Nessa Carey [00:00:01] The potential of thetechnology is so good that it changes the ethical question from Do we have theright to do it too? Do we have the right to withhold it? The really scary thingabout CRISPR in that environment, in the sense of how democratizing it is, isif someone's thinking, I don't want to give myself big muscles, I want to makea really powerful bacterium that really rare these days, and gene editing willmake that so much easier just because gene editing is so good at changinggenomes.

Steven Parton [00:00:44] Helloeveryone. My name is Steven Parton and you are listening to the feedback loopby Singularity. This week my guest is British biologist Nessa Carey, who hasresearched and written extensively about the latest trends in molecular biologyand biotechnology for several decades. This includes her 2011 book, TheEpigenetics Revolution and her more recent 2019 book, Hacking The Code of Life.In this episode, we lay some biological groundwork by first discussing theoften misunderstood field of epigenetics, a process wherein our DNA changes howit's expressed constantly throughout our lifetimes, potentially to the pointwhere we might even pass on genetic changes to our offspring. From there, wedive deeply into gene editing and CRISPR discussing the current state of theart, what's possible and what isn't, and how to use gene editing to healdisease and address ecological issues. We also discuss the existential threatsthat gene editing poses for both our species and our planet. How to thereforeregulate this technology and much more. NASA's background in scientificcommunication truly shines in this conversation as she provides some of themost succinct and easy to understand descriptions of these topics that I'veever come across. So if you're looking to get a good understanding of thesetopics, this is a great place to start. So without further ado, please welcometo the feedback loop, Nessa Carey. Well, if we can, I would like to start with epigenetics.Epigenetics with you, because I feel like it lays the groundwork for kind of anatural conversation around how genes can edit themselves even without ourinterference. However, epigenetics to me feels like a concept, like quantumphysics that gets talked about in ways that undermine the science constantlyand is very confusing and everyone has misconceptions. So could you just giveus an overview and take away some of the things that epigenetics is it and tellus what it is?

Nessa Carey [00:03:03] Okay. So epigenetics,one of the things that's really difficult with epigenetics is if you could youcould ask six different epigenetic scientists to define epigenetics and youwill get at least seven different descriptions. So it's really not helped bythe terminology. And I think of epigenetics as operating at two levels, Ithink. So one is the phenomena that you can see. So every time you see twothings which have exactly the same DNA code, but those two things arephenotypic very different from each other. And so they differ in appearance orbehavior or anything like that. That's an example of an epigenetic phenomenon,which is a phenomenon where there is something else as well as genetics playinga role, because the phrase epi just means at on in addition to it's just areally old Greek word. So you have epigenetic phenomena and those have beenknown about for decades. There's been lots of situations where you can see thattwo things must have the same DNA, and yet they're different. And a great examplewould be if you look at your cells, the cells in the retina of your eye, forexample, have exactly the same cells sorry, exactly the same DNA sequence asthe cells lining the tubules in your kidneys. And yet they're completelydifferent cell types. So something is happening in addition to the DNA. So forthe decades, all we really had was this phenomenological description. Now whatwe have is a molecular explanation to some extent of how those things happened.Now you can end up using the same DNA script to create different outcomes. Soif you look at the molecular definition of epigenetics, and that's where itgets into terribly angels dancing on the head of a pin type debates betweenscientists. There is no one perfect description of what type of greens. But theway I would describe it is that you have a set of chemical modifications, theDNA and the proteins that are associated with DNA, and those modifications canchange gene expression. They can be passed on when a soldier fights, but theydon't change the sequence of the DNA. So I always think of them as being likePost-it notes on a script.

Steven Parton [00:05:33] Is it fairto say that that script has parts of it that can be turned on and turned off?And that's what it's really what we call the epigenetic shift?

Nessa Carey [00:05:43] Exactly. So whathappens during development, for example, when you start with one cell phonefrom the egg and sperm fuzing and then that divides into four days and 16, youkeep going to these trillions of cells. What happens is, I suppose, as theembryo becomes increasingly differentiated, so instead of being one mass ofcells that are the same, you start seeing the spinal cord and the placenta.What you see is that epigenetic modifications are being established and thenturning certain genes on, keeping certain genes repressed. And those are reallyimportant for how we maintain different cell types. So remember, I was sayingthat cells in your retina look completely different from the cells in yourkidney. So explicit modifications can be ways of switching genes offpermanently so that I can switch. But there are certain epigeneticmodifications which can act like a volume switch. So you can have genes whichhave the potential to be old and they might be old just a little bit. Well,they might come on really quietly in response to an environmental stimulus. Andagain, that is really influenced by which epigenetic modifications get put onthat DNA and its associated proteins or which ones get taken off. So it's bothan on off switch and a volume switch, and it doesn't act in isolation. There'sall sorts of other cellular systems as well. But it's a really importantsystem.

Steven Parton [00:07:18] And as youalluded to, a lot of these shifts occur in response to environmental stimuli.

Nessa Carey [00:07:23] Yes.

Steven Parton [00:07:24] Is thissomething that is taking place constantly where pretty much everything we'redoing at a given moment?

Nessa Carey [00:07:30] Absolutely. Yeah,absolutely. Because in some ways, you can think of epigenetics as being thelink between nature and nurture. It's how the environment and your genescommunicate. And we're changing all the time because our environment ischanging every second. So sometimes I see people writing complete rubbish, realpseudo science, saying that this compound or this food or this actually getsterribly good for you or terribly bad for you because it changes yourepigenetics. Everything changes your epigenetics. It's an incredibly dynamicsystem. The bits of epigenetics that are involved with the sort of volumecontrol of your genes, they are much more dynamic. They are the ones thatchange much more easily in response to the environmental changes that getestablished in early embryogenesis that result in you having different cells inyour eyes from your kidneys. Those are incredibly stable and they only thoseepigenetic changes probably only go wrong during cancer.

Steven Parton [00:08:30] Yeah.Speaking of that stability, what what causes a shift then to be either atransient one that may be just as as fleetingly active versus one that becomesa long term shift that almost permanently, indefinitely changes your DNAexpression.

Nessa Carey [00:08:47] It's to do with thekind of chemical modification that's added to our genome. So there's a veryparticular type that is added to DNA directly, and that's called methylation.It's just one carbon atom, the three hydrogen atoms. And if you get a lot ofthat methylation on a gene, it tends to switch it off. And that modification isincredibly stable. It doesn't fall loads and it gets reproduced every time acell divides. So those are really stable. But DNA is not a naked molecule in acell. We think of it as we picture it as the double helix. And you always justsee that sort of trademark twisty train tracks. But actually, DNA is wrapped uparound proteins called histones, and you get lots of modifications to thosehistone proteins. And those are the ones that on the whole act as the and sorryact as the volume switch and they are chemically less stable and they're alsoenzymatic less stable. So it's much easier for the chain, the cell to changethose. And so those tend to be the ones that respond to the environment morevigorously. It's not an absolute, but that's the kind of basic situation.

Steven Parton [00:09:58] And isthere a. Well, I would say one of the things that seems to be the mostcomplicated or maybe pseudoscientific aspects of this is what happens in termsof reproduction. So is that what causes something to be passed on versus not?Are the epigenetic shifts that occurs in one's life basically always passed onor not?

Nessa Carey [00:10:21] Right. So the majorityso if you're a guy, you probably have sperm and those have particularepigenetic modifications on them, partly because that's they end up beingspent. If you're a woman and you're producing eggs, those have differentmodifications on them. When the egg and sperm fuze, they have to stop being anegg in the sperm and become something else. And so most of the epigeneticmodifications get wiped away and then new ones get established. And so and alsothe cells that produce sperm and the cells that produce what we call veryprotective. So they tend not to they tend to try and protect the eggs and thesperm from what's happening environmentally. So the majority of epigeneticmodifications are lost during reproduction, certainly in mammals. But there aresome that are retained and it's possible that that's where you can get sometransmission of epigenetic information from parent to offspring. However, thereis an awful lot of nonsense talks about this and ridiculous claims made me. Iabsolutely believe that epigenetic information can be passed on and thatinformation may have changed in response to the environment. And I believe thatbecause of all sorts of funky and mad experiments in things like water fleasand in mice and in a tiny microscopic worm and in solid tones. So you see thething. But that isn't the same as being able to prove it ever happens inhumans. Hmm. And the reason is because when we demonstrate that it happens inmice, I use the oil. We demonstrate to this other people demonstrations. Whatyou have is you take three genetically inbred mice and you keep them underreally standardized conditions, and then you give them this huge stimulus andthen you see if that's had consequences for the next generation. And if so, ifthey were mediated through epigenetics, that's the complete opposite to whatyou see in humans. So humans, we're not genetically identical. We haveincredibly difficult different environments from each other. Our environmentsare really, really noisy. So you can't on the whole, just get one massivestimulus. So it is possible that this happens in humans. We will almost neverbe able to detect it, not in an individual. We can detect it potentially at apopulation level. But you can't say it's going to inherit an epigenetic orgoing just transmitted epigenetic coumarin, GEMA, isn't it? It doesn't worklike that. It's also not clear. It seems very unlikely that what happens is anepigenetic modification in the brain. Those of human gets passed onto theirchild directly and into the epigenetics of their brain. It's much more likelythat what's actually happening is that we're not passing on the direct DNA orhistone protein modification that what seems to be happening is it's all to dowith small little bits of RNA that also get carried over in the egg and thesperm, and they potentially set up signaling cascade that result in the sameepigenetics development. Basically, if someone says to you, Oh, we've seentransgenerational trauma through the three families of drug addicts, and that'sall epigenetic, it's like, yeah, it probably isn't and you'll never prove thatit was. So it's an area that requires caution. It's created fantastically forthe experiments. But in humans, most of what's important is happening to youduring your lifetime. I wouldn't worry too much about the examples I alwaysgive is you absolutely, as a human cannot say. The reason why I am £140overweight is because my granddad 83 donuts. That's not how it works. Itabsolutely doesn't operate like a monkey. Get out of jail free card. What we'redoing during our lifetimes is important, but not sure.

Steven Parton [00:14:32] Well, thisis a bit of a big sidestep, but one that I think is an important one as we kindof look now into the technology side of things a bit. How do you think ourrelationship with technology then is impacting our epigenetics? Because for mepersonally, one of the things I'm highly interested in is as humans,maladaptive relationship with their environment. And it seems to me that we arebathing in a maladaptive world that would cause all kinds of epigenetic shifts.You know, I think of like the the grasshopper and the locusts, right? I don'tknow if you're familiar with that gregarious phase, but this radical change inbehavior that just comes from being in a slightly different environment. Do youfeel like technology is probably bringing a lot of epigenetic shifts topeople's life by virtue of being such an environment?

Nessa Carey [00:15:20] Possibly it would. Itwould make a lot of sense that explicitly we change as our environment changes.What It's much harder to say if it is, whether it's those are maladaptivechanges or not, They're just changes. And it's it's really tempting to fallinto the way of thinking of these environmental changes about things andadaptations to them, all bad things. But it's really important to think aboutwhat we mean by good and bad in this circumstance. So, you know, everygeneration has always thought that, for example, children are all turning intoidiots because of the new technology to which they are exposed. I'm sure whensomebody first invented the whoop, a mistake. Yeah, we see those pictures ofVictorian kids rolling a hoop with, you know, the subway going, well, that'sit. Children are doomed. Now. They're just going to spend their lives buildinga hoop with a stick, you know? And I think we have to be very, very careful. Wedon't really know what is good for us and what is bad for sometimes and what wemean by that. So, you know, I'm of an age where I think children should bereading books and they should be going outside, not because that's what I did,but I'm not sure I'm anyone's ideal role model. And it's very tempting to go.They shouldn't be inside playing computer games all the time, and they probablyshouldn't be. You probably shouldn't be doing anything to extreme. So it's it'sreally. You have to be really careful if you start saying things like, Are allthose children playing computer games? We've seen they have the followingepigenetic changes. Well, maybe they do, but maybe it's a change saying, Oh,this person now a bit smarter because their hand-eye coordination sort of good.You know, it's very, very difficult to do that. On the other hand, I do thinkwe live in crazy times. Certainly those of us in Western societies where we'reinactive, we eat really crap, we eat far too much of it, etc.. I think thereare things which are very, very bad for us as populations, but I wouldn't wantto say that all the negative consequences of those are being mediated byepigenetics. There's an awful lot of other things happening as well, and itcould be our epigenetic systems are changing because they're getting older.Let's just try and minimize the damage to this. And we don't know enough tounderstand if these changes are maladaptive or actually quite protective.

Steven Parton [00:17:39] Well, thisbrings us to a question I was going to maybe safer a bit later, but I thinkfeels really important now, bearing that ignorance in mind, what are we doinggoing in and messing with genes? You know, we if we don't understand what'smaladaptive or not, it feels like we're playing God in a at a time period wherewe don't even know what God can do or you know what I mean?

Nessa Carey [00:18:05] It it depends what wemean by messing with genes. So when someone's epigenetics is changing, the onething you're not doing is basically changing the gene sequence. So theepigenetic modifications may change, but that's just like putting differentPost-it notes on your plate. You're still you're still delivering Alphabet ascript, so. We're not epigenetically. We don't change genes. And also, anotherthing we need to consider is that you can't control what epigenetic changeshappen. So again, I see pseudoscience where it's like, Oh, if you take thissupplement, you will change the epigenetics on the genes involved in this. No,I think that's very unlikely. We can't actually direct that right. Where we canchange states, of course, is with the technology of gene editing so that we canchange genes. And it's a really interesting field and it's an ethically incrediblyfought field. I'm never convinced by the concerns around we shouldn't beplaying gold because that's what we've always done. If you take the idea ofplaying God as interfering with what is natural, we shouldn't have vaccines, weshouldn't have antibiotics, etc. You know, we've always done it. But there'ssomething about DNA and or genomes and our gene sequences, even though we don'tknow them most of the time, for some reason we feel incredibly proprietaryabout. And I'm really interested in why we do. We somehow feel that that ismessing with the basic essence of this. And I don't know why you feel that. Imean, if you think about, say, 70 years ago, nobody knew the structure of DNA.You know, a hundred years ago, nobody even knew DNA existed, or certainly notthat it was the genetic material. And yet we've become incredibly possessiveabout it, which I find quite interesting culturally.

Steven Parton [00:19:56] Yeah. Imean, for me personally, building on that idea, I feel like part of it's justthat pattern idea, right? We feel like kind of informational patterns. And whenyou really boil down to it, that DNA is our pattern.

Nessa Carey [00:20:10] And I would say it'sour starting point. DNA is necessary, but not sufficient. I don't think you'llever explain all of human complexity just by genetic small DNA sequences.Nobody knows why Einstein was super smart, and I don't think we'll ever workthat out more by sequencing bits of his DNA, which I'm sure lying around invarious places. We. We know that humans are an incredibly plastic species, butvery good at adapting to our environment. Not necessarily, not through genechanges, just through being adaptive. And so. That that happens no matter whatyour genetic sequence. Of course, there are some people who are down to really,really bad genetic. And so that build that delta mutation that will have adevastating impact on their life, of course. But even if you look at peoplewith exactly the same genetic mutation, they're not the same person based on verydifferent people. If you look at identical twins, they begin to differepigenetically. So even though they have exactly the same DNA script, theydon't have exactly the same risk of certain diseases, for example. So you addDNA. Yes. It's important that your DNA sequence is not a technical term wouldbe absolutely stopped, but that's just your baseline. Then it's all the nature.Sorry, Then it's all the nurture stuff. Then it's your environment that prettymuch governs your life outcomes. It's not necessarily your genetics.

Steven Parton [00:21:46] Well, andspeaking of, I guess that the nurture side of things, I think we could put geneediting in that bucket. Let's maybe get specific about gene editing. Wherewhere are we with gene editing these days and what really are we doing? Youknow, are we doing things like causing intentional epigenetic shifts withthings like CRISPR or are we doing other things?

Nessa Carey [00:22:07] What has is now beingadaptive so it can actually create precise epigenetic changes to a particulargene. And that was a technologies that was something we were never able to dobefore. So it was always really difficult to investigate hypotheses. That said,I think this epigenetic change, this gene causes this consequence. That wasvery difficult to do because you couldn't go in and interfere with the geneticmodifications. And now the technology is becoming established to do that,though it's still very early days. And that's that's kind of mind bending,really. And it will ultimately put a stop to lots of the arguments about isepigenetics important or isn't it? Alternatively, we can just wait for somepeople to die or retire, etc. put a stop to the arguments as well, which is theway science really progresses. My special gene editing is and Chris CRISPR geneediting, which I we want to call it, is an extraordinarily powerful technique,but most of its applications are going to be in changing genetic sequences, notin changing epigenetic sequences. And it's it's a technique which is.Magnificent. And the best thing about it is it's so easy. And the worst thingabout it is it's so easy because you cannot control the technology. Pretty muchanyone can use. And that's a really scary situation to be in and so much. Me,I'm quite positive. I think the benefits will far outweigh the negatives, butthat's just me liking science of being a geek.

Steven Parton [00:23:42] Yeah, well,one thing that is another conflation or maybe pseudoscientific aspect of thisis what is possible with with technologies like CRISPR, right? Is thissomething that we can do in a living adult or is this something that has tohappen in vitro before germination? You know, when we actually come in and toywith the you.

Nessa Carey [00:24:04] Can do it's in theory,but the consequences are different. So CRISPR is already being used as a drug,essentially as a medical intervention in adult humans. It's being used inpeople who have particular genetic conditions. So the one in which it's mostadvanced is in sickle cell disease, and it's related to condition policy andthe use of the technology. There is beautifully would say people with sicklecell disease have a mutation, which means that bone marrow produces red bloodcells which are not functioning properly, and that is caused by mutations. Thereason why I think the sickle cell approach is so elegant is if you're trying anew way of creating treatments for a condition, you always have that risk ofknow. You give a patient something and what if it goes horribly wrong? So withCRISPR, what they did with sickle cell disease patients is to take some bonemarrow out of patients and then use CRISPR to kill to correct the defect in thehemoglobin gene that creates sickle cell disease. And then they could test thecells to make sure the correction would go well and the cells will behave well.And then they put them back into the patient. So they never injected thepatients with CRISPR itself. They injected them with their corrected cells,which then recapitulated the biometrics and produced normal red blood cells.And sickle cell disease is something for which we have had no effectivetreatment and no drugs. Basically what you see is there was nothing to offerpatients who were going through crippling sickle cell crises every month,having to be hospitalized for long periods of time every month. The patientswho are in the clinical trials for CRISPR as a sickle cell show, not just as atreatment, it's actually a cure. We're seeing patients who have now gone over ayear and who have not had a single sickle cell crisis, have not needed to gointo hospital. Their quality of life is absolutely transformed. And that ispretty astonishing. It will probably the latest suggestion is that that willprobably have a $2 million price tag if it gets all the way through to beinglicensed as a drug. But it will still be cheaper than treating patients withsickle cell crises every month. So in a situation like that, it hasextraordinary potentials, those patients. They will be cursed because theChristmas date change happens and then gets passed on to all the daughter cellsin the bone marrow. Excuse me. Hopefully they should have a very, very longperiod when they are essentially killed. What they won't do is pass on thatCRISPR change to their offspring because that change hasn't been made in thereproductive cells and that that sort of use of CRISPR in treating. Patiencewith it and hopefully curing patients with it. That, I think, is on the whole,relatively uncontroversial, as long as the benefits outweigh the risk, justlike any and any drug is not quite the same as any drug. Because once you'vemade the change, if you then decide that was a bad thing. The only thing youcan do is go back and try and undo it, which is complicated, but.

Steven Parton [00:27:22] It's to.

Nessa Carey [00:27:22] Get.

Steven Parton [00:27:23] Reallyquickly. Is sickle cell unique in that regard? Is there something about it thatmaybe makes it easier for this process that isn't applicable to a lot of othercommon diseases?

Nessa Carey [00:27:33] Thing that's reallygood about sickle cell was to take the cells of the body and treat. So anydisease, genetic disease which is caused by a mutation in the cells that createblood cells that could be red blood cells or white blood cells. So some of theimmunodeficiencies, for example, where there's genetic defects in the cells intheory will be treatable by a CRISPR approach. In theory, you could treat everygenetic disease in an adult using CRISPR. The difficulty is not the crisp, butthe difficulty is getting the reagents crisp, but the bits that do the work andmake the change, the difficulty of getting them into the right tissues to dothe right change. So with sickle cell disease, you take the bone marrow out, sothat's fine because you know you're not going to be able to you're not going tostart changing the sequence in the brain and in the liver. It's just becauseyou have to put it into actually probably after the blood disorders have beentackled with CRISPR, we'll start seeing it being used for disorders that theproblem is in genes, that all people look up and operate in the liver. And thereason for that is you can inject the Christmas stuff into a patient'sbloodstream that will go to the and the livers job is literally to go, what thehell is that? And the liver cells take up this phone thing. And that's greatbecause now you've got your crystal where you want it. What's much morecomplicated is to do things like to deliver large amounts of CRISPR reagents tothe skeletal muscles. If you're trying to treat Duchenne muscular dystrophy orthe brain, if you're trying to treat Huntington's disease, it's much harder toget enough material to make the genetic changes in cells in those sorts oftissues. The other place where we're already seeing Chris making an impact isin the AI, in genetic disorders in the ICU as nice and small and you can getstuff to. So that's why I won't see it. On the whole, there isn't that muchcontroversy about using XML for these kind of applications. Jennifer Doudna,who won the Nobel Prize for Creating Respect, said The potential of thetechnology is so good that it changes the ethical question from Do we have theright to do it too? Do we have the right to withhold it because it ispotentially so good? What's much more controversial is to edit very earlyembryos by deliberately hoping that change will happen in all the cells as thatembryo develops. And therefore, you've created an individual who has adifferent DNA sequence from what you expected them to have, and they will passon that change to their offspring. And the result is always going to beoppression.

Steven Parton [00:30:13] And there'sa lot more power there than in the adult, right? Because at that stage youdon't have to worry about not being able to get it to the right area because itgoes to every cell, it goes.

Nessa Carey [00:30:22] To every single cell.So it does bring its own technical problems because you're dealing with a tinyembryo in a dish. It's not like the blood cells, but you can go, oh, we'll takeout a few hundred thousand. Those who've grown in the lab and will check thatthey're okay. You know, if you're dealing with an embryo that's only got eightcells in it and you've put the CRISPR reagents in, how do you check that alleight cells have got exactly the right change and also that they haven't gotany what are called of targeted effects that you've only changing. We want tochange. That's incredibly challenging to do on tiny embryos so the risk isgreater and therefore there has to be a much more pressing need to do it. Andat the moment, in every well regulated states, it's illegal to do that. Youcan't edit a human embryo and then re implant matter that implant that embryointo a woman. It's against the law and pretty much everyone. Yeah, go ahead.

Steven Parton [00:31:30] Well, yeah.So I was going to go a little sci fi here, so maybe a weird tangent, but thisthis makes me think a lot of people, when they hear gene editing, they start talkingabout things like using senescent cells from squid or octopi or using, youknow, chameleon like cells, like what is possible in terms of the changes, howmuch can we really get in there? And even more, more than just change what'sthere.

Nessa Carey [00:31:57] Like, can you addother genes?

Steven Parton [00:31:59] Can you addthings that just don't fit as.

Nessa Carey [00:32:02] Quickly or you can? Imean, in theory you could do that with the old technology of gene modificationas well. But gene modification is just so inefficient compared to medicine. Soin theory you could do that. But genomes are extraordinarily complex. It's notjust to do with the sequence of genomes, human genomes. They have to structurecorrectly and putting in big new genes in unexpected places. That's unlikely toend well. You wouldn't be allowed to do it, although I have to say right now,the idea of having chameleon genes is really, really appealing to me. I reallylike coming out. I think that kind of that sort of trends, human value, butwhere you're doing a trans effect, i.e. taking from another species. Mm hmm. Ithink is it's theoretically possible, but it's in the real kind of madscientist realm. I think the chances of anyone ever being allowed to do thatare vanishingly remote. That, of course, doesn't mean some lunatic might not doit. And they would, but they would have to do it in a very poorly regulatedenvironment. And then, of course, it's almost. Environments which are verypoorly regulated to do really mad experiments and mad human interventions areoften not the environments in which the technology exists to do what you wantto do. So the CRISPR was relatively easy, but getting those early embryos,that's very difficult. Then maintaining them while you do the CRISPR is reallydifficult and then making sure they're healthy enough to put into a woman thechances of finding an environment, a country where you have all theinfrastructure that you need. It was a complete lack of regulation was actuallyquite tricky. So it could happen. But it's you know, it's it's certainly notthe intention.

Steven Parton [00:33:55] Right. Butthat's more formal. Right. I think one of the concerns with CRISPR for a lot ofpeople is that you can get your garage hackers, the people who just set up aCRISPR studio in their garage.

Nessa Carey [00:34:06] You absolutely can.Guys already done this. Yeah, he injected CRISPR. Reagents that can be used in.In general. He injected CRISPR reagents to basically manipulate the way thatmuscle grows and the way the muscle stops growing. And he injected himself inhis bicep and he believed it. And sadly, absolutely nothing happened. And I saysadly, because I think it would have been amazingly funny if he'd ended up withlike one huge bicep. So one half of him is like Popeye and the other is stillthis geeky guy. Nothing happened, which doesn't tell us CRISPR doesn't work. Itjust says it'll do the experiment. It is the big problem and that is that thistechnology is cheap, the reagents are pretty readily available. You can'tcontrol it. This is not like enriched uranium. And you look who's got thecentrifuges and you stop them using it. You know, this is pretty basic stuff. Ihave no problem with people deciding to crisp themselves if they really insistthey want to do so. I mean, you've got it. We ever interfere with the potentialof a human to make a complete egis of themselves and to do something reallydumb? You know, that seems to be the right for which we all fight, is that weshould all be allowed to be as ridiculously dumb as possible. I have no problemwith people doing that type of vague overlooks. They make themselves trivialand then the health care system has to pick up. You know, I have a bit of aproblem. The fact that it gets people ride motorbikes, people smoke. We stillexpect to be treated in hospitals. The really scary thing about CRISPR in thatenvironment, in the sense of how democratizing it is, is if someone's thinking,I don't want to give myself big muscles, I want to make a really pathogenicbacteria, or I want to make a pathogenic virus. In theory, that would be reallyeasy to do. The thing that would stand between somebody doing that and thenthen causing a massive global pandemic or even a localized outbreak of greatdisease would simply be the fact that it's relatively easy to do the course,but it's really quite hard to grow up large quantities of really dangerousbacteria and viruses in your garage. That requires sophisticated equipment. Itrequires a level of containment so you don't constantly kill yourself or infectyourself. But that is a concern. But that is one to me, the biggest risks, ofcourse, are much more concerned about that than about. Genetically enhancedhumans will be able to think of much.

Steven Parton [00:36:43] Have youseen much lately in terms of how this kind of artificial intelligence boomwe're experiencing is impacting things? Is there an empowerment of the CRISPRtour or other gene technologies because of artificial intelligence that you seecoming down the line?

Nessa Carey [00:37:00] So we could useartificial intelligence to make it much easier to predict which of targeteffects of the sea with CRISPR. So to start getting to get a much better set ofdata of if you use this CRISPR sequence, there is a chance that not only willit bind to the gene you're interested in, but it will bind to these otherregions of the genome. These are the ones you should be looking at, so I willprobably be useful for that. The other reason why I will be useful is it'sgetting much, much better at identifying various bits of the genome which allcontribute to complex diseases. So the diseases which are not 100% genetic orare not caused by one mutation, if you look at something like multiple sclerosisor lots of chronic diseases, rheumatoid arthritis, etc., schizophrenia thatcaused by a complex interaction between the environment and the genome. Butit's not that there's one area of gene that is really badly disrupted. It'sthat there are lots of genes that are all contributing, say 5% of increasedrisk. I is getting much better at identifying what the combination of genes isthat gives an increased risk. And then you can test that hypothesis by changingways with questions. So that's where I see the animals coming. In its mostimmediate application. I'd love to speculate about something wild, but it justall moves to false locally. So I just look at the short term and the best I canthink about.

Steven Parton [00:38:25] I mean,makes sense to me. We've been talking about humans predominantly thus far, butone of the things I'm worried about with our company, a lot of things we try totackle or things like energy and food production and some of these UNsustainable development goals that are facing the world. What are we looking atin terms of maybe making things like drought resistant strains for food orenergy producing algae, things like this that might contribute to other aspectsof the world that aren't human specific yet?

Nessa Carey [00:38:59] That's a greatquestion, and CRISPR has enormous potential in that field. I think again,because I'm just a cheerful kind of a person on the whole, I think it has thepotential to make a really big difference. So if we look at agriculture,agriculture is one of the major drivers of greenhouse gas emissions and alsoloss of biodiversity because agriculture uses up such a huge amount of land anddegrades land as well. The way that we do agriculture. So CRISPR has alreadybeen used, for example, to create rice, which are more tolerant of salt. Andthat's really important because intensive agriculture creates saltier soil anddry soil and rice yields start to drop. And so farmers then have to startgrowing in new areas, and so you lose more and more natural lands. So what areyou already cooking was used to create rice, which until very much high levelsof salt would have increased yield of rice, which is great and. That was agreat technical triumph because I have a really complicated genome and I havegreat, great technical so. One way of looking at it is that it's fantasticbecause now we can keep growing rice on this agricultural land, but previouslywe would have that to go, okay, we're going to use more land. So that's greatbecause we should be able to start decreasing the amount of land that we usefor agriculture. If you apply that principle to lots of crops except. Let'simagine you're a farmer in a fairly poor part of the world. And your income andyour ability to send your children to school or to get the medicines isdependent on the yields that you will grow on, rice or whatever crop you'reinterested. If you're then presented with a rice variety that can toleratehigher levels of salt, you're probably not going to think, Oh, that's great. Ican just keep growing on the same dish I've been growing, or you're going tothink I can keep growing on that bed. Plus I can start growing on that bit downat the edge near the mangrove swamps, which was previously too salty. Now,nobody could blame a problem for doing that. He or she needs to support thechildren, but the minute they can expand their acreage into areas thatpreviously were the bits nobody was interested in, then you have another lossof biodiversity. Yeah. So it's a real it's a potentially brilliant breakthroughtechnology, but it's going to be how we use it that matters. One of the thingsthat is very good about CRISPR, though, is because you can make precise changesin crops. We actually maintain genetic diversity rather than losing it. So ifyou look at current plant breeding. Solutions, which are very old fashioned andare based on reading crossing varieties, you often end up losing a lot ofdiversity to create the variety that you want, the characteristics that youwant. With CRISPR, you can take, say, eight different strains, all of which areadapted to different environments, and you could do the same CRISPR change ineach one just to produce the one effect that you wanted and you maintain allthat other diversity. So it's. It's a very, very complex juggling act that wehave here.

Steven Parton [00:42:22] In the sameway that we talked about a potential almost like gain of function from a garagehacker issue and the human circumstance. Do we then, like you were saying,never run into a potential issue with a runaway ecological issue? Could wecould we create a strain of like an invasive species or something that thatstarts to ravage the landscape?

Nessa Carey [00:42:44] Absolutely. I thinkwhat's the biggest to the thing that I am most uncomfortable about gene editingand what it can deliver is when you combine gene editing with something calledgene drives and gene drawings is a way in which you can increase how quickly aparticular characteristic spreads in a population. So normally if forms. Thateasy type scrubbing. If you have a fly and it's got a red gene and a yellow andred version of the yellow version to say, Gee, I'm just using those tovisualize it. When it passes on its DNA, it will half its offspring will havethe red gene and half will have the yellow version of that. Yeah, it's a genedrive system, a genetic system that you can introduce into things like insects.And instead of 50% of the offspring having the red version and 50% inheritingyellow versions, you can find that you can create saturation so that 75%inherit the red version and 25 the yellow version. And you can keep making itmore and more extreme. So you get rid of particular versions and there's a waythat you can do this, which means what you actually cause is populationcollapse and wiping out populations. So if you use gene editing to create thesekinds of gene drives, that scares the life out. Because if you then release,say, mosquito populations, genetically edited gene driven mosquito populations,and they cause an absolute collapse and an irreversible collapse in mosquitopopulations in the wild. I don't think we're very good at predicting theconsequences of something like that. We have had we've tried biological controland not in the past and sometimes it's like really, really well. And othertimes we've done things like introduce cane toads to Australia and completelydestroy entire ecosystems. So the idea of irreversible interference with an ecosystem, I think it's pretty appalling that really radio station and geneediting will make that so much easier just because gene editing is so good atchanging genes.

Steven Parton [00:44:55] Right.Well, all of this, you know, a lot of people talk about A.I., and I think it'sprofound, of course, but it feels like gene editing really has a chance to toreshape the world in a way we've never imagined before. And this all begs thequestion. What are we doing in terms of legislation? How do we handle policyaround this? Where are things right now and maybe where should they be?

Nessa Carey [00:45:21] Yeah, I think one ofthe difficulties is that we cannot have global regulation. They're all they'reable to be almost impossible. And in some ways that's right. Because if youlook at states attitudes to what would be considered a serious condition, thosewill vary enormously between different countries, between different culturalgroups, between different religious groups. So it's very difficult to get aglobal moratorium on anything. We do see that there are. Big drives to try tocreate ethical frameworks that at least will be recognized and observed bypractitioners throughout. The most advanced economies. And that hopefully thatwill also translate into other less advanced economies. That's particularly thecase when it comes to using gene editing in humans. In the UK. We have theadvantage that we've had for a long time, something called the HumanVictimization and Embryology Authority, which is very, very good at getting togrips with these kinds of questions and also regulating practice withincountries. So I think in terms of what is acceptable in. Human populations willstart seeing consensus, at least in the countries that have the most advancedtechnological infrastructures. We will start to see more of that. I think it'sgoing to be a bit harder in the world of crops and foodstuffs, and it's goingto be harder in terms of pest control as well, because, you know, I can sithere and I can say, well, I think it'll be a terrible thing if we cause thecollapse of the malaria at the mosquito populations, because that could playhavoc with ecosystems. Because I live in the east of England, we don't have aproblem with malaria. Right. What if I were a parent in an area where thelatter is endemic and maybe two of my children have already died? I would notbe quite so friendly towards the mosquitoes. And so it's you know, this isgoing to require an awful lot of local. And regional and national andinternational cooperation. Because everybody has different drivers and is gettingsensible uses that this technology is not going to work. Well, if those of uswho have always been in the most privileged positions keep telling those peoplein the less privileged positions who are just like the affluence that we have,that what they should and shouldn't do. So it's going to be a tricky one, but Ithink that is true of almost every technology.

Steven Parton [00:48:01] Yeah, well,respecting your aforementioned sovereignty of the idiot, how much how muchregulation do you think we should then bring to the table? I mean, do you wantto see this kind of be a little looser? Do you think we should get pretty rigidand really kind of walk carefully?

Nessa Carey [00:48:23] I think the problem isgetting really rigid, and particularly with tight legislation at the moment, isthat the technology is moving too fast. So if you could put in place laws nowthat would actually turn out to be very counterproductive. And one of theexamples you might want. We might think is relevant is the very different waythat, say, Americans dealt with stem cell research compared with Europe. Andthat has had implications for the research that can be carried out. It's hadimplications for the logical parts of the US and Europe in this sphere, and it'spotentially not necessarily been helpful. So I suspect where we're going to endup will be in that situation of creating regulatory authorities who have thecapacity to. Operate within parameters rather than having very strict legalframeworks in the same way that USDA is empowered to do things. So I think wewill start seeing more of that kind of regulation coming in. I think mostscientists working in the field would like a global moratorium at the moment ongermline gene editing in humans. But they don't necessarily want to seeresearch on not stopping. But I think at the moment we have in the UK, forexample, as there have always been rules about how long you can continue towork on early embryos. So you can't take beyond a particular date. And I think we'llsee more of that kind of thing happening. I think a global moratorium ongermline editing right now, if it could be enforced, wouldn't be the worstthing ever. But it's about what you can enforce it.

Steven Parton [00:50:14] Right?That's always the hard part. Whereas we talk about looking forward and we startto come to a close here as we reach the end of our time. What what are yourthoughts looking forward? Are there promises or pitfalls that you'reparticularly interested in that you would like to bring to attention?

Nessa Carey [00:50:33] I like the promise ofthe use of this in agriculture and the potential of this to really be one ofthe tools that we use to deal with the fact with, you know, the planet is onfire and it has very little resilience left in it. We have disrupted naturalsystems to an extent which is unsustainable, that there's just no redundancyleft in the systems. We are reaching tipping points and having better ways ofcreating food with less of an environmental impact. That would be an excellentthing. But also one of the areas you touched on how can we use this to startcreating better fuels from things like algae, etc.? Can we use this to createstrains of bacteria that can deal with a huge plastic waste problem? Can we useit to create strains that can extract rare metals so we don't start deep seamining and destroying the only intact ecosystem that's still left to somedegree? So I think it's really important for all of those things, but that'sgoing to take enormous. It's going to take enormous effort and not just by thescientists, the. This is like most science. It's the economic and socialenvironment in which it works. That makes it either good or bad. And we coulduse CRISPR for all sorts of really positive things. But if you still havetrillions of dollars going into oil subsidies, it's not going to compete. Verymuch so. But on the other hand, it's much easier to do geeky experiments and tochange people's attitudes and to change political and economic systems. So,yeah, it's a crystal.

Steven Parton [00:52:19] Yeah. Isn'tthat the truth? That's the statement of the century, I would say. Any well, anyclosing thoughts, Anything you'd like to talk about? Anything you're working onthese days that you'd like to promote or share?

Nessa Carey [00:52:31] I would just say thisis a topic that I think I would really like everyone to. Not about to educateabout themselves because there are really big decisions to be made. And weshould, all of us as citizens of whatever country we live in, we should allactually contribute to those discussions and we should contribute from aninformed viewpoint, not from a knee jerk reaction of certain types of science,or that it's always the applications of the science and it's going to affect usall, either directly or indirectly. So I think it's one of those things wherewe really just kind of take ownership of it.

‍