 Thanks everyone for being here. This is a nicely correlated talk about food and agriculture, which I think fits pretty well with this being at least here in the United States Thanksgiving week. Hopefully you all had a wonderful feeling big meal, probably full of some of the staples, some of which I might reference here, but hopefully lots of very bountiful food as well. All right, so let me begin. I am Stephen Gager, Stephen Suitfly in World, and my talk today will be a brief history of genetic modification in agriculture, breeding to biotech to genome editing, and I forgot to you know put in the original title, this will be entirely a talk about plants in agriculture. I will not be covering a course to be very relevant, but not as advanced field of animal husbandry and breeding. Maybe I'll save that for a future talk. So the structure of the talk will be origins, chronological in a sense to the some of the touching upon archaic breeding techniques, what are some modern breeding techniques, and then get into the exciting, at least from my perspective anyway, biotechnology and genome editing aspects, which is where in my professional histories where I came into this field around the same time. No, I won't be talking about Turkey's law, Phil, unless you come up again in conversation. So I do want to make a quick point that I am a researcher at Corteva Agro Sciences, which is an international ag biotech company that operates in the space. I'm not here to represent the company's positions and nothing that I say should be construed as investment advice or company forward looking statements. And in fact, to some degree, I've tried to exclude or downplay some of the interesting things the company is doing to try and not represent any sort of bias coming in there. So early human history and when we think about dividing up the geological epics and eras of the history of the planet, the most recent that interface with when humans are available are the paleolithic ends somewhere around 12,000 BC, 14,000 before common era type of dates. And what's represented here is that in essence, the human lifestyle at the time was nomadic and did not have a lot of in terms of group organization, a lot of advancement. They were dependent upon the environment for food. They were not aggregating and larger complexes for the most part. And so very non non technological advance as well. And again, everybody was participating in the activities of any given group. Now what's represented on the white is the neolithic, which is what we consider to be the essential beginning of a modern way of humans living. This represents the organization into townships, the fact that people settle into the same geographical space. We see within these larger population centers, the actual development of what we would start consider modern society where again, the key thing here, where agriculture is relevant is that once you have fewer people engaged and necessary for the gathering, the provision of food, then more people get freed up to be able to do more professions, more work, even have leisure time and leisure time in many ways is credited with scientific, technological, literature, art advances that are very important. And I am mentioning here at the bottom that one of the things that's kind of a little bit counterintuitive is that there actually ends up being overall less healthy people within that within that time period. And partly that's because you're now compressing the variability of food that's being available that if you are trying to make sure you are providing abundance of calories, what ends up happening is that the diversity of food ends up becoming lower. And then this also kind of begins the era of seeing tooth decay that again, as some of these staples are being provided and are trying to go for those higher calorie density things, you actually start having more sugar based diets and you can actually see tooth decay in the archaeological record at this time. But then in addition, because people can be sedentary with their lifestyle, again, when they were hunter gatherers, they were always moving, right? There was a lot of movements involved. And so that aspect of it as well related as related to the food, but also the lifestyle was different. Which again, is maybe to some degree something we see again today in the modern era as well. So one of the big questions has always been, you know, what is the progression of having cultivated food versus the actual implementation of domestication? And how does that relate to, again, the sort of cooking and technology we had at the time? And so one of the things that came out just in the past five years, and this has been debated several times, but this is probably the paper that kind of broke through the concept, is that bread preparation clearly predates domestication of foods. And so now again, domestication being a slightly different concept than just the kind of careful cultivation of food, where again, you might be making sure you're collecting foods, if you're collecting seeds, you might replant them. But in terms of actually domesticating them into varieties, and that's where domestication, how I'll use the term domestication, where there's very specific culturing, selection, regrowth of saved foods, and then recultured for re replanted for another season. And you start to see these adaptations in the plants for a civil study purpose. And so this is just work that came out in 2018. Very interesting demonstrating that if you look in the Middle East, that they were able to find what is now kind of modern day Jordan examples of fireplaces that again, between carbon dating, other cultural artifacts that are available, they can get a much better clear picture of when these existed. And so now they're they're dating these as to to be around 14.4 to 14.2,000 years ago. And again, this is using what's now called a a radio carbon dating that's properly calibrated. And now what was and then when they took plants residue planted artifacts from this, they're able to show that in these electron micrograph pictures, that you see stuff that is very indicative of bread. And this has to do with the poor size. This has to do with the composition that you see of them, the shaping and a bunch of other characteristics that make it clear that bread is being prepared. And that but the main fact was that this fireplace that they uncovered that they could get a very nice and reliable accurate dating of when it actually was in action and was being used. And so I think this is one thing that's important that the, you know, the ability to recognize that there are useful food stuffs that there are things that one can turn into food that are available in the environment that did precede the actual organized domestication of plants. And this kind of makes sense. Again, you can have a fireplace and still be nomads. But the actual settling of a ground of an area is what you need to then have crops, cropland, etc. And they're with the dryer. Alright, so what I'm going to highlight are a few major crops. Again, when in researching this, we think about crop domestication. I'm going to highlight some of the big ones in terms of overall calorie and acreage planted worldwide. I'm not going to cover some of the smaller ones. I'm even going to focus on some that have more relevance to the genetic modification topics as well. They do think that, you know, there probably are at least 24 independent domestication events in history in all around the globe that represents a variety of different types of foods that are being domesticated. And one thing to kind of point out, when you think about how rice is highly prevalent in Asia, and its main way of making bread is usually to steam it as compared to what you might have with wheat and its cultivation and baking that's more common in the Middle East, that some of the reasons why some crops get cultivated in different areas may have actually had to do with these predetermined or pre established habits that one had and the types of food that one liked in the first place on how to prepare it. So I will mention so rice. This is one where nice example of how we actually analyze these is that they will so the husks and the shells. And there's just part of these that are hard protective covering that you have in rice grains that are known as phytoliths. And so when these are preserved and they tend to be relatively well preserved in the archaeological record that based on their size and their composition and their shape, that those are relatively reliable proxies for the crop having actually been domesticated. And so this is one where there's a nice amount of analysis showing that and 94th out sorry 9400 years before common before now that they were clearly domesticated in the lower Yankees Basin wheat is well characterized as having been first domesticated in the fertile crescent. Exactly where and when is not entirely established, but it's very clear that based even on genetic evidence and the pre existing still domestic the wild forms of wheat that are in that area that somewhere on 10,000 years BC. And there's a low established known wild varieties known as einkorn, emmer and spelt. And what I have here on the left hand side is some examples of the grains from these domesticated versions. And on the right, again, highlighting yet again, yet again, another geographic area, South America, that corn, which again, people actually starting to call maize now, but it's the genus Zia, that about 9000 years ago somewhere in the, you know, somewhere in the nine to 7000 BC time that these were essentially grasses that became domesticated into what you see and so the image on the right is showing Tia Sente, which for a long time people missed was the actual wild ancestor to corn on the right. And you can see why be relatively easy to miss that based on morphology, because on the right, you have a cob. And today doesn't seem to have one, but somewhere in the line, natural selection, domestication converted it from the Tia Sente to a much more bountiful kernel on a calm basis that we know in modern corn. So those are the cereals. And I just want to mention a couple other fruit and veggie that banana is something that was cultivated in Southeast Asia, again, somewhere in the range of 7000 BC. It's interesting, there's a high diversity of cultivars that in terms of how people use them and how people domesticated them actually are quite a number. But what's one thing that I want to mention, as for those of you who love bananas have a scary story coming up, if you're not already aware, that the domesticated forms are propagated vegetatively. And these have actually been managed to be cultivated around the world. So one of the places where banana plantations were set up, of course, was in Latin America, which had a nice tropic climate for its for its cultivation, but actually plantains, the third most valuable crop in Africa. And so potato is another one. Again, we think of it as being highly associated with Ireland. But in fact, it was probably cultivated in the Andes in South America. Again, another one in that range of about 9000 BC. So and again, whether it's a pretty wide variety of cultivars that are out there. So what is domestication? Yeah, so since she asked kind of an interesting question, again, the way people tend to distinguish, and I have this here, I'll start with this on the right, is that when you think about what is the term plantain versus banana? Again, I'm not entirely sure of all the specific genus species and proper taxonomic naming of them. But people tend to refer to bananas as ones that are, again, these are the same species, right? But the banana is something that is a handheld fruit. It's very peelable. And it's something that you eat uncooked. Whereas the plantain is extremely high in starch has a tend to be a much tougher, thicker peel. And so they're really only suitable for cooking. So in many ways, I think that's one of the classic ways of distinguishing the nomenclatures that plantains you cook, bananas you eat raw. And so that's an interesting point, right? Is that bananas and cooking, the way you actually end up domesticating these is you keep selecting for ones that keep having favorable traits that you want. And so an example of plantain, you might be cooking that you might be selecting the ones that just keep producing the best cookable types of product. Whereas bananas, you'd like for them to one be nicely easily peelable. Another big feature, for example, in the kind more modern global aspect of bananas is how well they ship. And so the ripening time, how durable they are when being moved, those are all things that end up becoming important things to look at. Kind of what's the more classic and more well known examples on the left, showing rice here on the left, that you know, a lot of these original domestic or say wild cultivars, just we're making enough seed to propagate themselves. And in many cases, you didn't have very, very many seeds per stalk. And that's what you see on the right hand side is a couple of variations, which is one, the fact that you have much more bountiful in terms of what you're actually the useful part of the plant, more bountiful per per plant. Each one is thicker, you know, so the seeds are actually much bigger. You also have a lot more per per branch that are available as well. And then another important topic, which is known as shatter. So again, one thing you want to do as a seed in the wild is you definitely want to be dropping off. As soon as you're mature, so that you can then get spread around and keep propagating your species. But in domestic, a domesticated form, you really want the seed to be on there durably enough, that it maintains until harvest time. But then once you harvest it, you want it to be able to fall off and then be usable more easily. And so those are some of the main characteristics that you see, but a lot of it has to do with yield potential. So one term you might hear is productivity or yield. Now interestingly, this is true for corn, and you see this in wheat, that one of the downsides, and something that does happen as you try to increase the yield is you actually make them more vulnerable to environmental challenges. And so one thing that you can have in cases where if there's a lot of wind that comes through, it can actually blow down on the stock. And then suddenly you can't harvest anything actually lose your harvest. And so a really good recent example of this in the United States was here in Iowa, a derecho came through which basically was a land based but hurricane force winds that knocked down and basically ruined 30% of the Iowa corn crop. So again, these are things you have to balance all the different aspects of the yield versus vulnerability. Oh, sorry, one other quick thing to mention, of course, that does come up is, especially in the case of wheat, you know, how usable your domesticated crop is can relate and things that you try and breed into it. So gluten is a really good example that when it comes to making nice bread loaves, you want to have enough stuff that sticks it all together. So it's a nice solid compound. And so gluten is an example of something where again, there also can be in small situations, downsides to its prevalence within the within the food sources. So let's talk about some of these original domestication events and how they relate to modifying the genome in particular. So this concept here, you guys should be familiar with the concept. Hopefully that you're you have two copies of each of your chromosomes, one copy that came from your father, one that came from your mother. And you are a so called diploid diploid for two, meaning you have two copies of the genes. But in nature, the examples of being tetra ploid. So tetra meaning four, or in some cases, actually, we talk about things being hex ploys, so six copies of each genome. And so what I'm showing here in this diagram is kind of the history of domesticated wheat, that in the wild, there were typically diploid versions of the different wheat. In the wild, emmer actually was an example of a hybridization, where two species and again, the chromosome contents is denoted by either an A or a B or a D. That wild emmer in this diagram, you'll notice is actually AABB. So again, it's a it's a tetra ploid because two different species hybridized. And then what happened during the cultivation time, one of the key events was the cultivated emmer being bred, but then a variation of it on its genome led to a nice wheat based variety. And then another hybridization with I think it's actually characterized by the time by by now, but they're pretty sure it's this one DD species, that that actually now is hex ploid. And that hex ploid is what we most commonly think of as bread wheat. So again, these cultivation, these hybridization events occurred in the wild. But because they were noticed, and they provided an advantage for the cultivation, for the cultivation, the higher yield, higher grain, again, better gluten, they were actually then cultivated and maintained and became more predominant. So this example here shows the next one, this is a nice one where it's actually showing the relative yield from a from a tassel for each one of these, that the AA diploid, the BB diploid, and the DD diploid, which you'll see at the top and on the right, the amount of grain you're getting from any one of those is a lot less than the three most commonly cultivated versions that are the result of, again, hybridization. And so again, very nice example of how genome modification on the whole genome wide scale can lead to at least in this type of species, this type of kind of advantages for for society and humans. Another example comes from bananas. And so what's interesting about bananas is that a lot of them that are being cultivated in the wild actually do purposely hybridize them to make the yield, and they are maintaining those, you know, parental diploids. But what was kind of recognized is that if you're a triploid, again, you have some event that leads to three copies of the chromosome, then those are not able to reproduce. And in fact, they don't even go through the reproductive mechanism to making seeds. And so when it comes to a hand fruit, then there's clearly a big advantage for not having to remove seeds. They're much easier to work with much easier to eat directly, like as a hand fruit. And so some of you might remember the Big Mike banana or the gross Michel, which was popular for the 1950s, which again, this was something that was a little bit of a history of it was just being brought back to Europe and then being cultivated. And one of these ones where because they don't make seeds, they have to be propagated vegetatively. Again, you take, well, you can in modern days take some cells in them. But in most cases, you take a sampling of a branch, and you manage to get it to root and that becomes this whole new tree. And so the problem with this, and this is something that's really important to recognize when things are diploid organisms, that things that sexually reproduce is that it gives you a lot of genetic variability. And so the other way of thinking about these triploids is that they're all clones. They're all clones of each other. And so if there's, if there's a disease that affects one example of the cultivar, it will affect all of them. And that's what happened with the gross Michel was that the Panama disease basically wiped it out worldwide. So fungus, as somebody mentioned in the text chat, fungi are extremely interesting and robust, eukaryotic single cell organisms that do a lot of really interesting metabolic things. And they also in many cases make very persistent, durable parasites. And so that's what we found in this particular example is that the Panama disease wiped them out worldwide. And most people think that as Brian is mentioning the big mic had a much more flavor to it than the Cavendish. But the Cavendish end up being resistant. Again, it's also is a triploid. It's something that again, is clearly propagated. But in the day waning days, the big mic, they found that the Cavendish was in fact resistant to the tropical race one of Panama disease was also again, very commercially friendly, you could cultivate it, grow it, it was easily shipable, it had a had a nice flavor to it. And so. But even today, the Cavendish itself was also under threat, because the Panama disease has basically evolved over time to what's now known as tropical race four. And Cavendish is quite vulnerable to it too. So tagline asks, I think an interesting question where I presume there's an implication behind it, which is, you know, do we archive these seeds? Are they something that? Hey, if we get rid of the disease, can we bring back this particular banana? And so yeah, again, there are some examples of big mic plants that exist out there. There are a variety of seed vaults. Again, if you're not, if you're not, I've talked about seed vaults. And before there's actually one in Norway, that's kind of the world seed vault, but every country largely maintains their own seed vaults. But the problem is, if you think, oh, well, you know, the disease comes through the way. And so let's just replant everything after say 30 or 40 years. This is one particular problem with fungi is that they are durable in the environment for decades. And so if you were to go out and try and reestablish a big mic plantation, then, you know, you're just going to basically be dealing with the same problems, unless unless, of course, we use some modern biotechnology, unless we science these things to be resistant. Okay. Let's move on. So these are things that classically existed. And when I think about these hybridization events, people recognizing that over time, that they basically domesticated them and had their best cultivars and again, tend to be a little bit regionally inclined as to what were the dominant cereals, dominant food sources. So you know, we've talked about this a little bit in the past that rice is obviously quite predominant in Asia, you have wheat middle in the Western world, the Middle East. What you have is a lot more maize and corn, we think about Latin America in terms of more archaic civilizations. Sorghum and millet are some ones that are worth talking about soybean, a variety of other beans and peas in Asia are also highly prevalent. But these are kind of like the big three that account for a pretty large, I think these cereals accounted for about 80%. But plantains, potatoes, or also, in some cases, the staple food crop for different regions, where you don't actually see the cereals as popular. So modern breeding, this is like a really good example. This is something that's highly accelerated. Again, in terms of the amount of time that these different varieties have existed. These are things that, you know, we know from the past few 100 years. And so the mustard is a good example where very intense, artificial breeding, selection, again, not changed in the genome per se, but just intensified short term selection can get you things that look very morphologically and in terms of taste very different. So cauliflower, broccoli, cabbage, kohlrabi and kale are all examples that these are all derived from one plant, the mustard. So brassica is something we'll do a little bit too. Yeah, I know. I learned this in grad school. I was like, no way. Again, so one model organism that you might have heard about is something known as Arabidopsis. And Arabidopsis ends up being a very useful plant. And if that was the first plant that had its whole genome sequence as well. So the one of the other major advances in modern breeding was the recognition that you can have two parental lines. And these can be bred in a way that they're very inbred that a lot of their genetics are very similar to each other. But was recognized by a shawl. I think kind of serendipitously is that you can take two inbreds that themselves seem to suffer from a lack of genetic diversity aren't growing, aren't necessarily all that robust. But if you cross breed them, then the hybrid that comes out of it is incredibly robust. It's more robust than either of the inbreds alone. And can really maximize a lot of genetic diversity. And so this idea of doing what are called hybrid crosses, which then ultimately became what are known as dihybrid crosses. So you do two rounds of inbreeding before you actually make the final hybrid has been an amazing advance in corn. And so what I'm showing you on the right are the parental corn from what are known as is the infamous copper cross. And so the copper cross again pioneer in May's agriculture, Henry Wallace, who actually ultimately became department, sorry, the secretary for the Department of Agriculture and actually vice president. He here was in Iowa. And he basically generated this hybrid cross and showed and basically started winning, you know, state fair year races year after year and shows how much bushels per acre he would get. He ultimately founded pioneer, which, sorry, well, pioneer hybrid, which I'll show in the next line, which ultimately was purchased by DuPont and then merged with Dow, and then has spun off to the company I currently work for, known as Cortava Agro Science. But what the hybrid hybrid corn company did, again, founded by Wallace was to really maximize and understand this hybrid hybrid vigor, and then actually specifically breed inbreds that then they sold the hybrid seed. And so what we're seeing here is the average yield per acre in the United States of corn, starting with this idea of selling inbred lines to farmers and what that how that dramatically increased starting the 1940s. I know it's basically an exponential, well, I guess it doubles over a certain span of time. It's a linear linear increase. Again, this is not entirely due to the use of inbreds. There's obviously been mechanical, agronomic practices, fertilizer, so but what's very clear, and I'm not showing this here, is that the actual yield potential of corn right now when they have these contests where people are trying to maximize the amount of corn they can get per bushel, that's actually in the 600 bushels per acre. So this 177 average is just what you have in your standard environment, but the actual potential yield of corn from these hybrid crosses is actually a few fold higher. Let's double times higher, I should say. Now, one thing that I think is important to recognize is that this inbred strategy has another value to it, which is that what breeders can do is find inbred crosses that really maximize the genetic potential for any given region or any given expected climate change that you're going to have that year. So if you can basically customize your inbreds for being better for growing the south versus being better for growing in the north versus insect resistance versus drought resistance, et cetera. And I think it should be really interesting. Hopefully this will make it a lot more than popular press. But here this year in Iowa, we had basically pretty persistent drought with a couple bits of relief from rain. But we had a really high long drought season. But the actual yield is going to be basically around this 177 bushels per acre. And so the fact that pioneer, now other companies have been trying to breed drought resistance, while not sacrificing yield over these past few decades has really made that possible. Alright, so again, this is one example. Again, there are attempts to take things like wheat, as well as rice, people when the Holy Grail has been to try and make those a hybrid vigor, you know, inbred crossbreeding types of plants, but they don't exist that really that way right now. Okay. But some of these concepts of looking for the best cultivating and breeding for the best well adapted crops that you plant, again, not necessarily inbred crossbreeding technology, but just in general, really had a profound consequence when it came time to what we also have as an incredible population growth, as well as, you know, let's just say the distribution of food. So Nolan Borlaug, he basically is most famous for having ushered in what's called the Green Revolution. And he was working in Mexico, trying to devise and very rapidly breed new varieties of wheat, in order to basically feed the population, basically to have a sustenance level of food for Mexico to be able to feed its own population. And so I think that's an important point is that at the same time that we have a lot of population growth, we needed agriculture to keep up with that. But North America is not is not really set up to feed the whole world with all the different varieties of food, all the different cultural practices are the best calorie density, and people need to be able to grow enough of their own food. And as I mentioned before, having good food security within the country also means that other economic factors can help take off. So Borlaug is most he basically initiated this around Mexico. But his lessons from this, and basically the people who learn from him, the his trainees or acolytes, basically spread this around the world. So India was another big beneficiary of better rice cultivation practices, and around and in China, Africa, other places. And so he actually won the Nobel Peace Prize for these contributions to society in 1970. So far, he's the only agricultural person to have won the Nobel Peace Prize. But really people credit him as probably being the Nobel Prize lawyer that saved most lives, because that basically numbers even in that decade of time, probably in the tens of millions of people. And that's just that's not even counting the amount of Okay, my heart is not advanced. Okay, here we go. All right. And so some of the work that I think is really relevant to talk about and how we cultivation worked is taking advantage of the polyploid. And so the diagram on the right, kind of a nice, a little bit better picture picture recapitulation of the diagram I showed before, really showing that, you know, you have this strain, this parental erotu, which is green as the AA, and the spelltoids that are the BB those are blue, you can basically get your dihybrid, that is now a tetraploid. And then that outbred with cross with the DD gives you this hexaploid, the bread wheat stadium. And what's really important and has been been going on for some time is that the artificial ability to create a base of the hybrid, which is shown here on the left hand side was an AB, and then a D prime, which is now being showed as red, that you can basically inbreed new varieties of wheat that are diploid into and help create more genetic diversity, that then you rebreed with these classical cultivars. And so this strategy of trying to bring in more genetic diversity, using this trick of genome doubling, which is getting done a little bit artificially in this case, is a really powerful method for maintaining diversity of wheat, as well as helping them become more specialized or adapted to different situations. And again, maintaining the increase in yields. Yeah, I don't really want to get into Malthus. I don't talk about Malthus as being a, someone helped inspire Darwin. But but I also don't want to dismiss it too much right now either, because one thing to keep in mind is that, you know, the amount of cultivated land, and what, what cultivating and agronomic practices, especially when done poorly, means the amount of arable and land we have for growing crops is becoming limited. And we are straining that capacity. So but I don't want to get too much into that. We can maybe talk about that at the end. Okay, so let's talk about, again, the stuff I've described so far. In many cases are people recognizing cultivars or strains or examples of plants. And you keep breeding them because you've noticed that they're special and have that extra power to them. Again, while people knew genetics, the amount, the ability to apply a lot of fast molecular biology genetic markers to things was so relatively limited up and through the 1990s, even early 2000s, just because the amount of genome and the amount of computational data needed to look at that. But these are very powerful things that set us up for this next phase. Yes, that's what I was mentioning is that, you know, our soil nutrient depletion is a big part of the strain on soil, which, again, we can actually come back to a little bit at the end. But that is one of the things to try and address with biotechnology and genome editing is, you know, how can we actually help maintain soil nutrition? So I want to talk about a bacterium first, which is the agribacterium tumifaceans, which is a natural predator plants. And in fact, it helps, it was recognized as creating these things known as crown gall or crown gall disease, which you see in the left. So if you look at that, it looks like, oh, it's an out of control plant growth. And that's kind of where the name comes from. It looks like a tumor, right? It looks like a cancer tumor on the plant. And so this has caused, again, a nice amount of work starting in the 1940s and through the 50s helped establish that what's creating these goals is an infection by a bacterium. But what the special thing that this bacterium does that was kind of new and novel at the time was it will actually inject its chromosome, its DNA and integrate it into the host plant. And then once it's integrated to the host plant, it basically drives the genes and genetics to make it go with this out of out of control growth. Now, you know, you look at that, you know, as a scientist, you're like, oh, it's bad for the plant, but maybe that's good for me. And that's actually what, as people figure out how the biology of the agribacterium works, how the infection works, how it actually integrates into the genome. They realize this is actually an incredibly powerful gene delivery method for agriculture. And so what I'm showing the left is the vector construction, it's a bunch of diagrams, you don't need to know it. Let's just basically showing this idea that as a scientist, you can basically take a gene, get the gene of interest you have put together in a way that will go into the agribacterium. And then the agribacterium will integrate it into the plant. And so this was first applied for in patents from Monsanto. And this was used, okay, so the first techniques were actually just to prove that you can put a gene into plants. And then something that was a can of mice and resistance. But in terms of an agronomically useful trait, glyphosate resistance was what was done first and patented by Monsanto. And so I have, and this diagram is coming from that that European patent. So soybeans were the first to undergo the field trials and commercially sold. But cotton, alfalfa, canola, sugar beet, maize, all followed. You guys have just heard of Roundup Ready, right? No, no, so Phil, I mean, I what I should be very careful to say is that, and I'll show this in the next. Oh, where is that diagram? There's this Mary Beth Chilton. They did this work in the 1980s. And so really the first genetically modified plants were the ability to grow in the presence of an antibiotic known as can of mice. And so that was all done in 1983 and published then. But in terms of a commercially valuable, genetically modified plant, then basically this was the first one that was was put out. Yeah, so Roundup, again, that's the glyphosate that kills plants very effectively. But if you basically have put in a gene where the target of glyphosate is not affected by it, basically have this wonderful, very targeted herbicide. The other major commercial success in terms of GMOs early on is basically what are known as BT toxins. So bacillus or engensis is this bacterium that is found in soil. And it makes these little crystals and what these crystals do are make what are what we now term as cry proteins. And I have here in the top left, an example of cry three BB one, it's a small little protein. But what it has is this incredible power. And this is beneficial to the bacteria to these crystals. And this is what's in the bottom diagram is that these crystals get ingested by the insect. And then the stomach gastric juices process it so it changes form. It binds to a receptor. It then forms a larger order complex that then integrates into these plasma membrane of the stomach cells and creates holes. And so creating holes in stomachs is an incredibly good way to kill insects. It actually works on a lot of organisms and species. But what's really, really interesting with these BT toxins is that they tend to be highly specialized to target only certain insects. So first of all, they do not work in humans. There are they do not work outside of insects for the most part, except in like some very specific experimental conditions with like red blood cells, but they do not work to be lethal or toxic to really any animal other than insects. And in fact, the amount the targeting within insects tends to be very specific. And so this is something that again, also Monsanto was a pioneer in this, that they figured out, Hey, we can express these in plants. Once we use the agrobacterium to put them into the we put them into the plants, the plants express them when the insects eat the plants, these cry proteins get released and killed the insects. So again, tagline asks, is there any effect on birds? No, no effect on birds. No effect on amphibians because what I'm showing down here in the diagram is that there are in some what they think in many cases, two different receptors that are specific to insects for the cry protein to have any ability to affect anything. So they have to have that. Yeah, it's an incredibly powerful thing. People from the early 1900s were actually crops with the BT bacteria, right, you can actually cultivate and grow in large quantities, the bacteria themselves, and then spray them on the crops and get insects killing insecticidal activity there. And that's actually, some people call that an early organic form of pest control. Yeah, max, I can't go on all that right now. I mean, basically, from an, from an industrial agricultural point of view, we try and find cry proteins that affect the crops, the insects that we know are affecting crops. So fall army worm, European corn worm, European corn borer, soybean looper. There's a Japanese Asian beetle that affects soybeans and stuff like that. But there are versions of it that affect mosquitoes, which I find very weird because mosquitoes don't really live all that much in soil. Anyway, so when we think about these two traits of herbicide resistance, as well as BT varieties, you know, in terms of these being very powerful ways to, again, these aren't increasing the yield potential of the crop. But what they are doing is that when there is a very specific stress to the crop, then in fact, you maintain the yield potential because they're not just being eaten up, and not being crowded up by weeds. And so that's the important thing that these are very popular products that have been shown to be year after year shown to be safe for human consumption. And are going to get through very costly, as well as long term regulatory approval. Okay, so let's talk more about tech. And so, you know, one great example, that's a little bit kind of think under, underappreciated, and not not very well known, outside of the Western United States, in many cases, or Taiwan, is the papaya. So again, very similar to bananas. There was a virus known as rings, ring spot virus, that basically created major production problems for papaya in Hawaii. And again, even as it is not a triploid clone, these aren't, these are actually, you know, deployed or deployed plants that have breeding potential. Because it was a pretty as a monoculture in terms of the overall amount of genetic diversity was not that high. This is creating big yield problems for the papaya crops. But they invented a modified version that basically limits the ability of the virus to get expressed, or to be transmitted by the aphids are the ones that that are carrying it around. And so, within two years of commercialization of this transgenic papaya, basically half of the papaya grown in Hawaii was a GMO. And over a decade later, 90% of papaya production are the GMOs. And so what's a highly quotable sciences would say, if you didn't have a GMO, you would have no papaya. That's really the way it is. I'm not a big eater of them either. Yeah, so let me just backtrack real quick to mention that the term GMO as typically used in this regulatory schematic that was the 90s is the presence of a foreign species gene in the plant. So for example, a bacterial bacillus thuringiensis cry protein, or in this case actually over express a viral version of the protein in the papaya. Okay, here's another well advertised example is the golden rice. And so basically they've engineered it in a way to express and to make high levels of beta carotene, which is the precursor to vitamin A. You can easily look up more statistics of how much you want to get into this. But vitamin A deficiency is something that affects 250 million people worldwide. And you know, we think about China, Bangladesh, many parts of Asia, India as well. And again, this is something that's affecting the poorest people where in many cases, the staple of their diet, again, their calorie, caloric needs are being met by rice, but not their nutritional needs. And that's because rice naturally when you you know, harvest the grain, you remove it's, it's, it's beta carotene stores. And so, you know, vitamin A deficiency is the leading cause of preventable blindness in children, as well as some other diseases. And so one thing that's very clear is that by providing high levels of vitamin of sorry, beta carotene in the diet, that is incredibly easy to treat. Now, I won't have, I won't belabor the fact that there's been a big fight over this, because this was actually developed in the early 2000s, 2003, by a scientist who actually sold it, who patented it, but then Syngenta bought it and then basically made it free for anybody there. Syngenta is in no way trying to profit off of golden rice seed sales. And so it was only, it was not until last year, the first country approved the sale, the cultivation and the sale to consumers of rice, and that would be in the Philippines. So I think it's also been since that time, I talked about this at my CRISPR talk, I think Bangladesh is also deregulated it. But again, this is an example where, you know, a lot of modern agriculture with this wide scale, you can be meeting calorie needs, but you're not necessarily meeting nutritionally. So I think this this balance is something that will see a lot in the oncoming biotech and genome editing days. Alright, so let me finish off giving kind of a general introduction about CRISPR and what we'll call the next phase of plant biotech of genome engineering. And that is scientists have developed the ability, and this was something only discovered and put into play in 2012. That and with this first example known as Cas9, where you can basically easily program it with an RNA molecule to cut wherever you want in the genome. As long as you know the target sequence of what organism you want, and you have a way to get these things into the cell, like for example, with agribacterium, you can basically start making cuts, and then that can modify how the genome works. Now, there are a couple things that are very powerful about this guided genome targeting ability, which is one, you can basically go editing something where you don't leave behind any trans genes. So again, in most regulatory schematics, that's not a GMO, right? A GMO has some gene in it. And so this basically, we, the terminology is advanced breeding. You can also knock out genes. And now sometimes you think getting rid of the gene is not necessarily a beneficial thing. But if you're talking about, say, a disease susceptibility gene, then removing that is actually something that creates a powerful trait product that benefits the cultivation of the plant. And then also, because this targeting, you can still put trans genes in, you can still put make something a GMO. But because you're putting it into a specific known target, you can put it into what you might call a safe harbor, something that's been used before, something that we know is basically a safe place to put an extra gene in the genome. And so that becomes much more regulatory friendly. Again, I think there's a lot of debate and argument about what this will be. But this is for this talk, the point is trying to provide some degree of thinking about how it can be useful. So I give two examples, both of which are landmark examples of things getting onto product shelves. So the first one is something from a company called pairwise, and they're in Durham, North Carolina. But they've developed a product line called conscious greens. And basically, what they're doing is taking the purpose is to make more nutritious, but still very tasty, and eating friendly and cultivation friendly salads. And they're basically going back to mustard. So brassica juncia is nutritious and has good texture, but has not been used as a consumer good, because it tastes super bitter. And this is the process known as being a mustard bomb, that once you tear the leaf, it releases a bunch of glucosinate molecules that an enzyme very rapidly turns into a bitter tasting compound. And so we have demonstrated here, in this case, aloe isothiocyanate, that's the bitter taste you have, when you actually start carrying the leaf. And so that's from one enzyme activity. But what's always been very complicated. And as I mentioned before, this mustard is a tetrapoid. And so you basically have lots and lots of copies of this gene as well as extra copies that exist for other reasons. And so what the company did was use CRISPR, CAS to basically knock out all the copies of the gene. And so what the diagram and the chart is showing here at the bottom is that the blue chart is the amount of the compound that basically contributes to making a bitter taste. And the blue one is the normal version of the plant. And then on the white, the red is how much of that compound you get and consequently how much less bitterness you get in the mutants. And so this is something that's now in store shelves. Take a look for it. You might try it out. And it's basically the first CRISPR edited consumer available product. And then another one, then this was the very first consumer based CRISPR edited product in the in the world. This was in Japan, something that is the Gabba tomato. And so without going into too much detail, my time is short. Gabba is something that is well known to help with hypertension. And it's something that you can get through dietary means. It's something that actually people supplement in Japan, a lot of foods get supplemented with Gabba. This is well to the easy ask to basically engineer tomato where they amount of it in the fruit. And that's what you're seeing. And what they did was they basically knocked out two genes that take Gabba in the tomato and convert it to another metabolite. So they're basically blocking its conversion to something else. So the Gabba again, alf gamma amino butyric acid is basically at a higher concentration. That's what the chart here showing the very far left hand bar is the control wild type. And what you'll see is all these other mutant versions that they made of it, these bars are much higher. So they have much higher amounts of Gabba in them. All right, so let me finish that when we think about genome engineering, and the types of targets and types of genes and types of things that we can do, the future of CRISPR and talons and zinc frigid nucleases. You're going to see a lot more insect resistance and herbicide tolerance traits. Disease resistance is something that's always possible once we identify how the pathogen interacts with the host. But drought, heat, salinity, again, environmental impacts that we have. I didn't even mention trying to find ways to help them make, you know, better utilization of nutrients or nitrogen. The concept of shatter. And in fact, we're changing what some of these plants do. So, you know, I was mentioned in the text chat that it's about 60% of the acreage of corn planted in Iowa is actually that acreage goes towards ethanol to fuel production. It's not even a food source. And so the ability to make more oil from things like soybean, camelina, some other beans, those are actually a big area as well. So increase in the oil, but then also the protein content of beans are something else that you know editing is being applied toward. And also it's being done with hopefully less regulatory hurdles. So my last data slide is this one. And I want to highlight something about how the increases in agricultural productivity, which have been from these modern breeding techniques, which are seen through biotech, which are seen through lots of other agricultural agonomic practices. The orange and light blue bars, those represent productivity and total output. But the one I want you to really highlight is the dashed dark blue line, which is the amount of land planted in North America by year. And that's actually gone down. And so the fact that we have managed to make plants so productive per acre means that we actually are more environmentally friendly, in the sense of needing less acreage to get the same amount of food. And so if that weren't the case, estimates right now would be that one third of to get the amount of output that we had in 1948, we would have basically have to plant those major crops on one third of all the land in in America in the United States. And so that type of efficiency is really important for sustainability. Okay, so with that, I just want to summarize that, you know, in terms of female genetic modification and agriculture, you know, the genomes of lot of domesticated plants are not exactly natural. They're not exactly the wild form of things. And that this is something that's been very useful and helpful for domestication, and all the benefits that you get from various cultivars. Modern breeding and biotech have dramatically enhanced agricultural productivity. And really what this very beginning of this next phase of genome editing, and the things you can do with genome editing and improve transformation and other improved technologies to basically pushes forward for the next several hundred years. So with that, I will close up here and take any questions. I'm happy to stick around for as long as necessary. I hope you enjoyed. I want to thank again, Chantel, the science circle for hosting and for your attention and and interest. Alright, let me go back to one. Okay, so I'll start with Phil's question. What is the future of all this? You know, I think the future is making sure we can feed the world. And let's let's list some of the pressures. One pressure is more people to be fed. Another pressure is less air will land because so agricultural use of soil can depleted of nutrients. We also have climate change, which is changing how things grow in particular place. There's also having effects on what is arable land. We have insects that are constantly trying to eat our plants. And what's really tricky with insects is that you create something that kills them. And eventually they develop resistance. And then they also migrate all around the world. Or also fungal, viral, other pathogens, where again, because there is climate change, some of these more voracious insects are going all over the planet. And so in Latin America, you have actually multiple seasons of insects here in North America. One reason we don't have the same problems as Latin America is because we have winter. We have winter and it kills insects or basically they have to adapt to that climate. You know, water scarcity is another good one that not only are there increased pressures to use, you know, water for human consumption and direct use. But climate change is changing how much of that is available. And so we need to grow plants with less water. Another example is in China, of course, that salinity. You know, you basically get salt infiltration of fresh water. And so rice can become more difficult to grow. I mean, that's, I mean, that's just a list of the ones off the top of my head. You know, but the future, I think the future really is, you know, with genome editing, with biotechnology, with so much money and value that comes out of having resilient productive crops. These are things that we're just going to keep doing over and over. And so hopefully we'll find again those varieties that are very robust for any given challenge. Yeah, salt tolerance and rice is a very big one. Yeah. And so, you know, Dee mentions an interesting one too, which is, you know, if you have an area that wasn't very friendly to good growing seasons for many major crops, like Finland or say, you know, Canada, or because they're more cold, like, you know, or you know, the northern parts of Ukraine, you think, oh, well, you're going to change the seasons and have more heat. But that's not necessarily adjusting for the daylight cycles. That's not necessarily knowing exactly how the drought and the water and the seasonal changes will occur. And so, you know, we could be creating areas where right now there's no plan actually adapted for, you know, for exactly what you're looking for. You know, the corn that we have in Iowa won't necessarily grow in a climate-warmed North Dakota because the water seasonal cycles can all be very different. So, Tadmey mentioned something. He says, I think two of the greatest challenges will be to restore soil after nutrient depletion and water for agricultural use. Oh, okay. Yeah, let me answer it. Let me mention something. Let me respond to the challenge part first about restoring soil, that there are two things that are major trends, which is one, regenerative agriculture. And that, in some cases, is where some of the best examples are, is having a perennial that forms a nice deep root system that then regenerates the actual amount of topsoil that you have, as well as the nutrients. The problem has been that regenerative agriculture is not as productive. And so, I think one of the big challenges we have, and something that can be improved, is to make perennials better at being productive crops. So, I think that's one area, or an agronomic practice where they're good enough that you can do crop rotations and help regenerate plots of land while using, you know, the other plots of land for highly productive agriculture. So, I think that's a very important point. You know, in terms of gastrointestinal intolerance, I think it's worth mentioning that gluten intolerance celiac disease is, in fact, very, very rare, right? And that's something that's kind of on the human end that are very specific genes that relate to that. Now, the term intolerance, I mean, I have to imagine that, well, let me preface this by saying I'm not an expert in this aspect of it. One thing we definitely do in the biotechnology space is to make sure that any biotechnology product we have is digestible. We do these things called gastrointestinal digestion or gastrointestinal juice assays to make sure that anything that we're putting in as a specific biotech trait is digestible. And also non-allergenic. Again, we have these allergy profiles that we, can I use computers to screen for things that might cause allergies? There's probably still a little bit of that that that that sneaks through. But I'm not convinced that it's the agricultural practices alone that lead to food intolerance. It can just be other aspects of how immune systems develop in modern-day society. Well, if you look up the actual prevalence of tried and true celiac disease, that's only in the 1%. I just want to make that distinction that celiac disease is very distinct from what you're describing as food intolerance. So now food intolerance, I do believe that there can be aspects of allergies, not necessarily from just biotech and genome modification, but from the gradient practices. Again, when you're trying to get better gluten into your plants for bread baking, you might be introducing low levels of allergenicity. This is also peanuts. Peanuts are actually a really good example as well. So how much of that is some low level of stuff sneaking through that, you know, with modern-day society and modern-day immune systems, how they develop, you know, there probably could be some synergy that's creating problems there. But I, yeah, I don't know exactly enough about it the same more than that. Digestive tracks would be interesting. I mean, you know, one good example in agriculture in a sense, right, is lactose. You know, so I mentioned earlier in the text chat that milk is really the only complete food, right, and that's because, at least for mammals, because basically it is the entirety of our food when we're first born, at least in your naturalized nomadic ancestry days. We didn't really have substitutes for mother's milk, but because it's highly nutritious, it became something that people, you know, domesticated goats, cattle, in order to produce at high volume. But in the normal history of people developing, we actually turned off our ability to digest lactose as adults, right. Those lactase genes are only naturally turned on in most archaic populations when we're young. But what we found is that those genes have changed. People have activated lactose in certain populations that had a high prevalence of dairy production. Thanks for coming, Max. And so, you know, that's maybe, you know, that's kind of a good example. I mean, that's not an allergy, that's not an immune tolerance. What happens is the lactose is a highly abundant sugar that normally is not present in that part of your small intestine. And so now you have these bacteria that are like, oh my gosh, all the sugar, I'm going to do a bunch of, you know, metabolism. And it's not exactly the bacteria you want. And so then all of a sudden, you know, you get all the downsides of lactose intolerance. So conscious brings up something that eating cheese and drinking milk makes you more tolerant to it. I am not aware that that's the case, no. I mean, I think the genes just naturally turn off as you get older. And there's not some sort of sensing mechanism where if you're suddenly having milk again, those genes turn back on. I mean, I personally think that'd be great, though. That'd be a great CRISPR target, is just basically, you know, invade people's small intestines with a, with a liposome that just basically activates lactose, lactase genes in people. That'd be an easy target in that sense. Any other questions? Anybody, anybody want to stir up some controversy? You have, I would love to see that, because I'm just not aware of any sensing mechanism that the human intestine has to turn those genes on. Yeah, I mean, I think, well, the nutritional profile of all the things that come from milk are interesting. In fact, like getting iron from milk, you can't just add iron to formula milk and have it get digested and absorbed very well. It's the actual process of iron being made and conjugated with all the other compounds in milk that make it digestible and absorbable. So, there's a lot of complication with how milk actually works. So, as Stefan, Leven, Levenke, Levenke, yeah, what's your comment? Okay, so Stefan kind of brings up an interesting, larger, maybe some of your philosophical point, but also a practical one, that, you know, is our increased agricultural output contributing to overpopulation of the earth. And I think, I mean, certainly one thing you can say is that our agricultural output has allowed, has enabled us to so far support this degree of population. Something that, again, without modern agricultural practices and breeding and everything, clearly we could not sustain this number of people. You know, but a lot of driving forces that people reproduce, really doesn't necessarily have to do with that, right? So, some of the most overpopulated, so now there's just one thing you can say, there's this transition period, and this is something that has to do with behavioral psychology of people and reproduction, is that, you know, in archaic and many poor third world countries in the United, in the world, they try and have more children to compensate for an increased mortality rate of those getting, of their children getting to adulthood. And so in cases where there's low food availability traditionally, and low medicine availability traditionally, you can't have this period of time in this transition where people are overproducing compared to the needs of the population, compared to the, the ability to sustain that population, but it's more sustainable because people are dying, the mortality rate is much lower, because of more food for that area as well as medicine. So I think there's an argument you can make in that, in that relationship. You know, but I consider the question becomes, well, how do you define an overpopulation? And I think, you know, you know, we can fit more people on the earth, and I think the best way to maybe calculate that, there's been this thing called, there are ways to try and calculate the sustainability on a per surface area basis for people. And it's basically, it's a type of accounting. So I don't know, you know, I think from a behavioral psychology point of view, I would say that being able to produce more food is not a driving psychology of why we are overpopulated. But it is something that keeps enabling the populations we have to largely be sustainable. Yeah, I think, so no wonder here's the most recent chat, I'm sorry I missed some of these other ones, but you know, one thing that is clear, one way that agriculture can help reduce overpopulation is, as I mentioned, you know, once a society has the ability to sustain itself with agriculture, and fewer and fewer people work in agriculture, and then there's more leisure time, there's more economic prosperity that can come about, again, think Europe, think United States, think China, think India, then people actually start reproducing less. And so people start having fewer fewer children. So when you look at population rates or growth rates of populations, Europe right now has negative population growth and has for past 20 years. The United States is very much on that border that if we didn't have immigration, the population in the United States would be decreasing because the average number of children per person is decreasing. And we're also at this point where the death rate starts becoming very close to the birth rate. Although again there are obviously population disparities and unevenness there. So I think one thing to keep in mind is that having good agricultural sustainable practices within the country is actually a way to head off over population. I think maybe that's the best answer I want to give right now to that question Stefan. But that was an interesting question. Female education is mentioned and I think again that that is a key part of it. Although in many cases female education in some ways is probably a proxy for other good policies and fairness and civil rights and productivity that is going on all at the same time. Do you want any more follow-up on your questions Stefan? You should say well maybe we can talk offline sometime or just at a different time. Um yeah no I think there are a lot of really interesting dynamics of course occur with civilizations, technology. I will even just admit it's not really my specialty so I don't want to get too much into it. I'm just a macro biologist Jim. Yeah but I think that's one of the interesting things about so Neera mentioned behavioral change you know when that is occurring on a society-wide level you know it's a lot of these macro economic or macro societal forces or technologies that end up influencing it in this indirect but very powerful way. And so when you think about how society and this is the argument you know the archaeologists and anthropologists make is that society would be very different if we had to spend 50 percent of our waking hours gathering food right and that basically everybody had to be involved in doing that all at the same time that's just a completely different society than what ultimately developed because agriculture. Any other questions? Some pretty nice attendance this week and nobody trying to take over the voice chat. Well I think you know so Neera mentions energy expenditures of people but let's just also face it that the food distribution you know we basically produce worldwide I think three times as much calories as we technically need to feed people and that's even with our current agriculture production where you know some 80 percent of those calories end up going to feeding livestock right and so if you were to think about the distribution issues and distribution problems of food and take away some of the macro economic counter forces to that you know in fact let's just face it if we just stopped eating meat you know that would also free up a lot of agricultural productivity for more food. So Cesarji asked an interesting question can we effectively increase arable land by having new crops that grow in land that was once non-arable effectively? Yeah I think that's actually one of the big pushes we have right now in Africa and so Africa is particularly problematic where again some of it it's arable some of the time right but if you have these relatively frequent droughts and low precipitation which again precipitation is low to begin with but even beyond you know the average below the average that's where the land is hardly usable for crops and so but one of the things we do know is that natural forms of these plants do exist that can live in that space but right now they're economically friendly for scale so two crops that have become real interesting targets are sorghum as well as millet so millet is actually classically domesticated in China probably 9,000 BC and we're on the same time as rice um but that those societies have kind of moved away from that being like a major calorie contributing crop but in Africa a lot of scientists a lot of agricultural companies and in academics are looking at ways to either a make millet and sorghum more economically agronomically friendly or to take corn and figure out what makes millet so good at being drought tolerant and basically engineer that drought tolerance from millet into say mates and so those are examples of of the thinking and so we are really trying to find ways to make let's just call it right now boardable borderline arable land or you know occasional arable land more useful yeah i some of the numbers i hear is that about 30 percent of all food north america produces is just absolutely 100 wasted well okay so tagline mentions arsenic and and rice um let me give a better let me give a slightly better example which is cassava which is um i'm trying to remember it's a tuber right but cassava is a staple food in um a lot of parts of latin america it has the same type of thing where it naturally in certain parts of the plant makes cyanide and so we now have made cassava that doesn't make cyanide we basically um have either breaded out or used genome editing oh yeah yeah so um let me say i think the one for coming we're gonna close the official um video recording so anything being said here this is just not going to be recorded in terms of voice or anything or even the text chat so let's thank skier skira for having or mike for having um recorded and then let me get back to that that answer that you know i think your rice for the longest time people try to breed out its arsenic potential and that's been done pretty well and but now we can go back and say oh these are the genes that contribute to arsenic um build up and we can actually either we know how to breed that out or we can specifically knock those genes out that you know are them that make them tabloid and then take that from you know wild versions that maybe have other advantages like salinity tolerance well so tagline yeah so bringing out certain genes can lead to you know other changes that you don't want but again with enough time enough genome editing other biotechnology a lot of times as long as you're identifying what's being lost you can basically find a way to breed it back in yeah plants like a lot of multicellular organisms are rather complicated all right thanks for coming scissor g good to have you thanks Fiona yeah well rice is this really interesting thing right that rice requires a huge amount of water to grow at only a certain elevation compared to the plant itself and then it needs to be dry after that and so what's really kind of weird about rice is you want it to be in a place where there's an abundance of water but where it's actually being like flooded and then for the rest of the growing season is pretty dry and is well drained and so that's one where they're definitely trying to breed varieties this is actually pretty well known in India trying to find ones that are sustainable on much less water in terms of that flooding period