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CAST Genome Editing in Agriculture—Methods, Applications, and Governance



today very pleased to be with you to share our most recent publication on genome editing and agriculture methods application governance and very pleased to introduce dr. Adam McDonough of who served as the task force chair chair of the task force of scientists and subject matter experts that put this together I thought about Donna was a professor of plant pathology of plantain microbiology at Cornell University if you recheck research as the mechanisms of plant pathogenesis and plant defense to develop improved crop resistance to build diseases using genome editing dr. Barragan of is a pioneer of some of the technology used in genome editing and played with a major role in development here in his Bachelor of Science from Yale in biology in 1987 his PhD in Plant Pathology from Cornell and many son did postdoctoral work at Purdue University and voice Thompson Institute before joining the factory at Iowa State and then moving to Cornell so please help me in welcoming dr. adam by donna to share the highlights and the key findings of this paper thank you thanks very much for the introduction Kent and thanks again to everyone for coming I'm really glad for the opportunity to be able to share with you that at least the highlights and some of the contents of this cast paper that that I served this task force chair for um that was a really interesting ride actually when Kent first contacted me and asked asked me to to serve his task force chair our first task was to assemble the the group of authors who would put this together and the other thing that can't really try to drive home for me was that cast papers should be factual and not speculative and they should provide insight but not opinions right so the challenge then is to find a bunch of experts who are not opinionated and don't speculate too much so my solution to that challenge and Kant was very helpful this was to find people who feel strongly about the technology and its use and its applications and how we should govern it and make sure that I just had people from sort of opposite sides in the room and in that way we're able to sort of expunge all of the value Laden language from the paper and all the opinions so it's dense and it's and it's long but it's informative and I guess the goal here for me today is just to give you sort of the Reader's Digest version and then I would refer to the paper for parts of it that might might really piqued your interest if you cut the stamina read the whole thing from so this is the taskforce I won't detail introductions of all these folks but for those of you who might know some of these people you'll see what I mean about number one experts in the field and number two people who have kind of strong feelings about it as well I think you've got a good mix in us as Ken mentioned we were able to recruit Katja Powell's from Belgium she's with a nonprofit organization currently there and she was really helpful in kind of keeping us up-to-date on all the happenings in Europe with respect to how genome editing might be governed there so these are sort of some excerpted topics from the from the paper this is all be covering today I think to define genome editing to tell you about the principles of genome editing the methods that that are behind it the tools and sort of the types of edits that can be made then I'd like to give you some examples of applications and crops examples of applications in livestock and then sort of to put genome editing in perspective especially as it relates to governance of the technology I'd like to compare briefly to other methods ranging from classical breeding to conventional transgenic or GMO technology and touched on a couple of things especially some recent happenings in the regulatory landscape there's a few perspectives and conclusions I hope to do is leave all over the time at the end for questions and answers and in I just said at the end if you have a question or something's not clear during the presentation I definitely welcome you to till you drop me and help me clarify particularly if I start dropping jargon which I tend to do I talk about this stuff all the time with folks in my lab and we sometimes blur the line between English and in jargon right so keep me on task if I if I start to drop some jargon that's not making sense so to understand genome editing I think it's good to bring everybody to the same page and to do that I just downloaded this video which shows because Ingham is the set of instructions needed to create an organism genomes are stored in cells as DNA DNA is short for deoxyribonucleic acid an amazing molecule that stores information using a special code you can think of a genome as a coded cookbook to build and grow an organism for example you the human genome contains about 23,000 recipes that code for different proteins each recipe or functional unit of DNA is called a gene but only about 2% codes for protein the rest is non-coding DNA with regulatory or other yet unknown functions kind of cheesy narration there I really like this video because of the analogy that it draws between a genome and that's particularly useful when we start thinking about genome editing because we understand editing a book we open it up to a specific page we find a word on that page and we change the spelling or in some cases we might remove remove a few sentences or add another sentence or word or tear out a whole page or insert a page and depending on what we how we change it the meanings changes slightly and the big codes in the out of the oven might change so genome editing is just that it's it's reaching into a living cell opening the book of the genome and making spelling changes sequence changes may be targeted sequence changes to a gym and it's not hyperbole to say that it's revolutionising biology nor is it hyperbole to say that it's really driving this revolution and discovery and application in many different fields in medicine and industry and in agriculture Oh you can find lots of really useful videos it has permeated the popular press I just wanted to point out three here and you won't have printouts of these but they're very easy to find this one on the top left here is from the Royal Society and it gives a nice overview in like two minutes and a half of genome editing you're not getting to tackle the one of the on the right is from McGovern Institute at MIT and that gives you specifically some fine grained information about the leading tool for genome editing the CRISPR caste system and then this one on the bottom here this is John Oliver's last week tonight it's actually last last week's last week tonight anyway he did a really nice job of covering genome editing so if you want to laugh and learn at the same time tune into that one technically really accurate in deep too he goes into a lot of deep drawers oh I just recommend those to you they're easy to find by googling so in a nutshell though in the time that we have what is genome editing and what of it what's the most common approach the key to genome editing is to make a targeted cut in the DNA to go in and to break a chromosome and then let the cell takeover and repair that cut and there are different ways that a cell can repair the cut and what we're doing is harnessing the different repair pathways right so the key thing is to be able to make a targeted cut in a complex genome and then harness those repair pathways to get the desired our outcome so what about these breaks is that a really weird thing no DNA breaks happen all the time in nature they're really important for example during production of germline cells egg sperm ovules pollen because they're critical for recombination that takes place during meiosis it can also occur in all of our cells in response to environmental insult UV light ionizing radiation chemicals it all cause breaks in DNA so from single-celled organisms all the way through to plants and humans we all know how to repair DNA breaks this is a fundamentally ancient and conserved process that takes place in skulls how to repair those breaks it turns out there's actually two ways to do it in these two ways that cells from Paraty of DNA breaks are the basis for the types of edits that we can do in genomes these repair pathways are usually faithful otherwise we'd all be walking around looking like new cancer what would be you know slime so they're usually repaired faithfully but repair can introduce changes and thankfully for us as genome editors as technologists we can capture those rare events right so there are two pathways as I mentioned the first is called non-homologous end joining the details of what that exactly means is not terribly important but essentially the process is simply a realization or re joining gluing together of the two ends reforming the bonds that make up the and normally that happens seamlessly but with some frequency a couple of bases drop out they get trimmed off or even less frequently a couple of bases actually drop in and if you remember how DNA codes for protein there's this triplet codon sequence right where 3 bases code for one amino acid one part of a protein so reading frame is really important in jeans frame that you're reading it if you add a base or take a piece out base out could you get out of step you could imagine you know waltzing and then getting off by one beat with the music so these are these n hej mutations that insert one or two bases or move one or two bases are really good for knocking out genes for destroying the function of a gene because it takes it out of the out of beat with the music if their pathway is called homology directed repair and homology roughly means similar in sequence deriving from the same ancestry so in our cells in all living cells typically what happens when you get a DNA break in the repair pathway for homology directed repair is initiated this being a chromosomal Pacific get my here this being a chromosome over here on the right this is actually a paired chromosome with two chromatids here this sequence on the on the right over here is used as a repair template to patch the sequence over here what happens then is the break is here this sort of donor DNA crosses over and integrates here and integrates here it all gets sort of copied in and resolved and all smoothed out again and essentially what you have is whatever was in this sequence similar DNA is now spanning the break in the broken giving and that allows us if you think about it to do a couple of different things we could swap in for example a version of a gene from one variety or one breed for the Jib version of a gene in another or we could insert DNA as long as these arms over here on either side are similar in sequence to the ends of the break essentially we can insert any any DNA in between them we like and that could be the change as small as one single base pair to gene sized fragments so that brings us to how we make these targeted breaks the tools generally are called sight directed nucleases nuclease is an enzyme that just cuts DNA that's that's what the the enzyme name is called and historically they've been several classes of these going back to probably 20 or 25 years the first of these were homing endonucleases these are monster proteins that huge they're very often symmetrical they can be really pretty attacked and they sit on large stretches of DNA usually between 20 to 50 base pairs large so we're talking about and they they recognize that specific sequence and they cut so people very early on recognize that these would be really great tools for targeting a break if you could engineer them to change their specificity if you customize their specificity so that turned out to be really difficult or challenging these are still used but a lot of effort a lot of time and a lot of money is to go into changing their specificity to retarget to a sequence that you're interested in so they've sort of fallen out of favor next in line were the zinc finger nucleases a lot of excitement about these when they first came out because they look sort of modular it looks like each of these fingers you could would interact with three different bases and you could put the different fingers together in the right sequence in order and you get something that would bind exactly what you want it turns out that the fingers have specificity that changes depending on what figures next to them so these also became sort of slogging along laborious reagents that took a lot of empirical testing to develop and then in 2009 and this is where I came into the field tell effective who cases were invented and these are based on proteins from a bacterial pathogen a plant that's the connection and these proteins naturally are injected into plant cells you go into the nucleus they seep they search the genome and they find a specific sequence they find there and they do stuff and what we figured out is how they find their target and when we learned how they find their target we learned that we could engineer them they're very much like Lego blocks each of these little turns in these sort of super helical proteins are looking at can be reassembled in whichever order you like to create a custom protein that will bind whatever sequence he likes Oh the trick was simply to attach the nucleus to these proteins and then you have a good sight directed nucleus and then in 2012 the field really started to explode with with the debut of the CRISPR caste system and this is far the easiest to engineer the targeting here is done by an RNA molecule that base pairs with the DNA and it's really easy for us to simply order up a little fragment of RNA or DNA encoding that RNA and to incorporate it into our into the tool oh I would say currently talents talents active new places and predominantly CRISPR cats are the major classes of tools that are driving the whole genome editing field so it's also important to think about particularly when it comes to the regulatory landscape the types of edits that can be done and this conceptual framework has sort of built up particularly in the regulatory context in Europe to divide the types of edits into three different classes they're referred to as site directed nucleus one Sdn two and Sdn three Sdn one is that non-homologous end joining I talked about when you break the DNA and get stuck back together a couple bases come in or a couple bases drop out so it's very very similar to targeted mutagenesis Sdn two you make a targeted break but instead of random changes happening when you glue those back together it's done in such a way that small but precise changes to the spelling get made so you change it a C to an na where you change a ga to a TC if you know what's happening there and that's it usually it's a template change a template or a donor that that allows you to make that change STM 3 is really only different from Sdn to in that you're using bigger chunks of DNA so you're either swapping out larger pieces or inserting large pieces and the definition of large is not really quantified yet but gene sized fragments typically are what people have in mind when they distinguish Sdn 3 from misty and I wouldn't I wouldn't do justice to the rapidly advancing field if I didn't talk to you a little bit about some some recent advances in addition to targeting these breaks and harnessing the repair pathways there are other ways to make spelling choices of a genome and recently some reagents some tools for doing specific base editing have come online these depend on enzymes that chemically modify one of the letters of the DNA and these enzymes are hooked up to a targeting reagent in this case it's the CRISPR caste system and they've in this particular iteration the nucleus part of the cache line is half disrupted it's half dead so what happens is you get chemical modification for example of an a there is a deamination that's called as a deaminase and that converts it to an unusual base called play machine at the same time the other strand of the DNA gets nicked that stimulates repair and during repair a machine is recognized there's something that should bind with steam and then during replication opposite the C you get a gene so just to cut to the chase there there are reagents that allow us to do specific spelling changes without making a double-stranded break and that has particular applications in addition to this A to G edit we can also do with different enzymes C to team so that our power to make specific targeted changes is ever increasing another way to do this that's that's being pursued with some success is to introduce a piece of DNA that's protected from getting chewed up in a couple of different ways one by making a double-stranded and and having this hairpin structure at the end or by adding these chemical modifications at the end basically just to prevent the DNA from getting degraded once it's introduced to the cell then the sequence of the DNA here matches the sequence of your target except for the edit that you want to make what happens at least what's thought to happen is the DNA comes into the cell lots of and Crick base pairing finds the target sort of intercalates itself it disperses itself in the DNA so you get this triplet okay and then as that gets resolved with some frequency the base change that was introduced in this template here gets copied over into the DNA so I think those two things the base editing and all of the nucleotide directed mutagenesis the DNA directed mutagenesis to this overall framework they probably fit best in the SDN to class because they're they're targeted and they are precise changes so I'm gonna move right along now you can imagine that with these with these types of with these methods and these reagents we can knock out genes we can change the spelling of genes so that they behave differently well we can insert an entirely new genes so we start to think about how can that be applied in crops and how can that be applied in livestock one of the first challenges we have to think about is getting those reagents into the plant cell and I bring this up here to this group is because some of the stuff here for delivery of the reagents is relevant to the governance piece to the regulatory piece so when we talk about delivering these tools into plant cells by far the most common way is to have these proteins at the CRISPR caste system or whatever you are encoded in in a gene on a piece of DNA and to introduce that DNA into the pens team using agro bacterium or a gene gun okay and then what happens is the gene gets integrated into the cell genome it expresses the tool with the CRISPR caste or the talent that goes and does the editing right and so you end up with plants that are edited but have this reagent as a transgene so what's done next is to cross the plants or to self the plants and then the next generation is those segregate out you find the individuals that have the edit but no longer carry the transgene those are called null segregates another method is to avoid the DNA encoding CRISPR cast from ever getting into the genome in the first place we start with single cells and we introduce DNA or messenger RNA or protein itself so that it goes in it does the editing and then it gets tuned up it gets degraded in the cell the challenge there is you have to be able to regenerate whole plants from single cells and for some species this is relatively easy and worked out and for some it's it's quite difficult third way to deliver these reagents in plants is to use plant viruses so sort of disarmed viruses that normally infect plants can be used to deliver the reagents or a DNA encoding their agents but the challenge here is to make sure that the virus can get access to what we call the meristem to a petition growing in that gives rise to the flowers and seeds because otherwise we won't get a heritable mutation so there are sort of technical four fronts here and they vary depending on the plant species that you're dealing with but they're good to be to be aware of because there's a lot of excitement and a lot of hype about genome editing but depending on the crop that you're talking about crop species there are lots of other sort of technical barriers that are being worked through to really realize the promise in the technology and just to just sum that up really quickly being able to transform the the crop species you're working with having well worked out methods for tissue culture regenerating whole plants from and also developing these viral vectors are all important sort of technological well it's the carrier's technological frontiers so in terms of what we can do in crops and these are all examples that that are either in in progress or or assumed to come to market in fact probably the first genome editing edited foodstuff that we'll see on the market is this high oleic acid soybean so it doesn't make trans fats it's good for a shelf life and you know buying it without without making trans fats trans fatty acids which have been banned by the FDA it's one example of improving quality you could imagine examples of biofortification increasing the nutrient content of of grains for example increasing iron in rice for example resistance disease is a really important one this is wheat its genome is extraordinarily complex there's six copies of every gene in this genome but one of these genes here is called mlo and if you knock out all six copies the wheat becomes resistant to a disease called powdery mildew you can see here the normal wild-type weed and here wheat that have been edited to knock out the gene at each location location that occurred in the genome so that was a real technical technological feat but obviously disease important disease resistance is a hugely important target for genome editing flowering time fruit quality storage properties herbicide tolerance the list goes on we'll be moving to applications in livestock we have sort of similar considerations about delivering the reagents so I'll talk for just for a moment about delivery typically what we're talking about here is delivering the reagents into embryos or into cultured cells cultured stem cells for example because the goal of course is to regenerate the whole organism delivery methods usually are I nucleic acid the DNA or an RNA that encodes the site-directed nucleonic into place and they usually just introduced directly there are ways to get these molecules into a plant into so sometimes they're delivered using a virus sometimes a messenger RNA which degrades rapidly or the protein itself is delivered and sometimes there are actually micro needles that are small enough to physically inject a solution of these reagents into an embryo for example analogous to the sort of technical frontiers that exist with with applying genome editing implants in animals cell culture clothing techniques are essential and again those are those depend on the species what techniques have been worked out so in livestock lots of different applications are being pursued and the paper doesn't talk about and I won't I won't really talk about kind of the distinct field of improving animals as models for human disease I'm gonna talk about that too much but in terms of agricultural traits for livestock there's a knockout mutation in the gene called myostatin that you can make this knockout occurs naturally in the breed of cattle called Belgian blue since you ever seen the Arnold Schwarzenegger cattle maybe you seen a picture of those guys so it's a naturally occurring mutation you can replicate that mutation using genome editing and you get pigs that make this kind of muscle relative to this this is wild here you can also have this has been done in goats and cows now reduce the allergenicity of milk using the Knockouts reduce the lactose content there are applications that focus on animal welfare and health one that you might have seen already the popular press is this pulled phenotype in dairy cattle dairy cattle normally have horns some beef cattle don't there's a beef cattle breed called Red Angus that doesn't have horns and geneticists discovered why they found it at this one gene the gene which gives you the recipe for horns there was a spelling change relative to other breeds and so what they did was by genome editing they took that spelling they the book of the Holstein genome and they change the spelling and so now instead of this painful and costly process of electro cauterizing born butts when the calf's are are less than a year old now genetically for genome editing thousands of dairy cows have been generated that nationally don't have forms and the DNA that they have is no different from that one particular gene no different from the Red Angus an interesting application in animal health was to bring a gene variant from warthog into domesticated think there's a African swine fever virus which is a hemorrhagic fever in domesticated pigs and warthogs tolerate this virus so there's there's an effort to move the recipe for resistance to this virus into the best kitty Pig from work life then another kind of interesting application is to do genome editing in chickens so that we can use eggs as bio act reactors to create pharmaceutical proteins or to produce proteins yes one of the important things there is to decrease the amount of albumin that are produced in these eggs so that it has more machinery available to make the recombinant okay so let me touch really quickly on a lot of these things we can do with breeding right but you can imagine the scale of the problem if you come back to that dairy cattle issue let's try and move in the polled phenotype the know born phenotype from Red Angus beef into into Holstein in that first cross you can get something between the two and you're gonna have to cross again to a Holstein all the while selecting for the polled phenotype it's going to take many generations maybe a breeders lifetime to get back to these high-quality sort of delete Holstein breeds that have just that DNA from the from the Red Angus so if we look at genome editing compared to conventional breeding for example the first thing that jumps out is the time that to achieve with genome editing we're on the scale of months with breeding we're on the scale of years and sometimes decades particularly leading a tree for example through treatments um precision with genome editing is very high with breeding it's high for the trait we can track that the horn gene but even if we do all the back crossing to the Holstein there's gonna be bits and pieces of the Red Angus do you know they're gonna persist and we don't know where they're gonna be and we can't control what they are so with regard to the rest of the changes in the genome genome editing improves on conventional breathing quite a bit she changes from the original parental genome I just touched on this you'll have the targeted edit often no other changes you might imagine that if the sequence that you're trying to cut at as a sequence similar to it somewhere else in the genome there's some probability you might cut there as well these are so-called off target cuts so those need to be taken into account with breeding however as I mentioned you'll get bits and pieces of the donor apart from the gene you're interested in and those can integrate at random in another method for generating changes is to mutate randomly so let's not talk about targeting a place and making a cut but having a population mutating it and then just finding that individual that has the trait that you want happened to happen to have just the right spelling change in that gene on that page in the recipe book and then trying to restore that you didn't back to the wild-type by crossing it to the to the parent again that's a months or years long process with extensive Brack processing it can be years there's absolutely no precision with that it's been used successfully in breeding for a long time but again the the changes from the original parental genome will be many and they'll be random with you if you do a lot of back crossing to the to the original parent you can eventually get to about only five percent of the genome being different still as a far cry from the precision then the last sort of method of modifying is Janette of that water plant is conventional genetic engineering so this is trans gene insertion we have no precision with this because when we introduce the trans gene that could integrate anywhere into the into the genome of the organism this process is not typically as long as breeding but it's it's months to a few years the difference from the original kernel genome will be the presence of the trans gene but if you think about it since we can't control where that trans gene goes it could insert someplace and just right in the middle of another gene and disrupt that gene or it could insert upstream of a gene that's usually off in five expression of that gene so there can be sort of these off-target effects these position effects that have traditional genetic engineering as well what about the regulatory landscape I guess all of that is sort of the background that you need I think to to consider the issues that come to bear with regard to the regulatory landscape so in the u.s. there are three federal agencies as many of you may well know that have a hand in this the USDA the how the organism was made matters as much as what how they were cannabis is different matters and specifically the USDA is is concerned with whether any plant pests DNA was used or whether the product is now a plant pest or a weed so if it's very strict rigid definition and if you think back to the ways that I mentioned introducing the DNA to the plant I mentioned agro bacterium Mycobacterium is a plant pathogen right it causes crown gall diseases disarmed and only its ability to move DNA and is retained but bits and pieces of the DNA that go in our plant pathogen or plant pest arrived with the FDA the trait is the focused and their question is is the product a drug or is it a food and if so is it safe so they have to sort of that mission that directive with the EPA similar to the FDA the trade is the focus but the question is different does the trade allow the production of a pesticide VDU Brian Canada all bubble plant traits are regulated equally regardless of how they were generated so if something comes to the regulatory agency having been bred having been generated by as a GMO by traditional conventional transgenesis or genome editing the first question is not about that the first question is how is it different and what's the trait difference here is that safe METU the process is sort of reigns the GMO directive of the European Union has a very strict definition and all the regulation is based on was the product made using transgenic technology so that's why it becomes important to understand the differences in these these delivery mechanisms you can deliver as a trans gene and get that null segregate and the second generation or if you're able to do it in the plant species you're working with or the animal species are working with introduce the reagents transiently so they do their job and disappear and then the challenge is to regenerate the whole or in a single cell so recently in the US a couple things have come to the fore for some time now the USDA animal Plant Health Inspection Service has been publishing responses to letters of inquiry that they get from researchers from nonprofits from from companies then these letters of inquiry ask here's what we've developed does it fall under your regulatory purview and you can go in online you can just google these terms you'll find it right away you'll see that without exception genome edited plants for which the trans gene has been segregated away so the only difference now is the edit the USDA has declined to to review them further and so as long as there's no evidence of any plant pests DNA and the plants are not weedy they clear that hurdle in March of this year secretary Purdue released a statement saying that the USDA does not regulate or have to regulate plants that could otherwise have been developed through traditional breeding techniques that's huge if you think about it so that kind of covers that STS vestian one class of the STM to class and in some cases the SDM three class if the piece of DNA that's inserted comes from a species that can be crossed but he left in this part as long as they're not plant pests we're developed using plant pests so that leaves gray this area of whether you can use agro bacterium braving some of those plant viruses that I talked about the European Commission commissioned a group called the new techniques in agricultural biotechnology working group and asked them to sort of you know take a bite try to digest this this whole field that makes some recommendations and their recommendations were that Sdn one its from random mutagenesis you get by making the cut and having the pieces stuck back together should be excluded from the European GMO directive because it's similar to conventional mutagenesis which has been used and generally regarded as safe for years Sdn two and then all of the nucleotide directed mutagenesis are equivalent to mutagenesis Ora they didn't really provide clarity on the size limit well is that one base two bases a few bases after how many bases does it become Sdn three so that was left unclear they further recommended that that Sdn three clearly creates new combinations of genetic material and should be covered by GML directives so there was partial clarity here but still incomplete on exactly defining what Sdn to is and where where the line between those two in an ongoing case which I had already expected to be resolved by now but it hasn't been but sort of an early opinion issued in that case by European Court of Justice advocate stated that some genome and organisms need not be regulated in the same way as conventional GM organisms that's great but what right but at least it's trending in that direction further went on to say that Sdn one and STM two are generally quit to mutagenesis but again provided no clarity on whether integration of a repair template constitutes genetic modification Regina and what size and nature of the edits distinguish the SDM to from the SDM screen so we're expecting a definitive legal interpretation from the European Court of Justice soon maybe don't hold your breath I'm not sure I thought we'd have a rate of weather stm-1 an SDM tour to be excluded from the GMO directive paper ends with with some perspectives and here this was the most challenging part not to insert opinions I think but but we just tried to keep it as perspectives and and regarding the economics of Agriculture and how this new technology might impact it it's really clear that provided a conducive intellectual property landscape and that's a topic for another time you know mandating may help smaller companies and public institutions to innovate particularly in specialty crops and livestock species the technology is accessible you know you hear about people doing it in their garage and stuff it's not quite that easy but it's it's it's quite easy to do and and if there's a conducive intellectual property landscape regulatory landscape to really stimulate innovation in this small and by small industry so with regard to public attitudes it's a bit of an unknown right now but our conclusion was that genome editing is likely to be subject to the same underlying factors of information processing and and risk perception that have been found to influence attitudes toward other technologies and the key point here is that for human beings the unknown or the unfamiliar gets assigned a higher risk right and that's just as part of a natural part of I saw a psychology so I think it'll be important for everyone who's thinking talking about GMOs or sorry genome editing doing the genome editing to do their best to make to make the technology accessible to the public so people understand it and aren't subject to that from overblown risk perception of the uncompleted there were some surveys of subject matter expert Stan and kind of disappointingly recommendations vary quite a bit and the message that came out all this from from the studies that our social scientists did was that these recommendations by subject matter experts were influenced strongly by their own perceptions of the precision and safety of the technology but also by their world views about technology and society generally so that is to say that we can't necessarily rely on subject matter experts to provide us unbiased assessments I just shoot myself in the foot maybe I don't know anyway so what about nation-states here's another kind of interesting perspective and we think about trying to think about whether it's even possible to get the coordinated framework for for governance across international borders national priorities cultural perceptions politics trade issues our conclusion was all of these things make harmonization of governance unlikely if not impossible it may be even undesirable so I'll leave you with just some conclusion that I hope I have a few minutes for for questions we conclude the paper with two two statements one that the power of genome editing suggests that again is conducive the conditions exist social and regulatory conditions you can substantially increase the positive impacts of plant and animal breeding on human welfare and sustainability but it's successful deployment for crop and livestock improvement will benefit from science informed value attentive regulation promotes both innovation and transparency so the jury is out still on on how the public will view genome editing and our conclusion was that for us to realize the potential of this technology scientists including myself we tend to think if people just understood it you know right it's not so scary but it's more than that I think the regulation has to be attentive to values and then there has to be a concerned effort to make it transparent so that's kind of how we end and the paper now is available online so you can share it with your friends if you find it valuable and I hope that leaves us just a couple of minutes for questions and I thank you for your attention we've got a backlog of information of genes just crying out to be edited and actually part of my my day job in fact is is to find and characterize genes that play a role in my defense resistance genes both knockouts or allylic replacements I mean breeders have been working with material for a long time there are there's a again sort of a backlog of molecular biology studies that have given us great candidates so anything from biofortification and we know how iron levels are controlled in the seed we know what types of genes can give us resistance there you know enzymes in particular pathways that we can either knock out or swap in to change the oil content of a seed for example so it's critical to keep that research going we need the fundamental research so that we understand diversity of genes that look for that trait all the different recipes that you could that would work and how they all differ but there's certainly no shortage of traits to be pursued and there's a lot of stuff going on already one thing I would stress so again though that that's I think we need a strong emphasis on at the federal funding level and even in terms of curricula in universities is this issue of plant transformation and tissue culture it's kind of a dying art and it's been it's it's absolutely you know critical nature has been brought to lighting in by this yeah right yeah I should have qualified that something you're right yeah I'd like it very much depends on the crop especially crops are way behind in that right right crops like rice which was the second genome to be sequenced after the mom allah rabbun OPS's cluster it is to a model or the the more readily knowledge from mammals plants can be translated sort of a better situation we're in right now but you have to say right the long generation plants like trees it's a little bit more regeneration tissue culture absolutely even within one plant species surprises are easy uns alarmed at a magic wand I would get Berkley and caribou Biosciences and MIT and the road institute to cross license their technologies and be done with it so these guys have the dominant IP in CRISPR cast and the fight continues about we clearly Jennifer Doudna in her group were the first to show that the system could be customized to target DNA sequences of choice and their patent made claims to using the technology in eukaryotic cells delivering the reagents into a nucleus so it would meet up with the genome but there there the data they had were in a test tube and then Fung Jung and colleagues and George church on the East Coast were the first to put it into human cells and get it to work in that context so they're fighting it out and until that gets settled you know people certainly some companies I'm aware of are sort of hesitating to which you know to throw their hat in the ring until that gets squared away they don't want to pay licensing to this company and that happen I put that IP be devalued by a talyn's caliphate the nucleus is sort of avoid that problem the landscape has been settled for some years now there was some cross licensing of the parties that owned the dominant IP to that you know exactly going to go to four four towns if you means that technology so there's an advantage there so it's not a completely unsettled regulatory landscape but for Chris Burke acid is still and so people still hesitate we touch briefly on gene drives but we don't go into into depth about that but you're right that's a really exciting an interesting application of genome editing there are strategies that can be developed to introduce a genome spelling change into a single organism there's that organism goes out into the wild and interacts with and breeds with other primers that population you can skew things so that the inheritance of that change is close to 100 percent and so some really common examples when we talk about genome editing are sterile mosquitoes or mosquitoes that are resistant to the podium that causes malaria that's right so gene gene drives been around in concept since way before genome editing the ones I've seen are pretty technical not so maybe that's a good suggestion is to talk about to send a suggestion to Kent on a cafe protein drives it was a little bit larger than the scope of our paper here yeah thanks bring that up for fishing yes that's a great question so for people who are listening to the recording let me try and summarize that question given the ever-expanding tools and approaches that we're getting lumped into this topic of genome editing you know how's the definition of genome editing gonna change over time and we know talyn's and we had CRISPR so it's sort of easy to grasp but now we have these bass editors with you know DM we have Ted cast 9 attaching different enzymes to it I think one thing that comes to mind right away is that the competition for intellectual property is driven discovery in this area for sure we want to find variants then to things in ways that the currently existing tools don't there's one good example of that it's a tiller cast protein called cast 13a or V I can't recall right now and that targets actually RNA so message rather than the genome itself there are ramifications of that you may imagine and there are there are applications being developed in which a targeting reagent is fused not to an enzyme that cuts deep but that chemically modifies DNA and for those of you who might be familiar with the term epigenetics these are chemical modifications to our DNA that effect which the genes are expressed and it's a dynamic thing or epigenetic state your liver is different in the morning from what is an evening your epigenetic state is different when you're in particular cells when you're under stress and whatnot so being able to engineer a genetic state and craft which genes get turned on and off is also a burgeoning field right now I have colleagues who say with genome editing if we restrict it to this sir you know making targeted changes in the DNA sequence tomorrow there may be a completely different system that's even easier to use and in terms of the issues that come along with this it's not so much the technology that allows you to make the changes it's it's about the changes and what changes you can make and how they're and how the technology is applied I can tell you when we got our patent for talent after nucleuses was it how could it get better than these I mean these are like Lego blocks you can put them together than 18 months later we had whispered hands it was amazing so maybe nothing comes it's easier or better than CRISPR cast but certainly variants are coming all thanks know if I answered that very well if the page in the book is not there in the mustard if the recipe is missing you'd be inserting a gene and that would be an escape ibly st in screen if the recipe was there and he uses molasses instead of brown sugar right and you go in and change it to brown sugar that would be SDM – if what gives you resistance is the absence of the gene the gene is absent in the resistant kale its present in the in the susceptible mustard you could use Sdn one just to knock it out so the the right answer to your question depends on what we know about the genetics yeah and it's not entirely clear yet you know what the US DEA is gonna do about stm-1 stn – Sdn 3 because you can imagine even examples of Sdn 3 that could be achieved by conventional breeding interesting a new gene according to you know their current position that would not be subject to regulation as long as it were not didn't the plant didn't retain DNA from a pest we need so the time we ever yeah okay

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