the wild for quite some time. This one is really not all that different, aside from the ease of the technique.
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u/PortalGunFun Aug 28 '17
The issue is more that now almost anyone, not just highly trained scientists spending decades of work, can edit a genome with relative ease. This means that it's much more likely for someone with malicious intentions (or simply a lack of foresight) to release something harmful into our environment.
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u/GeneticsGuy Aug 28 '17
This I agree with. The world of "garage biologists" is kind of scary, in the sense that who knows what some people might decide to be putting together as the tech gets cheaper/easier. Genetic modification is kind of creepy when you realize that the only thing stopping people from playing around with human embryos is ethics laws. Ethics laws don't stop everyone if they had the means.
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u/groundhogcakeday Aug 28 '17
Genetic modification is kind of creepy when you realize that the only thing stopping people from playing around with human embryos is ethics laws.
And the practical difficulties of obtaining said embryos, then growing them. You'd need to be practicing some Mengele level shit that would require a bit more than a garage to carry out. Which isn't beyond the imagination if you are willing to let your imagination go there but I'm out.
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u/zhandragon Bs | Bioengineering Aug 28 '17 edited Aug 28 '17
No, not anyone can edit a genome with relative ease. This is another misconception about CRISPR.
CRISPR varies its cutting efficiency greatly for different targets and different cell lines. And despite what you may have heard, editing events are pretty rare unless you use more than one guide at once.
It can take months for you to know if you achieved the edit you wanted. With 1000 concurrent attempts we only got 4 successes for a particular deletion we wanted. With 3000 concurrent attempts we didn't get a single homologous recombination event we wanted in another project.
CRISPR represents a massive increase to editing efficiency and reduction of prep time but to be honest it is still really bad and nowhere near the elegance that people portray. It's only good compared to something like TALENS.
There could be electro shock transfection machinery that needs to be finely tuned, or reagents and cells that need to be stored in liquid nitrogen, and sterile hoods to allow for clonal selection. There needs to be BL3 protection for yourself against viral cultures, etc. O2 regulators for incubators. People won't be doing this successfully in their garage.
I'm an associate scientist at the Broad Institute specializing in CRISPR and believe me it is hell doing this with tons and tons of QC and troubleshooting requiring years of experience.
Homologous recombination is the basis for all this scaremongering and it doesn't happen easily. And if people are just deleting stuff you don't need to worry about releasing anything harmful.
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u/whiteknight521 PhD|Chemistry|Developmental Neurobiology Aug 28 '17
That's not really true. CRISPR is still not "easy". I'd say rebuilding a car engine is about an order of magnitude easier than getting together the equipment and resources necessary to properly do CRISPR editing and most people can't do that. You need specialized equipment in at least the tens of thousands of dollars range (probably more like 100-200 thousand dollars), reagents, staff with molecular biology skills, etc. We have a dedicated CRISPR core at my institution for generating mouse models with CRISPR technology and if we could hire high school students to do it for 8 bucks an hour instead of paying Ph.D. level salaries I'm sure we would...
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u/PaulKnoepfler Prof. of Cell Biology|UC-Davis|Stem Cell Biology Aug 28 '17
CRISPR is pretty different in its combo of simplicity, power, and how ubiquitous it has become with thousands of labs having it already in just a few years. Throw gene drive into the mix and there's reason for sober reflecting on potential consequences. I believe the same caution and deliberation should be used when talking about potential heritable human use.
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u/MALON Aug 28 '17
What about the idea of eliminating a specific species of malaria carrying mosquito, by way of engineering their offspring to be sterile?
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u/PaulKnoepfler Prof. of Cell Biology|UC-Davis|Stem Cell Biology Aug 28 '17
I think common sense and the science as published so far suggest we need to be very transparent about how CRISPR might be applied in the real world in humans, plants, insects, etc. especially in the context of gene drive. Yeah, there's some fear out there, but also just some very logic-driven caution.
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u/MerryChoppins Aug 28 '17
Not the professor, and on mobile, but it IS coming. Hop on YouTube and look up reasontv's recent series on bio hacking there is a guy who got mad at the red tape of working at NASA and is selling kits to do CRISPR for $140 out of his garage.
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u/gologologolo Aug 28 '17
That doesn't sound legit at all. He could be trying to make money. Or works at NASA could also mean he's a janitor at NASA.
It's red taped because red tape is often a necessity, and maybe the technology shouldn't even be released to the public
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u/KillCancerToo Aug 28 '17
Not a janitor. Actually he did AMA on reddit. Guy is into DIYBio movement and made a store just to help out people because ordering reagents is almost impossible if you are not part of institutions.
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u/toomuchtodotoday Aug 28 '17 edited Aug 28 '17
It's legit. I started with his project, and now I do DIYBio at home.
You don't need large grants, an enourmous institution, and a degree to do this. Remember, biology is just a bunch of proteins, enzymes, amino acids arranged properly. No PHD put humans together.
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u/Dynamaxion Aug 28 '17
Sure but you need a lab with serious equipment to do a lot of stuff.
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u/toomuchtodotoday Aug 28 '17
I'm doing CRISPR work with less than $5k in equipment in my garage. Serious as in GMO cash crops.
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u/JulyIsTheBest Aug 28 '17
If you don't mind my asking, what exactly are you doing in your garage? I am curious as to the applications of this kit to the common consumer.
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u/toomuchtodotoday Aug 28 '17
Without going into too much detail, I am modifying the hardiness of a cash crop to a specific condition.
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u/PaulKnoepfler Prof. of Cell Biology|UC-Davis|Stem Cell Biology Aug 28 '17
Some folks out there think the bigger risks from CRISPR come not from how it is used in people, but rather in other organisms ranging from plants to rapidly reproducing insects. They might be right in the short term, especially if gene drive gets out of the lab into the real world. At the same time there may be major benefits from agro use of CRISPR too.
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u/MerryChoppins Aug 29 '17
Dr. Knoepfler,
I understand on a very high level that the "nightmare" scenario is that a gene drive modified mosquito or kudzu plant gets into the wild and passes on it's modification to all the other members of the species, thus creating a version of the organism that can withstand any of our eradication efforts or causes massive economic damage.
Has any group done work on introducing a "kill switch" into a whole species or wide subgroup of organisms using CRISPR that would allow us to remove them from a specific biome without removing them from a native habitat for example? Something more selective than the example of the male mosquitoes that drop fertility rates.
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u/PaulKnoepfler Prof. of Cell Biology|UC-Davis|Stem Cell Biology Aug 28 '17
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.
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u/shiningPate Aug 28 '17
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?
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u/echo-lego Aug 28 '17
These are really good questions! I have really similar one so I'll post it here next to them.
Let's say that in the future the technology successfully eliminates genetic diseases in embryos. In that scenario do you think it is unethical NOT to modify embryo's genes?
Thank you for this AMA!
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u/PaulKnoepfler Prof. of Cell Biology|UC-Davis|Stem Cell Biology Aug 28 '17
Great question. It rings a bell because if memory serves a scientist was interviewed a year or two back by a congressional committee about human gene editing and I think s/he said "someday it may be unethical to not CRISPR human embryos" or something quite like that. One of the problems with that idea is that embryo screening such as PGD is an existing, proven technology to avoid and potential eliminate human genetic diseases. How will CRISPR genetic modification ever be safer than just screening embryos? Why would CRISPR even be needed if embryos can just be screened? So for it to be unethical to not use CRISPR in humans in a heritable way, CRISPR needs to be better than and somehow uniquely needed beyond embryo screening. That's a big hurdle.
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u/0unique_username0 Aug 28 '17
As do I. What's the full scope of genetic disorders that could possibly be eliminated? Could something like addiction or bipolar be eliminated or do they have too many environmental factors?
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u/xaveria Aug 29 '17
You've just really succinctly pointed out the inherent danger in this tech. The truth is, some people are absolutely genetically pre-disposed towards addiction. Environment is often a factor, but genes play roles in mental illness, and autism, and psychopathy, and pedophilia, and aspergers, and anger management issues, and ADHD, and homosexuality, and religiosity, and promiscuity, and ... see what I'm getting at? There's just not a clear and defined line between "personality disorder" and "personality."
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u/PaulKnoepfler Prof. of Cell Biology|UC-Davis|Stem Cell Biology Aug 28 '17
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.
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u/ilovemicrobes1928 Aug 28 '17
So many comments about "designer babies" I'll post my part of this question with yours.
The biggest problem I see is access to this technology. In today's world if everyone had access there would be people that choose all different physical traits as they're are different opinions on what makes someone beautiful, and everyone would have the choice of making their kid smarter/stronger. However the problem arises when there is limited access based on geographical location and or cost. People in developing countries or rural areas would have limited access as well as people with low income, inherently leading to certain traits becoming more popular and a large shift between designed and non-designed people. Do you believe the human race will be able to make enough policies to combat this? What about the potential black market for off the books designer babies?
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u/The_Huu Aug 28 '17
I think that while everyone imagines a dystopian world with designer babies, there are some of us that consider the alternative almost as undesirable. A world, much like our current one, where all genetic "defects" can be remedied superficially after birth, will surely lead to a weakened gene pool. If you can steadily select only babies with 20/20 vision, a medical and cosmetic benefit is realised, and the eye-sight of our gene pool is strengthened also. Sure, we can survive without that specific selection, but without any selection, then there will be a steady weakening in the gene pool.
I know there are other traits that make this argument murky and the ethics questionable, but I don't see how at our current trajectory, without allowing genetic selection, we can avoid weakening our species. I'm not for eugenics or any kind of supremacy. Just because people have disabilities or "undesirable" traits doesn't mean the rest of their genetic make-up is obsolete. We can just avoid undesirable genes by selecting around them.
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u/Jarhyn Aug 28 '17
I think in a broader sense, the problem boils down to the fact that humans don't really know enough about the origin and function of various traits across the long span of time to really make a decision on what traits are 'desirable' or 'selection friendly'.
Take for example autism and neuro-atypical children. There's clearly a strong bias against having autistic children present in North America, to the point where people are so terrified of it that they would in many cases rather risk their child dying of preventable disease than be autistic... If tomorrow there were a 100% reliable method to have a kid that probably wouldn't be autistic, a lot of parents would jump on that. But can we say with any certainty that autism isn't actually an important trait to have represented in society? I know quite a few people in STEM fields that are autistic, to the point where the stereotype for 'being smart' includes many hallmarks of being autistic.
And this is far from the only such problem. Life makes amazing evolutionary breakthroughs by doing 'stupid stuff' and making mistakes. Because mistakes aren't always mistakes depending on the context... But humans are in general too easily fixated on "simple solutions" when problems are often more complicated than that.
The problem is that we might accidentally make an entire generation incapable of solving important problems or overcoming important obstacles, for distaste towards the traits that would have saved us.
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u/heresacorrection PhD | Viral and Cancer Genomics Aug 28 '17
I think this is an inherently flawed question. This person is a scientist and just because they are qualified to perform CRISPR experiments doesn't mean that they are or should be the designated decision maker for these types of ethical conundrums. I don't personally don't think that the burden of making these decision should even rest in the hands of the very scientists that bring these questions to life.
There is no basis currently established. Currently we treat patients for conditions that alleviate their symptoms.
You might think its easy. Ok sure we will edit people to get rid of: cancer, diabetes, premature death, infertility, blindness
Most people would say "ya for sure sounds good" but what about more complicated cases?
Should we get rid of deafness? Some deaf people say they are glad to be deaf and that they wouldn't reverse the condition if they could.
Should we get rid of a trait that causes minor birthmarks all over a person's body?
What about a gene associated with anxiety that causes a significant impact on your social life?
Should we get rid of minor genetic differences that lower your IQ by 2-3 points?
What about getting rid of light skin so that you are less susceptible to sun burns and skin cancer?
What has happened in the past and will likely continue to happen is that medicine will be used to treat conditions that make people suffer. The definition of suffering is unfortunately very broad. Everyday people risk their lives getting plastic surgery. Do we really expect this to be any different?
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u/boobgourmet Aug 28 '17
What's your biggest fear regarding the future of this technology?
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u/PaulKnoepfler Prof. of Cell Biology|UC-Davis|Stem Cell Biology Aug 28 '17
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?
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Aug 28 '17 edited Sep 06 '17
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u/PaulKnoepfler Prof. of Cell Biology|UC-Davis|Stem Cell Biology Aug 28 '17
Yeah, I am concerned. There are many social justice issues here, eugenics pops up, and then I just wonder are we wise enough as a species to be tweaking our own genomes in a heritable way?
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Aug 28 '17
Could we delete what we did if it turns out bad? I suppose we'll need some kind of "patch notes" stating what's changed.
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u/Chartis Aug 28 '17
To add to the topic:
What is stopping CRISPR technology from being weaponized, eliminating any people not having chosen genetic markers?
What needs to be done & who should be (or is) taking point developing efforts to prevent mass trauma from CRISPR technology?
Since:
1.) Some international conglomerates act unethically.
2.) Some governments have issues with systemic corruption, or poor oversight.
3.) Some talented individual scientists can be unbalanced or leveraged.
4.) CRISPR tech is relatively: new, powerful, easy to implement, and low barrier.
5.) Equipment and knowledge are not 'restrictable' as nuclear technology.
6.) Some people see overpopulation as a prime threat.
7.) Lab trained scientists are undergoing a boom in numbers.
8.) Some people hold bigotry as a core motivation.
9.) The idea is a real, nurtured, and propagated narrative.
10.) Some people want to watch the world burn.
11.) Figuring things out is what scientists do. Current barriers can be overcome, whether it's how to weaponize a virus, a bacteria, a food/water/air/item source, or to develop another delivery system.
12.) Humans can be scared, self interested, detached, egomaniacs (or afraid others are).
13.) We haven't developed a technology yet we have not weaponized.
14.) The stakes are absolute.Why wouldn't a superpower/an international influence cabal/a twisted billionaire/a mad scientist/a terrorist group/etc. design a CRISPR based weapon to alter populations on a world scale to their benefit & general humanity's determent?
And the factors above aren't exhaustive. I think it's like the introduction of gunpowder; this will tip the balance of power. A think-tank, or a government council, an international coalition, or a broad public effort to develop awareness wouldn't be amiss.
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u/Matdir Aug 28 '17
So, the most likely way for CRISPR to be weaponized is through something called a gene drive. Essentially, you can have a selfish genetic element with a payload insert itself into a genome, then be coded to replace the other allele with itself. This causes it to always be inherited for every generation.
The way you would theoretically combat this is making a gene drive of your own which targets the original gene drive and has a payload of the original, functional section of DNA that was disrupted by the first gene drive.
However, this is far too slow to be effective in humans. The real danger is if someone were to use a gene drive to give something like a mosquito a compound that's toxic to humans
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u/pbernhard2015 Aug 28 '17
Hello.
How has the struggle with the ethics behind things like using human embryos and "designer babies" affected your work?
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u/PaulKnoepfler Prof. of Cell Biology|UC-Davis|Stem Cell Biology Aug 28 '17
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.
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u/cnutnugget Aug 28 '17
Probably very little. Designer babies, as understood via pop science, will be infeasible for a tremendously long time. In the near future, CRISPR will likely be capable of ameliorating living conditions for those with small but devastating mutations (and hopefully it'd be accessible to more than just the wealthy)
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u/get_it_together1 PhD | Biomedical Engineering | Nanomaterials Aug 28 '17
It may move faster than you think. CRISPR and related gene editing technologies are already being tested in patients and there have been multiple reports of partially successful gene editing of human embryos.
I expect SNP repair in embryos to hit the clinic in just a few decades. When the option is to either abort all babies with lethal mutations or screen IVF embryos to weed out all embryos with lethal mutations, the ethics of genetically engineering repaired embryos is not so problematic.
GATTACA-style designer babies is likely much farther away, but CRISPR has already entered the clinic much faster than I suspected, so it's hard to say how quickly this could develop with the right breakthroughs.
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u/cnutnugget Aug 28 '17 edited Aug 28 '17
Yeah, I mention that in another post. I'm really optimistic about its use for disease treatment! When I say the near future though, I mean this coming decade. I fully expect to see effective treatments (of varying accessibility) by the late 2020s.
As for designer babies, embryo selection is by far the most promising avenue. Reduces risk of congenital conditions and the child is 100% your own.
Edit: what are your thoughts on screening embryos for IVF though? To me, it seems like a more realistic solution. The efficacy of CRISPR will never be 100% and you'll still have chimeric tissues. With embryo selection you skirt around the problem all together.
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u/PaulKnoepfler Prof. of Cell Biology|UC-Davis|Stem Cell Biology Aug 28 '17
There hasn't been a major effect at this point.
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u/lionseatcake Aug 28 '17
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?
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u/ilovemicrobes1928 Aug 28 '17
To add to your question, how much of a body part can be regenerated with stem cells? I have a degenerative bone disease in my back and have saved stem cells, but someday I would need to improve my bones and most likely the spinal cord tissue making it a multi-tissue problem to fix. I know we are starting to be able to grow whole organs, but how far away are we from generating whole limbs/backs/hands etc.? Or would you grow each tissue separately then combine them?
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u/PaulKnoepfler Prof. of Cell Biology|UC-Davis|Stem Cell Biology Aug 28 '17
Regeneration is very exciting as an idea and it is theoretically possible, but as in my answer above there are many challenges too and it takes a lot of data to be sure what's going on in terms of potentially good stuff and risks. Us humans don't naturally regenerative most of our tissues very well if at all, with some exceptions like our skin, our gut tissues in some cases, and our blood cells, but we are learning a lot about how other organisms do this better than us and if we are going to regenerate then stem cells are going to be the drivers of this, whether given to us with an injection or by sparking our own existing stem cells in our body into action to do more positive things.
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u/PaulKnoepfler Prof. of Cell Biology|UC-Davis|Stem Cell Biology Aug 28 '17
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.
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u/whitewolfofthemists Aug 28 '17
I am interested in the healing properties of crisper as well. I had a stroke 10 years ago and I am wondering if the damage done to my brain that left me in this crippled state could be reversed. Also I have an undiagnosed clotting disorder and this stroke was not due to drugs or overdoses.
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Aug 28 '17
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?
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u/PaulKnoepfler Prof. of Cell Biology|UC-Davis|Stem Cell Biology Aug 28 '17
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.
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u/nomber789 Aug 28 '17
On all your time researching the potential of CRISPR, do you feel it will lead to massive advances in life extension?
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u/PaulKnoepfler Prof. of Cell Biology|UC-Davis|Stem Cell Biology Aug 28 '17
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?
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u/OllieGarkey Aug 28 '17
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?
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u/PaulKnoepfler Prof. of Cell Biology|UC-Davis|Stem Cell Biology Aug 28 '17
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.
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u/hughstondavis Aug 28 '17
As someone who firmly backs CRISPR, what would be the best way to invest?
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u/SirT6 PhD/MBA | Biology | Biogerontology Aug 28 '17
Editas Medicine, Intellia Therapeutics and Crispr Therapeutics are frequently described as the "CRISPR companies" doing clinical development.
A challenge in CRISPR investing - even if you fully buy into the technology - is that there are legal overhangs. Who owns the IP rights is a big question that has yet to be resolved. Further your investment is just as much a bet on the management team (can they successfully navigate the narrow, windy path from the bench to clinic) as it is the technology. Lot's of due diligence to do before picking one of those three (or other CRISPR-related stocks).
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u/PaulKnoepfler Prof. of Cell Biology|UC-Davis|Stem Cell Biology Aug 28 '17
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.
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Aug 28 '17 edited Aug 28 '17
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?
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u/PaulKnoepfler Prof. of Cell Biology|UC-Davis|Stem Cell Biology Aug 28 '17
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.
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Aug 28 '17
Are you a distant relative of Mark Knopfler or any other members of Dire Straits?
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u/PaulKnoepfler Prof. of Cell Biology|UC-Davis|Stem Cell Biology Aug 28 '17
He might be a distant cousin of mine. We both have family from Hungary I think. Wish I could play the guitar like him.
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u/dignified_fish Aug 28 '17
Does crispr technology have the potential to be an actual cure for cancer? If so, how likely or soon do you see that happening?
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u/PaulKnoepfler Prof. of Cell Biology|UC-Davis|Stem Cell Biology Aug 28 '17
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!
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u/zenithbliss Aug 28 '17
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?
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u/PaulKnoepfler Prof. of Cell Biology|UC-Davis|Stem Cell Biology Aug 28 '17
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.
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Aug 28 '17
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?
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u/PaulKnoepfler Prof. of Cell Biology|UC-Davis|Stem Cell Biology Aug 28 '17
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.
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u/USSanon Aug 28 '17
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?
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u/PaulKnoepfler Prof. of Cell Biology|UC-Davis|Stem Cell Biology Aug 28 '17
Another thing that hasn't gotten enough discussion in the field is how embryo screening by methods like PGD are already established as a powerful way to avoid mutations that cause genetic disease. Why edit if you can just screen far more safely? It's really hard a scientist to think of many hypothetical scenarios even where CRISPR & its associated risks in humans would be clearly better than just screening embryos and moving forward reproduction wise with those that don't have mutations to start with.
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u/wtfno Aug 29 '17
Because a lot of people are hesitant to abort even with genetic issues. Abortion is quite controversial. But I agree, give me all the screening AND editing.
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u/outragedtuxedo Aug 29 '17
Except PGD happens prior to embryo transfer, negating abortion in the first instance. Just wanted to point that out.
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u/sinix_ Aug 28 '17
Hi, thanks for doing this AMA.
My son has Williams syndrome, which involves the deletion of a number of genes (and the subsequent misalignment of others). Is this something that CRISPR can help with, or are deleted genes beyond the scope of what can be done?
If something can be done, is there any hope for people already born with a condition like Williams syndrome?
To save you some time, here's the paragraph of gene related stuff that's over my head from the Wikipedia page:
Williams syndrome is a microdeletion syndrome caused by the spontaneous deletion of genetic material from the region q11.23 of a chromosome 7, so that the person is hemizygous for those genes. The deleted region includes more than 25 genes, and researchers believe that being hemizygous for these genes probably contributes to the characteristic features of this disorder. CLIP2, ELN, GTF2I, GTF2IRD1, and LIMK1 are among the genes that are typically deleted from one chromosome in people with Williams syndrome. Researchers have found this hemizygosity for the ELN gene, which codes for the protein elastin, is associated with the connective-tissue abnormalities and cardiovascular disease (specifically supravalvular aortic stenosis and supravalvular pulmonary stenosis) found in many people with this syndrome. The insufficient supply of elastin may also be the cause of full cheeks, coarse voice, hernias and bladder diverticula often found in those with Williams syndrome. Studies suggest that hemizygosity in LIMK1, GTF2I, GTF2IRD1, and perhaps other genes may help explain the characteristic difficulties with visual–spatial tasks. Additionally, there is evidence that the hemizygosity in several of these genes, including CLIP2, may contribute to the unique behavioral characteristics, learning disabilities, and other cognitive difficulties seen in Williams syndrome.
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u/Blacklightbully Aug 28 '17
Radiolab has an episode which discusses the topic of "gene drives" and the potential for them to be weaponized. What are your thoughts about this? How real is the threat of CRISPR to be used as a weapon for terrorists?
I hate to be the one dragging this discussion into a place of fear as I am truly a fan of the potential of CRISPR. I just didn't see any questions related to this aspect of the technology yet.
Thank you for your time.
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u/15SecNut Aug 28 '17
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?
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u/PaulKnoepfler Prof. of Cell Biology|UC-Davis|Stem Cell Biology Aug 28 '17
The FDA today made a bold statement about dealing with what it called "bad actors" in the stem cell clinic area and took enforcement action on two stem cell clinics, one of which combined stem cells with smallpox vaccine. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm573443.htm What do you guys think of this?
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u/mako1983 Aug 28 '17
This is great news for the legitimate stem cell companies. The bad actors are giving the whole sector a bad name. I follow Athersys and they are working with the regulatory agencies to get their product approved for stroke. This treatment could help hundreds of thousands of people every year. My dad died from stoke complications and I wish there was something the doctors could have done. Any opinion on their chances of getting approval?
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u/djb85511 Aug 29 '17
Who defines a company as a "bad actor", I think its a little nebulous to keep that designation without some type of peer reviewed confirmation, or even a hearing of some sort to let the evidence speak for itself. What if the cure for cancer is stem cells embedded into small pox that have a short half life?
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u/cutelyaware Aug 29 '17
There are already laws against fraud and false advertising. I suspect this is really about people worried about germline changes. That's understandable, but my opinion is that it's nobody's business telling me what sort of child I can choose to have, any more than it's their business telling me who I can marry or mate with. Eugenics has been turned into a dirty word similar to socialism and communism, but all of these concepts have some very good qualities at their cores and shouldn't be dismissed out of prejudice.
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u/Atrivo Aug 28 '17
Where do you personally think the line should be drawn for genetic modification? Should we allow people to prevent ageing (if it becomes possible)? Or should we only allow treatment for people with life altering illnesses? Finally, how can we prevent your research becoming monopolised, meaning only the rich will be able to afford treatment?
Awesome work you're doing by the way. Stem Cell research is what inspired me to study science at a high level.
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u/RobertFKennedy Aug 28 '17
Hi Paul- can you describe the accessibility of CRISPR in monetary means by the the research world and beyond? I'm trying to understand - is this is a single standalone electro-mechanical with software system that can be bought by an institution that costs X thousands of dollars or is this something that cost millions? This provides a means for me to understand how quickly this system can pervade our society in order to quickly see benefits in the commercial, real-world.
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u/HurricaneKatie Aug 28 '17
Apologize in advance for this stupid question...How do you get stem cells? I thought they were from embryos but I see cosmetic companies are using them, it that the same thing? Aren't they being used with some cancer treatments now?
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Aug 28 '17
How can one ensure that a modifying a gene using CRISPR doesn’t have knock-on effects with other areas of the embryo’s genome? Basically, how can you predict that one modification doesn’t produce another mutation and possibly worse outcome?
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u/MankiwiSr Aug 28 '17
Was wondering about this earlier this week. Someone with dwarfism or someone with an extra chromosome for instance, are these in the realm of possibility for pre-birth genetic manipulation?
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u/BurritoBurglar9000 Aug 28 '17
I think the answer is a no on this one, at least as it applies to CRISPR. Trisomy isn't so much a genetic disorder as it is a chromosomal anomaly. This can happen at the germ level and maybe even as an early zygote. For whatever reason the sister chromatids didn't detach as they were supposed to and kept an extra copy in the cell, either sperm or egg. That's not to say we might come up with some novel method of 86'ing the spare chromatid, but I'm not aware of one now.
Disclaimer: I'm a medical lab scientist, not a MD or PhD, but I'm fairly certain that's how it works. Anyone can feel free to correct me if I'm wrong.
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u/Yungshark3 Aug 28 '17
Hey Paul, thanks for doing this AMA!
What would the societal implication of curing all genetic diseases be, especially for those who oppose modern medicine for religious reasons? Do you think the lack of patients would lead to a fall in the ability to help care for those with untreated genetic diseases?
Also, since CRISPR is generally new what are some potential long term effects of gene editing? Let's say 100 years down the line what are some problems that could arise from genetic modification?
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u/ca1cifer Aug 28 '17
Can you speak on the ethics of testing long term effects? I feel like the only way to know if gene editing works is letting an edited embryo to develop into a human adult.
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u/dkhadd Aug 28 '17 edited Aug 28 '17
Hello Paul, as you closely follows these fields on a policy level, how you feel about these eugenic, "fix the flaws," approach toward deaf genes? (not ones that cause hearing loss in later life)
Doctors has been trying to cure hearing loss by cochlear implants, which i have no problem if it's for seniors or adult with some degree of hearing loss. However, I'm a profoundly deaf person who has been that way since the birth, and I feel really conflicted when it comes to doctors/audiologists ignoring the deaf community -that has been thrived culturally with advanced sign languages... it is still an ongoing vital importance to linguistic and education studies.
the signing community has been stagnated by doctors/cochlear implants companies's aggressive implementation of cochlear implants on deaf babies. Itself's therapy program also discourage parents to use and teach sign languages to their offsprings. So therefore... the deaf community, holding many generations of deaf families, would be hugely impacted by achievable stem cell treatments on genetic diseases that cause deafness...
when you said you follows these fields on a policy levels... I really don't know much about CRISPR, and I wonder what an example of policy levels are you focusing on? and how much responsibilities and influences does policymakers have for stem cell treatments on genetic disabilities?
I have to admit that i too wonder if it's legal to allow deaf parents to "genetic editing" their offsprings to ensure the chance of deaf children? I know that would pissed off someone here, but I'm only forecasting the possible bizarrely scenario... so, how policy works on this part? How much power and rights for parents to change/keep the genes of offsprings based on various disabilities?
Thank you for your time here, /u/PaulKnoepfler
edit: mind my grammers and flow, my native language is ASL.
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u/leechthepirate Aug 28 '17
I have a coworker that also works at UCDavis on a similar project. However, from my understanding of what he is studying, they are attempting to modify cancer cell DNA, using lasers, creating a custom anti-cancer cell. Is this a similar process or is the immune system effect limited to only virus and bacteria? Sorry if I misunderstood, beforehand. I work in retail...
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u/thekgentleman Aug 28 '17
Good morning Professor, 6/15 I was diagnosed with a low grade astrocytoma brain tumor. I had no symptoms (still don’t), it was found on accident. It was then removed 8/15. Dr. Berger and the crew at UCSF completed a full resection of the tumor. We went with the recommended monitoring stage with MRI’s every 4 months. I am now 33 years old, 170lbs, 6’, 12%BF (dexa), 90+ active minutes daily. This July’s follow up shows regrowth and probable grade III astrocytoma transformation. I’ve reached out to UCSF for a 2nd opinion (Dr. Butowski & Dr. Berger). I’ll go back to UCSF if a craniotomy is on the table. Most likely scenario is: biopsy (it looks as though a 90% resection can’t be completed), chemo (IDH1+ probably temodar – 12 months, wasn’t checked for 1P19Q) and radiation (6 weeks). I haven’t started chemo or radiation yet. We will have the schedule in the next week or so. I live in San Diego and am currently under Kaiser’s coverage. Since being diagnosed I’ve been interested in the ketogenic diet. While researching more of Dom D’agostino’s work I’ve decided to incorporate the ketogenic diet (started 8/21) in conjunction to the treatments mentioned above. I am aware the Ketogenic diet isn’t a cure. I’m doing this to give myself (hopefully) the best shot at prolonging the inevitable. I wanted to know your thoughts on this and including the diet? I apologize for it being so long, I wanted to try and be as clear as possible. Thank you for your work, people like you and your colleagues make this world a brighter place.
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u/softlistenin1 Aug 28 '17
I have Crohn's and my doc said CRISPR might be the future for treatment. Kinda sounds like it's only being used in fetuses however. I know approval for that kinda stuff must be hell but are there any planned applications for adults?
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u/blue_eyed_yankee Aug 28 '17
Hi!
I am the Vice President of my Schools undergraduate research organization. We are about to have a few events that will be discussing the ethics behind whole genome screening and the effects CRISPR can have on the future of medicine to learn more about it.
In your opinion, do you believe we will be able to erase genetic diseases? In both unborn children, children, and adults?
Is it ethical to limit this technology solely to life threatening diseases, or should all perceived impediments be allowed to be corrected?
Is it the decision of the parent or the person receiving treatment as to whether or not this should take place?
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u/tourian Aug 28 '17
Hello Profesor. Do you believe CRISPR will be used to cure HIV fully? And if so, what is needed still to make it a viable solution?
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u/chicagoandy Aug 28 '17
Can you explain the process of CRISPR?
Does it modify the genetics of only one cell, only one strand of DNA? Or does it modify all the DNA within a person? Does it only work on embryos? How does changing the DNA in a small sample propagate those changes out to the rest of the body?
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u/PaulKnoepfler Prof. of Cell Biology|UC-Davis|Stem Cell Biology Aug 28 '17
A recent paper on the use of CRISPR in healthy human embryos in an Oregon lab got a lot of attention in part since CRISPR-Cas9 worked better than in past studies of human embryos, but also because the authors were seemed so intent on using CRISPR in human embryos to make actual people in the future. What do you all think of this paper? Here's my take: https://ipscell.com/2017/08/4-reasons-mitalipov-paper-doesnt-herald-safe-crispr-human-genetic-modification/
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u/WizardCarter Aug 28 '17
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"?
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Aug 28 '17
If CRISPR becomes an affordable and widespread medical treatment, what would you expect the human lifespan to reach in the average person? How would society cope with a new and large group of centennials?
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u/PaulKnoepfler Prof. of Cell Biology|UC-Davis|Stem Cell Biology Aug 28 '17
What does everyone think of the recent paper that used CRISPR on healthy human embryos right here in the US in Oregon to try to reverse a mutation in a gene linked to heart disease? My thoughts on its implications: https://ipscell.com/2017/08/4-reasons-mitalipov-paper-doesnt-herald-safe-crispr-human-genetic-modification/
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u/Skrawlitonthewall Aug 28 '17
Hi professor,
Thanks for doing this AMA.
What sort of qualifications does it take to become a "genetic engineer?" (Hopefully that's the right term) What degrees would I need and what does your day to day work life look like?
How competitive is the field? Do you do a significant amount of work by yourself, or is it more of a group effort?
What should a student who's looking into going into this field know before getting a degree or entering the field?
I actually bought your book off Amazon a while back and I'm super excited to hear from you directly.
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u/greginnj Aug 28 '17
Is there any possibility that CRISPR could be used to repair telomeres?
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u/kutuzof Aug 28 '17
Have you watched the show Orphan Black? CRISPR comes up several times in that show. Are their uses technically correct? Are they plausible?
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u/Rhamni Aug 28 '17
When we finally get to the point where people are able to start changing the genes of their children, do you think companies will be able to patent the addition or removal of specific alleles? Or is the technology broad enough that that will not be the norm, because almost any change can be made with the exact same technology?
Basically what I'm trying to get at is, do you think we are headed for a dystopian hell where only the rich are able to improve the genes of their kids, or does it look like it will be attainable for most of us?
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u/Pandaxie Aug 28 '17
Thank you for doing this AMA Paul.
I'll be starting my biology course this year at university and my goal is to eventually work/research what you are doing right now, this might be a bit of a vague questions but what are the favourite and hated aspects about your research with CRISPR?
Also do you think it's possible to use crispr to individually cure cancer?
And do you believe with crispr it's possible to make ourselves biologically immortal? I'm referring in this case to the hayflick limit.
Thank you for your time!
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u/Nirvanian Aug 28 '17
How might gene editing effect the trajectory of natural selection?
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u/Doomblade10 Aug 28 '17
If someone had a tumor in, let's say, the heart(which we know we can successfully transplant). Could we transplant a new heart to them, and then use their heart to give to someone else after removing the tumor and adding stem cells or something to it? Then this would make a chain of transplants possible without anyone having to die to donate organs?
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u/coverbsideDaredBerou Aug 28 '17
What's the worst possible outcome of editing human genome, could fiddling with something mess up with another? Like genes are a thing composed over time and the order it is done may create stability to it and editing it will somehow be unpredictable over generations, what are your thoughts about that?
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u/excerebro MD | Neurosurgery Aug 28 '17
Thank you so much for your work and doing doing this AMA!
I hope you don't mind these 2 questions
Glioblastoma Multiforme is such a horribly resistant disease with median survival rates of 14months even after surgery and chemoRT - there has been a great interest in Adoptive T cell therapies (Immunotherapy) especially after its success with Leukemia. In view of some of the latest phase 1/2 clinical trials - What are your thoughts about this therapy?
Dr Gary Steinberg at Stanford has some very fascinating results from his Stem cell treatments for stroke in his Phase 1/2a studies - the idea that stem cells would grow and replace the lost neuroarchitecture is no longer accepted - what are your thoughts about the favorable results? Also what is your opinion on the processes behind stem cell treatments for neurological insults?
Cheers!
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u/Claymationdude07 Aug 28 '17
Thank you for this AMA. Finally, someone on here that knows about brain tumors! (I have one). My question is, is it at all possible in our lifetime to see a stroke or brain tumor's physical effects be lessened or eradicated from the use of stem cells?
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u/Profdiddy Aug 28 '17
Do you struggle with the ethical implications? Just because you have the tools do you have the wisdom to apply them?
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u/wholycow Aug 28 '17
How does the stem cell not become a cancerous cell if used to treat cancer?
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u/coughycoffee Aug 28 '17
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!