Welcome to All Things LGBTQ Plus Youth Edition. Today is July 15th. Yeah. Yes, 15th. Yes. 2019. My name is Jules. I use her pronouns. Next to me is. I'm Naven. I use he, him pronouns. I'm Jay and I use they, them pronouns. And today we're going to be talking about the word queer. We're going to delve into its history. We're going to talk about our personal opinions on it. It's going to be super fun. We're going to do a whole bunch of stuff. So let's start with the history, I guess. The Oxford English, I'm reading off notes, by the way. The Oxford English Dictionary credits the 16th century Scottish people for coming up with word queer. It depicted accusation of sexual perversion or weakness. And the first person to use the word queer as a homophobic slur was, God, I'm bad at names, John Sholto Douglas.   He is, as we will soon find out, in 1894. He was announcing snob queers, like the one his eldest son was involved in, in a letter to his youngest son. And fun fact, his youngest son was having an affair with Oscar Wilde. So karma. I wish. What was that? Nothing. Anyways. Anyways. So the use of the word queer as a slur reaches height and popularity in the late 1920s. But the Stonewall Riots. Riots. Riots. Riots. Riots. In 1969 marked the beginning of the gay rights movement in the U.S. And from the start of the movements, members of the community called themselves queer as an act of defiance. Yet that age of sexual liberation in the 70s turned a tragedy in the 80s when more than 16,000 Americans died of age-related complications in just five years. The eighth crisis sparked an era of activism. The crisis had a huge impact on the young activists who took up the word queer as a badge of courage. This all culminated in the founding of Queer Nation in 1990. And at Pride that same year, they passed out Queers Read This. For the first time, the world was hearing, we're here, we're queer. Get used to it. That's what I have for your history lesson. Got any Latin lessons? Got any Latin lessons? No, sadly we're not doing Latin this time. We're not talking about pansexuality. If we were, I'd have more Latin. We'll have another Latin lesson next time. We won't. We might. So anyways. Anyways, that sort of marked that, that kind of brought us into the early 2000s. And then from there, there's been a huge change in the way the word queer has been used or change in that it's really picked up as less of a slur and more of a identity or a common word used, especially with the online community growing, you see it a lot more. And the only time I really hear it as a slur, and it doesn't count as a slur, is usually people in the community using it at other people. A queer. Yeah. And they're not using it, like they're using it as a joke, I guess? Like not like, there are people who genuinely are like, oh yeah, you're queer. But then there's other people who are like, oh, you're queer, but they're in the community. So like.  And it's just, so I think that's why a lot of people don't like to use it for themselves because it has a relationship to those words, and that's more uncomfortable to them, I think. So. You don't like the word queer. I don't like the word queer, and I'm really interested to go into this. And I'm medium on the word queer. Yeah, so I'm kind of going to. Perfect.  And I just want to start by saying I'm fine.   I'm allowed to say like other slurs, too, because I might use examples. It's Glamour. If you have some problems with certain slurs, such as the T-slur, the F-slur, or the D-slur, they might come out. Yeah, yeah. It's Glamen. D-slur? Oh. Okay, anyways. So my experience with the word queer is that. The D-slur is doing this. Sorry. Okay. My experience with the word queer is that when I first came out and started to like figure out my identity as an LGBT person, it was used everywhere, like especially online, which was online. My school's GSA was the only exposure I had to the LGBT community whatsoever. T. So that word was used a lot. And it wasn't really regarded as a slur. And it was never presented to me.  So it never seemed to be a slur to me. And later as I got older and I became more comfortable in my identity and I was hearing different voices within the LGBT community, I realized queer does have a very violent history being used as a slur. And I wasn't comfortable being called queer. And I feel like a lot, this is a slight change, I feel like a lot of younger people, especially like when they first come out in like online communities or in their school GSAs, they sort of disregard queer's history and how heavy and like violent and awful it is. And I feel like there's just a lack of appreciation for the word queer in spaces that have younger kids. And I don't know, it just bothers me for them to be using that word without really understanding it. So my kind of personal experience with queer since we're going to go into that a little bit right now is to me queer has always been easier than having like individualized labels. Like even now I still have a slight aversion to saying like I'm bisexual or I'm pansexual because I still don't know the difference. But so queer has always just been more comfortable, kind of like I don't really, it literally just like not straight, not, not, I am so gendered, not straight. And just kind of I don't have to like delve into like oh I like men, women and everything and all of that. I can just be like queer. That's all you need to know. And like well a lot of people do like using it, using it because of that reason because it's easier to use and stuff. I personally as a bisexual, bisexuality, bisexual trans man boy, I'm not a man. So as a bisexual trans boy, especially bisexual, I've seen a lot of bisexual people's identities erased by people either calling them gay, straight or just queer.  But people tend to erase bisexual people's identities just by calling them queer. For whatever reason, I don't really know why. Maybe because you know I actually have no idea why but I've seen it happen a lot. I don't know. And just by like just owning my identity and like saying I'm bisexual has a lot of power for me personally because it's just not something I ever really see a lot. I get that a lot. And for me kind of saying like I'm queer has more power in saying like I'm bisexual at least to me. Like I think there's power in both. But for me it's just like queer is more like if I take this word that has been used to hurt people it can no longer hurt me. Yeah. And I don't know. I think my problem especially when I was younger is that it was forced on me a lot. And that like I just never got the chance to read. I never got the choice really to reclaim it for myself because it was always pushed on me so much.  But I still would find an offensive of someone else called me tranny.  I think like in life as you go up to get more time do you think you'd ever reclaim the word for yourself? Or do you think it's always going to be like an aversion towards that word? I think I very well could. It's just I have like I obviously have a lot of feelings about the have to work out and I don't know just maybe if it wasn't pushed on so many people like pushing so many kids especially really bothers me like younger kids. We'll talk about that a little bit so your labels push on to kids. Yeah and another thing before we move on because you also haven't said anything yet. I know. I was like I need to include Jay somehow. I was thinking in my head how do I do that.  Yeah I mean sorry I will include you in the conversation I promise. I like queer is an umbrella term because the acronym that we have is ever changing and growing like a lot and like everyone no one can really they decide on an acronym to me so I'm just like if there was a better word that wasn't queer that wasn't a slur. Yeah. I would use that to describe the whole LGBTQ plus community. Yeah. But I once had someone say wow it's really amazing how fast you can say LGBTQ plus and I'm like well yeah because I have to. Yeah you get used to saying.  Sometimes I think of like BLTs. Why do you think what? All the letters are in there. But anyways yeah I know I've seen people you know I agree with you first. That's not the letters. I'm sorry I just like get like a bisexual lesbian trans sandwich. Yeah so I again know I agree with you I would be fine with some. Gross. Using one word to describe the community. You don't want it to be queer I just. Yeah just because it's a reclaim slur right it's just not really. So anyways. What is your personal experience with the word queer because. Oh like I mean I've heard it use negatively I've had people in my life use it negatively. But I've never had it negatively used towards me per se. I've heard people use it as in like oh why is my phone being queer. Or that's kind of queer like that. And like I've never had a problem myself with it. I knew it's history. And I knew that it could be bad. And then I knew that people have been using it to identify as themselves. So like I don't I like I identify as I identify as queer. But at the same time like it's not like what I use like if I were just going to umbrella myself I normally just say gay. Which. Yeah gay is also kind of a turning into more of a.  Which is kind of weird because it's not a rich.   So who's going to like greet them like it's like if someone asks what your sexuality is you're not going to say oh I'm a homosexual.  I mean I would. You would because you're extra. I would call myself a homo though. Yeah I do. I have my own opinions about using gay as an umbrella term but should we. I mean I don't know like again I'm very middle on the using gay as an umbrella term. Because like that erases identities but also it gives us something I don't know. I feel like currently the the technical if we were going to umbrella term anything it would post to be LGBTQ plus. At the same time at the same time it's like people are lazy and not everyone's going to say the acronym.  I had a comment but I forgot it. Can I. Go. So well I've heard people say that like oh I just don't want to say the whole acronym as an excuse to just call the whole community queer. I've also heard people say that oh you can make cute freaking puns out of it as an excuse to use the word queer. And I don't know like I've actually heard people say that I can't remember who it was. I mean that's just really I feel like that just shows that they really don't appreciate the history of the word. Because like if they had a good reason to use it I might listen to them but since they're just like oh it's easy. It's easier to say trans than transgender. We don't see people doing that. Just say trans. I mean yeah. It's literally shorter than the floor anyways. Yeah. I know but like that's basically my point. Yeah. And. You can give me a. Sorry. Okay. And a slight tangent but about using gay as an umbrella term. Do you mind if I go into that. Sure. Okay. It's kind of well it's not I don't I don't think it should be used as an umbrella term because it definitely erases by people's identities.   I'm so yeah and it's just like if you were to okay this is a personal experience but I came out to my dad and I was like I'm gay. At the time I thought I was pansexual. I thought that would get the message across. Obviously it wouldn't. We talked about it in the last time. Last time. We did. I didn't hear it all.   Okay um I don't know and like I don't know using gays and umbrella terms just like never really made sense to me.   And like I'm not a lesbian. Fun fact I do like mad occasionally. I mean literally my family member like I've told you this or I don't know if I've told you. People just think I'm a lesbian. No. Do you have the same problem? Well literally I came back from the the the queer summit. I mean the I mean it's called the queer youth summit. Yeah I know and I have problems with that. And I was I was just sitting down eating dinner. My family sat down looked at me and goes I don't think you're pansexual. And so I just prepared myself to be like oh here we go like they're gonna say I'm straight.  And I'm like. You're all family and unison. Yeah it's all no one. Yes. All the dogs. All the six dogs in unison. And I mean I don't know if it's worse or better. Like oh my family doesn't think I'm straight. That's something. They know that. But. You're not straight. They're just not sure what else. They know I'm not straight but like yeah. So when it comes to like people using umbrella terms or people using slurs for themselves. Yeah in my mind I won't really ever police someone's language. So I think you have the right to say whatever you want to say. I think there are words you obviously shouldn't say. And I might be like hey white person don't go running around saying the N word. But I can't necessarily stop them. So I and like when it comes to like slurs especially within the LGBTQ plus community.  I mean you could just call it the community. If you're with a group of people that know what you're talking about. You can just call it the community. Especially in the community when it comes to like slurs and stuff. I do not care how you choose to use them. As long as you're not using them against other people. If you're using them towards yourself. I mean go ahead is how I feel. I just don't think you should use them at other people or label other people. Yes. And that's how I grew up with swears too. It's like as long as you're not using them to hurt someone. You can say them. Context matters. Which is how I grew up with swears. And that's how I treat slurs. Like I'll call myself queer. I know Naven doesn't like it. So I'm not gonna call him that. Yeah. But so that's the thing with umbrella terms though. Is that like you ask anyone. If you ask anyone like does trans fall under the queer umbrella. Does bisexual fall under the queer umbrella. They're gonna say yes. And that's me. So therefore they're labeling me as queer. And like even like really big organizations in the state. Like outright Vermont. Which I absolutely love. It's not supposed to be a call. But I absolutely love outright. But they use it. They use it all the time. The queer youth summit. The queer youth summit. My group is a group for queer questioning. Queer trans and questioning. And like I spent so much time. Like this is a little personal. I spent a lot of time trying to be like oh it's okay. They're not calling me queer. So there's the trans. That's what they're talking about with me. We're going Friday night group. And I'm like no. They're calling me queer. And like even at the youth summit. Like when we walked in like the doors. Like the welcoming presentation or whatever. It was like welcome queers.  Sorry. PG 13. You're allowed to say one. One. Okay. I'm sorry. I'm sorry guys. I just blew it. Anyways. Yeah. You used it Maven. I'm sorry. But like it just feels really awful having like this big organization that's supposed to like speak for me. And like protect me. And care about me. Calling me slurs. And like I know a lot of. I know some of the. People who run out right. Adults. Adults who run out right. Yeah. And like I know they care about me and all. But like. I'm still getting called queer. And I know if I were to talk to them they'd be like oh it's okay.  But they're still like using it whenever I'm not there. And I don't know. That was. Yeah. But yeah. Yeah. And I had a personal experience with word queer. Quite recently that actually fueled the fire to make this episode fun fact. That's literally why we're here. That's literally what I was saying. You both know what I'm talking about. Yeah. The Empower Mont Festival is held by my high school. It's this fun time where everyone goes. They invite clubs to go on table. So I got this water bottle. Yeah. They give you free swag. I took all the free stuff because I'm cheap. But I. My. The. The Empower Mont Festival people who are making it approach the GSA at our school. And it was like hey do you guys want a table here. And like. Have your stuff out. And we were like sure let's do it. So my advisors of the GSA came to me and they were. For some reason put me in charge. I don't know why. They were literally like you're doing this. And I was like great. That doesn't mean I'm responsible. You have a TV show. Anyways. But so I they were like okay. Sure I'll do it.  I brought button makers. I brought this flag and I made some pamphlets.  That I just randomly started to throw in there. And I limited myself to eight terms per like section of the pamphlet. That's what I wanted to make them rainbow. So I put queer on there.  Or it should have some sort of warning. Or essentially that it like shouldn't be on there. And they. These people took the pamphlets that I had made and started like crossing up. Crossing it off and changing them around. And that's. And then. And then that was the end of the night. And I got it led into this whole spiral of discussions about the word queer. Within our little school community. And led to me losing a lot of very close friends. So that's why that's why we're here. Because I wanted to talk about it as. In a more respectful place. Because like name and I talk about it a lot too. And you I actually enjoy talking about it. Because you're like. You know decent.  Yeah. And like. I. I wanted to have an episode who could be like a respectful discussion about it. Which I think is kind of lacking within the community. Respectful constructive discussions. Especially when it comes to things like this. Yeah. So I was like hey.  And I know you don't like the word queer. Let's chat about it. And then I was like I need a third person J. I love that I'm just the tag along now. Like I need someone else. This person will do. Yeah. Yeah. Do you want me to talk a bit about like. The very extreme. Extremely like opposing the word queer.  Yeah. Yeah. You might have got that. Sort of a segue coming from that story. But people are crazy. So there's some people in the community who think that you should never use the word queer ever. Even to describe yourself. Sometimes which isn't exactly what the people. At the Empowerment Festival thought but they were. Pretty close from what I can tell. I don't know. I don't want to speak on their opinions because I don't know them fully. But. So.  It doesn't count as an identity. And you shouldn't call the community that. And they'll they'll also this is mostly online that I've seen it. But they'll also like harass people who identify only as queer. Which is obviously messed up and. And it'll lead some people to do stuff like. Destroy the pamphlets which. I was. Sort of a part of like I was there for it and the people sort of dragged me along with it. And. Random little off topic didn't one of them they crossed out pan sexuality. Yeah. They crossed out pan. They crossed out Demi. They crossed out a bunch of them they felt shouldn't be on there. It was a time. It was a time. Keep going.  They had made. They had put the T-slur on pins. They had put the F-slur. They had put the D-slur. I mean like we weren't handing them out. I know. But if you. It makes. Personally it makes no sense to me because I feel like. Again for me. I think. I. Believe that like slurs into it's like different levels of badness. And I feel like queer is kind of. Less bad in my mind than like the D-slur. Or like. The F-slur. Like yeah. Some people obviously you probably disagree with that. No actually no I would agree. Like I'd take more offense to some calling me training and some calling me queer. But I still wouldn't like it. I would take. A lot more offense if someone used the F-slur at me. So that's sort of just like why I got like. Why not. The F-slur is probably the one that I'm the most uncomfortable with. Like. Queer in my mind isn't that bad compared to that. Yeah. So. I agree. To me. Mainly because I like reclaimed queer. Yeah. And I mean even. I mean I know some of my friends who do like have like they feel like they've reclaimed. The F-slur. But I. I don't know sometimes when I hear I legit like cringe. I get. Which I get.  Yeah it is. Especially if you're like in older generations too. Cause I feel like now obviously we hear a little bit less of the word queer. We still hear it. Yeah. But I think we hear it a little bit less. And then older generations they might have more of a problem with it cause it was so prevalent. As like a attacking word. Where like now like the F-slur the D-slur they're kind of the more attack like words now. So if someone who I know isn't joking around with me called me the D-slur I would also freeze up cause I'd be like gotta run. Like bye. So yeah. Going off of what you said about older people who might have actually had queer users slur against them. A lot of organizations. Not organizations but like more I don't know how to describe this.  Adult. No. Like people who have influence. I mean like I guess mostly adults but like. Influencers. Jesus Christ. Yes. So I've seen. Yes Jesus Christ. Yeah I'm just gonna say. Jesus Christ is the biggest influencer. He's bigger than James Charles. I mean. Yes. Anyways I'm just gonna say. He has an entire religion. I'm just gonna say some people I've seen. People who are like oh you shouldn't use queer around older people cause they might have trauma related to it and you don't want to sugar that and like well that's good and all. My personal problem is with that is like you don't have to have trauma associated with something to be uncomfortable with it. Yes. Like I don't have trauma associated with the F-slur but I still don't want to be called that. I'm still uncomfortable with that. Yeah. I don't know that's just like one excuse I've seen people used to not use queer all the time and like while I agree with that on some level it's also kind of ignoring a bigger problem or ignoring that like some people like might just not like the word. Yeah I mean I've never had any negative experience being called the F-slur or the DSL but if you call me that and you are serious and you're like being asked about it I'll get upset. I mean I've been called the F-slur. But like in a negative sense. Yeah. And it's not fun but at the same time people say that the older people might be triggered but I actually hear a lot of the older like older people of the community use it. I mean it's hard to talk in generalizations. Because everyone has different. Yeah.  Like it may not be the best but I really can't know until someone's like. Yeah but I'm letting you finish your thought. So that's just kind of how I feel about like a lot of words like with queer it's like if I I'll use it and then if you tell me hey I really don't like that word can you not use that for me or can you not call it the queer community then I'll stop. Like because with you like told me hey I don't like this word for myself and I will not call you that but Jay is like chill with it as far as I know. I mean I don't if I mean I don't have a problem with people using it it's just not something I will go out of my way to say. Yeah. Like it's kind of like a different like I said I'm indifferent on that word. Yeah. So I mean like like obviously I can't control what you say and that's more of a compromise than I've gotten from some people in the past but I don't know I just feel like when it comes to slurs it shouldn't be like I'm going to use it until someone say says no it should be I'm going to use it if someone says yes I guess. Yeah. But obviously like I don't know and it's also like a sort of amount of frustration of like watching people struggle to say LGBT in front of me.  Say I was with like a group of people who I know are like completely fine with the word queer like they even like it and I called it the queer community then would that would you still find that as an issue or would you still consider that a problem? I mean I don't know it's like I'm sort of for lack of a better word like sort of lenient on it like I wouldn't have so much of a problem with people saying it behind my back if like so many like straight and cis allies didn't call it the queer community if like I didn't get called queer by LGBT people all the time stuff like that I don't know. Like I probably wouldn't care as much if I didn't get called queer all the time. Yeah you would you'll only get ads forced on to you. Yeah. And that's fair I think no one really likes anything when it's being forced on to them. Yeah. And I don't know I guess for me queer has always just been more comforting because it's like a label that I know is never going to change because I went through label after label because obviously I'm a teenager. When you come out at 12 your labels are going to change a little bit. It's like I came out as bisexual. I've switched to pansexual. I came I'm bisexual but I stick with queer because I know well the terms underneath that may change queer is never going to change. Yeah. I know I'm always not going to be 100% straight. Yeah I mean as someone who came out as girls quite young as well I think I came out around 13. I mean my labels have changed. I thought I was trans for that sake. I mean yeah I have had a lot of label changes myself but I've always found that at least the people that I've been around has always been supportive of the whatever I am so. Thank God. So I think we have to wrap this up and I think what I try to do to end it is let's say a sentence or so is our final thought and our final take away. Jay you start. Words have powerful feelings behind them no matter what you use.  Yee-haw. Yee-haw. That's what all straight people say.  Yeah that was in a sentence but continue. I guess for me language is really tricky words have a lot of power and it's really difficult to have a kind of cohesive understanding about words right. This has been all things LGBTQ plus. Youth Edition. Thank you so much for watching and we'll see you next month or I'll see you next month. Bye.


Well, first of all, thank you for the opportunity to be here today and give a perspective of target validation using the vast amount of genetic data that's available in the context of pharmaceutical target selection and ultimately drug development. We've been partnering with Abroad and David Alshuler now for in excess of about three years. And it's really been in the last six months, I would say, that we begin to realize how disparate our conversations were initially with regard to expectations and how we might be able to help each other. And since we finally posed what are the fundamental questions that we're trying to get at, and we shared that kind of information, which seems so obvious at the time, we've really made some vast improvements in the utility that we're seeing from access to some of these databases. And so I'll take you through essentially how we go about selecting targets, what we consider to be a valid target, and how we're using human genetics. About two years ago, we had a pretty substantial reorganization. I'm in the cardiometabolic space, and it came from the powers that be that we were no longer going to pursue targets that were not founded in human genetics, at which point all the biologists and physiologists, including myself, threw up our hands and said, now what do we do? But it is absolutely our mission now to go after those targets that have very strong human genetic evidence to support them, and it's a reflection of the fact that we fail in phase two 50% of the time for lack of efficacy. So we can come up with great chemical matter, we can design great studies, but we're not very good at picking targets. In fact, it's a coin toss, essentially. So this is what I was asked to touch on today. So how could a database be used for drug target validation? What are the types of data that are required? How important is it for us to be able to re-contact these participants? And would you use this database or these studies differently depending upon what you were trying to accomplish? So this came out of last week's meeting in the Information Commons group, where we were talking about the different definitions of target validation. And I really work in the space of target identification at the bottom there. And it really is the generation of scientific evidence that a particular target is involved in a disease process, and we actually raise it up a level higher than that. We start at pathways. There's so many different ways that you can intervene in a pathway, so many different targets to choose from. First thing we just want to understand is, is this pathway going to have an effect on disease progression or reversal? Once we've kind of posed that question, then we start, or traditionally we would then start looking for animal models that had been developed that had tested that particular pathway to give us confidence that we had a good idea and it would translate to human efficacy. And human genetics, frankly, was an afterthought. We relied almost entirely on the animal models at that particular point. And I won't go through all the other definitions, you can look at them yourselves. But we came to work with the Broad through this realization that we needed to have a better understanding of the role that the human genetics plays in disease susceptibility and how we could use that information to select targets with a higher probability of success in phase two. We have a precision medicine group in Pfizer that is composed of a number of geneticists, quite a number of geneticists. And the question is, well, why don't we just do it all in-house? And one of the fundamental problems that we ran up against is, well, we just don't have access to the data. Or it's difficult to get the data. Or how do you combine all these different data sets so it ultimately becomes much easier for us to partner externally and at the time thinking that, well, if we would partner with an institution like the Broad, all the data sets would become quickly available. We could check the boxes, find the targets, and away we go. That's actually a little bit naive on our part. But the goals of the collaboration are stated up there. And it really is to validate human relevance of the targets in question. And then to apply novel methods to bring or to bridge from patients in the human population to biology that we can actually go after. Because the other problem that we run up against is when we see these GWAS studies that are published, they show or report all of these susceptibility variants in diabetes and cardiovascular disease, many of which are just not drugable, or they are associated with progression of disease. But from our standpoint, we have to be able to go in and show reversal of disease. So it has to have a very big functional effect. And then ideally, we could run a phase three study, a multiple year study, that shows not only in the short term can you reverse disease, but over the long term, you could slow the onset and progression of disease. And that's a big challenge for us. Of course, we all want to stop the onset and progression of type two diabetes, but when we run a clinical trial, we have to go first into a diabetic population and show that we can achieve a 1% improvement in A1C in 12 weeks or less. So the target has to have a lot of horsepower in the first place before we can even think about modifying disease onset and progression. So one of the terms or terms that we've come to use with David and the group there is this unbiased versus biased target validation. And the two kind of conversations that we're having are, can you find me a new target backed by human genetics? And so this would be going to the recent publications, seeing new papers that come out. GRB 14 is a recent example that came out last year. It's been publicized again as being involved in the onset of diabetes or susceptibility. So the question is at that point when you see a variant associated with the phenotype that you care about, do you go after that as a new target? It's a novel target, it hasn't been tried before. It would fit the criteria of being novel and potentially disease modifying. But we still don't understand whether it's going to have the horsepower, if you will, to really be a viable therapeutic strategy. The other conversation that we have is, we have a whole list of target hypotheses that may in fact be independent of any of genetic evidence. But we would want to know, is this target that I've already started to work on, is it supported by human genetic evidence as well? Or is this pathway have additional clues from the GWAS studies, et cetera, that would give me confidence that I've made a good decision to go down this particular track? And so what we see here is kind of the traditional GWAS. We have a patient phenotype type 2 diabetes, for instance. We identify a variant, and now we're looking for a target. And we refer to this as kind of the forward genetics approach. This is not the approach that we traditionally take. Absolutely not the approach we traditionally take. We do the reverse genetics. We have a target based on an animal model, associated with a pathway that we think is important. And we start looking for genetic evidence to support our good idea. And in the absence of that genetic evidence, we still chase that target because we think it's a good idea. And phase 2 success would tell you that's not a viable path forward. So back to the GRB14 story, it's interesting about this ability to combine all these large data sets is when the GRB paper was first published last summer, we weren't enthusiastic about it, but it had a very small effect on disease susceptibility. It was in the Southeast Asian population. We didn't know the relevance of that population to the broader population that we would be developing a drug for here in North America. But then following that particular publication last month comes out another study where they combined a number of different data sets. And now you're looking at, I believe this was north of 90,000 individuals in 50-some studies that had been looked at where they had additional phenotypic data and what they were able to demonstrate that in a population that we really care about in the cardiometabolic space with an elevated BMI, you do start to see a big change or separation in the susceptibility associated with this particular variant. So it was this kind of information that takes us from being modestly interested in pursuing this particular target to, well, this might be very appealing, because in the population that we're aiming to treat, it appears to have an even bigger effect. So should we pull the trigger and go after it? And when we combine these large data sets with that phenotypic data, and back to the earlier comment, are we interested in a genetics database or a metabolomics database? The answer is absolutely yes, because these studies that we see that come across our desks in the form of a nature paper or what have you, it shows susceptibility to disease, but it doesn't tell you much else about what that particular variant could be doing to the system. But when we start to combine some of these larger data sets or combine multiple data sets where there's additional phenotypic data, we start to get a very rich picture for how a particular perturbation can influence the entire cardiometabolic profile. And here's just an example of work that we did with the Broad where we went through and we looked at a number of different studies where there was a fair amount of phenotypic data, and that we see as we go from the heterozygic to the homozygic allele, as we move across things that we care about, such as blood pressure, LDL, cholesterol, triglyceride, HDL, fasting glucose. Glucose after a glucose challenge at the 120-minute mark, all of a sudden you can start to put together a compelling story that this particular variant plays a critical role in all things that we care about in the cardiometabolic space. But in the absence of having that database to go to, to look at these specific studies, to look at the phenotypic data, we're left with increased susceptibility to type 2 diabetes should you choose this target or not, with probably very little information about the functional effects. This kind of information for us starts to tell us a lot about potential functional effects of the variant that we can then make a more educated decision as to whether or not we want to pursue a particular target like this. So one of the things that we did with the Broad was we took this approach of we have a portfolio of roughly 20 programs in the cardiometabolic space. They range from early target discovery all the way to phase 2. Did we make good decisions? Was this a good portfolio in terms of is it founded or does it have supporting genetic evidence behind it? So we gave a list to the Broad. Here's all the targets that we care about. We have active programs in many of them. You see that they intersect with fatty acid metabolism, insulin signaling, metabolism of triglycerides, et cetera. Much of this based on what the competition is doing, what's been published in preclinical animal models, knockout models, different cell systems, et cetera. And then we ask the question how much of this, how many of these pathways or targets are supported by human genetics? Which thought was going to be a very easy question. Throw it over the wall and we would get quickly a spreadsheet that would come back and say yes diabetes, no diabetes, fasting, glucose, insulin. And it frankly wasn't the case. And so from a pharmaceutical perspective, we're wildly enthusiastic, I would say, about this idea of having these kind of lookup tables or access to these large databases where you could take your portfolio, ask the question is it supported by human genetics and the indication that I care about, as well as what are other things that should be safety concerns? Because now we're starting to go after a lot of targets that intersect metabolism and inflammation. And all of a sudden you have a target that you think is going to be very good for improving insulin sensitivity in the adipose and then you later come to find out that it's associated with an elevated risk of Crohn's disease or IBD or RA. And how do you screen for that using animal models? You simply can't. So I guess I would close with, from our perspective at Pfizer and we've talked to a number of other pharmaceutical companies that have been interested in going into pre-competitive consortia with us in academic groups or the NIH, do we want a database where we can compile all this information and have access to it? Absolutely. Do we want phenotypic data in there? For us it feels like a must because it gives us so much more information about the functional consequences of these variants or these signals that, you know, that's how we prioritize our portfolio. But you know, we'll take a variant to a pathway to a phenotype that we care about and then make the decision, do we think it's going to be disease modifying or not? So thank you. Please. So this is the path that you and Pfizer are taking with really focusing on human genetic validation. Is that true of your sister companies? Or is Pfizer at one end of the spectrum? Or how does that look? So we are having active conversations with a couple of other pharma partners that have either done this on their own or have done this with other academic collaborators and see the utility in it. They share the same frustration that we do. We simply don't understand how to access the data and even what data are out there. So I would say there's three or four companies that we're in active discussion with that would like to be involved in something like this. It's not clear how we progress forward. However. And just to follow up, that's three or four out of how many big companies? 25. But that's not to say that 22 have said no. These are companies that we have pre-competitive type of relationships with. So I could tell you that really in no instance have we floated the idea that would you be interested in going into a pre-competitive consortia looking at expanding the use of genetic data to pick better targets? The answer has always been, that's a good idea. We want to do that. But how do we do it? It really gets to the logistics. David. I just think the only other comment I would add to that, I do think there's a lot of interest in this in pharmaceutical companies. I think we have to be clear. It's not GWAS, per se. Like it's human genetics. So I mean GWAS is one kind of data. But I think you'll see more diversity. If you look at Novartis, for example, Novartis is very invested now in the idea that human proof of concept through genetics is incredibly important. They're betting more, in my understanding, from talking to Mark Fishman and others is betting more on rare genetic diseases where they get approval in small numbers of people and then extend to a bigger market. So if you take, but that would be equally served by such a system. Again, we shouldn't know. Again, it's not that we're saying it'll be a GWAS system or a Mendelian system. It would be whatever question you had that company. Look, I think you get a much broader uptake if you make it clear it's inclusive in that way. David. Yes, sir. I'd just like to make a comment with respect to this just to put things into perspective of what percentage of people in the pharmaceutical industry know anything about biology. And it's less than 1%. So this is why you're not going to get the biological understanding inside the pharmaceutical industry. It has to be people outside the pharmaceutical industry. That's the first point, actually. That's the only point. Except, Jeff, I wanted to ask you a question. How important do you think the granularity of the phenotype data is going to be to the utility of the database? So from our perspective, we think it's very important. So right now, if you look at our external collaborations, we have access to about 100,000 individuals that have been followed over population studies, cross-sectional studies. About 20,000 of them have had metabolomics work done on them. And that's what we prize the most. It's that ability to complete the picture. For this particular variant, what have you, is there a metabolic fingerprint associated with that that we can pull back to a particular pathway? And so the idea of being able to call people back, that's very appealing to us. Because we have collaborations now with a number of groups that they do metabolomic type of profiling on a wide scale. And we take advantage of that currently. Please. I don't know how to ask this without sounding critical. So I'll apologize in the beginning from the start. I guess given Pfizer's history the last five years, maybe 10, and given the recent experience with CETP inhibitors, I'm really surprised that you're interested in triglycerides, insulin, fatty acids, and not stroke, heart disease, kidney disease, peripheral vascular disease, and heart failure. So who cares about glucose? You care about dying. Yeah, I understand. This is not meant to be inclusive at all. This is just a snapshot. But we're absolutely interested in those areas as well. I just want to ask a question. Perhaps it's not part of this discussion. But one of the unique things still in industry is your experience as you move the target down into large animal biology. Most of the academic community is still largely involved in studying mice and rodents, really. In just improving the future biology, so to keep the circle moving, do you envision a point in time where that biology is also made pre-competitive and made available? So that we know what the next generation of effects of human phenotypes are? Yeah, so what I can say is that we're entering into more pre-competitive partnerships with our pharmaceutical peers, where we share that type of information. And I would say we're doing that on a more limited scale with our academic partners. But whenever we enter into an academic collaboration, we basically give up all IP. The only IP that we care about is the chemical matter. So when we do find an academic, and that's new for us. I mean, that might be a surprise to many of you. We have no aspirations of owning the IP around targets and pathways. It's all about the chemical matter. And I think as more academic collaborators become aware of that fact, that door will open up. But right now, there's a lot of folks in academia that just don't even consider partnering with us because their past experience has been that it's such an IP nightmare that it's not even worth the effort of the 24 months that it often takes to get a contract in place. Just curious, when you say chemical matter, does that include biologicals? Yes. But in terms of the biologicals, we're not going to try to assume for a moment that we could protect a GLP or something like that. But it's the novel construct, the way that we would extend the half-life for the potency or something like that, but not the protein itself or the biologic itself. Yes, please. I was interested in to what extent already available phenotypes that are being generated in the medical clinic would be useful or usable to you as opposed to these very careful research-driven prospective types of targeted phenotyping. Yeah, I mean, so I can say with Duke and their CAFGEN study, there's a study where they're looking at individuals that keep coming back to the CAFG clinic because of a variety of different risk factors. And so that's a data set that's very interesting to us because it has the GWAS, it has exome sequencing, now it has metabolomics, transcriptomics, proteomics. So those are the kind of studies that we're constantly looking to have access to. We're now just starting to engage in additional conversations with hospitals and clinics. Could we get similar types of information? In fact, with Tufts, we just started a study this week where we're going to have access to samples from individuals coming into the gastric bypass in the banding clinic. And that'll be evolving over time and we'll continue to get samples both for genetic analysis as well as getting adipose tissue to do cell-based assays as well. I guess what I was asking is phenotype data that's being generated anyway through the medical care system as opposed to these highly expensive phenotyping activities. Yeah, so I don't have a lot of those conversations but I do know that folks in our business development and our external research groups, they struggle with that because of the consent that's in place. And so when the pharma company comes in and says you're doing something of interest or potentially of interest to us, we would like to have access to it. There's a lot of consent issues that do come up and in the question always is, is this big bad pharma trying to get some information that they're not going to share with the rest of the community? And we have to figure out how to work through that. But we have not done that very well at this point. Thanks very much. Okay, thank you.


Hey guys, it's Nate, AKA The Foot Account, and welcome back to the channel. Today, midday upload, we are talking about trading with ones to watch cards. These are some of the most exciting and just nerve-wracking at the same time. Cards to trade with on this game because they're all based around in real life performances when these players do play in real life. It's so fun, right? Once to watch trading is one of the most fun ways you can trade in this game. It's risky, but it's fun. These cards fluctuate a lot, especially when they're hyped. And right now they are brand new to the game. So they are very hyped. There's a lot of eyes on these cards. There's a lot of games coming up as well that we can watch and possibly make coins and buy these cards on a low, sell them on a trend fluctuation high. And there's kind of weekly trends that you can do and make coins with these cards where you can actually kind of passively trade with them every single week. And I think that's gonna work really good this year with the hype cards and the big names and the performances that some of these players are putting in already. Even though they've been only at these clubs for a small amount of time with the seasons just starting about a month ago and more competitions on the horizon as well, like Champions League, Europa League, a lot of the cup games. Again, the biggest thing to remember with these once to watch cards is they're only upgraded from performance-based informs, man of the matches, or other items like team of the tournaments. There's a whole list, I think, on the EA website. But it's basically informs, man of the matches, and like team of the group stage cards. Anything that is a performance-based card, they will rise. So if a card gets a scream item, like if Odegard gets a scream, his once to watch is not gonna get upgraded. So again, it all is just based around in-game performance. So, of course, we have both sets of once to watch cars that are out in the game right now. We have team one and we have team two. And I wanna talk about a little bit of a difference between these two teams and also, because one is in packs right now, that's why there's a difference. But also talk about how you can trade with these cards on a weekly and how there's so many different market movements that you can do with these cards, whether you're just kind of trading with them weekly, or if you're trading with them on the spot during a game, we're gonna talk all about it. So we have a lot of great examples to go over this week because we have cards that scored goals that are possibly getting informs, cards that scored goals that, you know, didn't have as good of a performance to get an inform, and then also cards that didn't do anything, players that didn't play, and their cards going down after a game because of that. So let's look at our first example. It is Luis Suarez already receiving one inform this year. Luis Suarez has been banging in goals wherever he's been playing. National team Uruguay, Atletico Madrid, this guy's been playing goals. So what happened today was Luis Suarez before the game, and we can even go back to Friday, and look, he was 137, 136K, basically 136K early in the day on Friday, right? The day before a game. Suarez was 134, promo Friday, after we had the promo Friday, he starts to rise up 147. We get to the morning, he's 150. Right before game time, he's 150,000 coins, right? What happens in the early parts of the game? Luis Suarez scores a goal in the sixth minute of his game. Today is right here, Atletico Madrid versus Seltavigo. This is gonna, your SOFA score is pretty low on the website, slow on the website right now, I don't know why, but Luis Suarez scored, right? So I actually, on my transfer list, I had a Luis Suarez. I literally woke up at the perfect time because this is like midday for you guys in the UK, but for me, this is like early morning. So I woke up, Suarez, boom, he had scored his goal like five minutes before I woke up. So I was like, oh shoot, I gotta sell this card right away. Listed my Suarez at 160, got him out. Suarez is now back down as we saw in Footbin, back down to 123. So again, analyzing this graph, right? Suarez, 123 right now, he was at 160.   So the card goes up after that initial goal, and then what happens is if there's no goal for a little bit of while after that, the card starts to just kind of slowly go back down because people are like, all right, well, I have this card, I invested in him, I don't know if he's gonna score again, so I'm just selling it, and there's a little bit of undercutting that happens. He kind of starts to creep down. Now if he scores a second goal, kind of like what Timo Werner did today, he shoots back up, right? Because now with that second goal, they usually shoot higher with that second one. Let's look at Timo Werner's graph. It might be really hard to see on the daily graph. Yeah, it's kind of hard to see, but what happened likely here with Timo Werner was, he was 700,000 coins, he scored the first goal, he went up a bunch, and then he went down probably a little bit in between unless those goals were very close. I think the Timo goals were a bit spread apart. Okay, not much, Timo scored in the 15th and the 28th, so there wasn't a lot of time for that card to go down, but honestly what happened was he probably just shot right back up after that second goal, and then he kind of dropped back off after the game. This is a very, very common thing that happens. So again, right? You buy a player before the game, the player goes up, they score a goal, boom. You make your profit and you're in, right? That's number one way, and the easy, and the most just like stress-free way, and the perfect scenario for trading with the ones to watch, right? Here's the second thing that happens. Let's say you didn't buy before the game, or you bought the card when it was rising up, and it goes high for like an hour or so after people like, there's all the hype there. You know, Chelsea was ahead in this game, they were ahead three to two, they were at it two to two, actually, and they ended up drawing, but Timo Werner was basically a man of the match, right? Highest rating. So, Timo Werner is probably gonna get an inform this. It's very possible. Two goals, one assist. He doesn't have any special cards yet this year. It's possible he gets an inform this week. So what happens is, everybody who bought those cards, they're like, why is this price not staying up, right? They wanna take their coins, they're making coins, they start selling, people start undercutting. Undercutting, undercutting, and undercutting. So Timo was 725K PlayStation before the game. He went to 860. And then after the game, you know, two hours or so, he's back down to sub 800. He literally dropped like 60, 70,000 coins, right? And now look where he's at. He's rising back up. He was just 840 on the PlayStation. I don't know what was up at that, but he's kind of back up. Actually, he's about 800 to 20K. You can see there's a nice undercut right there on Timo. He's about 800 to 20K. So we went from 720 to 860, back down to 780, 740 on the Xbox. And now he's back up to 800K on both consoles. Xbox, if you got in here at 740, that was a huge drop-off. But this is the second biggest thing, right? If a player has a really, really good performance, there's a really high chance, and this happens almost every time, if that player is gonna get an inform, there's an opportunity to actually buy after the game when there's panic selling, and then you'll have another opportunity to reinvest in that card and then sell it as it rises up into the week. Wow, Timo's at 790 right now. This is getting really interesting. Obviously I don't have enough coins right now to look at this, but this is almost as low as he got earlier this week. And I still think Timo is in line for an inform. Now I know the market's kind of crashing right now, and the menus are laggy as always, as you can see here. But this card might be a little bit overvalued, so that's the only thing that I would take a little bit of consideration with and be careful with. But in a normal market, what you see is, is you see this exactly thing right here. You see the big jump, the drop-off after the game, another buy opportunity, and then as we head into Wednesday with Team of the Week, this guy's gonna start getting into Team of the Week predictions.  That means this card's gonna get upgraded, that means it's gonna rise in value. Kinda like what happened with Thomas Partay last week, right? He's gonna rise into Wednesday, he's gonna get that inform, and then you're gonna be able to sell in the hype just in case he doesn't get an inform for whatever reason. That's the safest way to do it for the amount of coins. It's kinda like one of the easiest ways. Those are the two, I guess, ways to trade with ones to watch. Now, of course, that's if a player scores goals and has a good game. Let's talk about a player that maybe does not have a good game or doesn't even play, right? Let's talk about ZH, right? This is another popular player on Chelsea. He was like 100,000 coins before the game today, right around there. He was actually 115, 110, wasn't named in the starting lineup, so kinda dropped off before the game, and then of course, as the game is going on, he just drops off, he's not getting in the game, not playing, or just does not have a good performance, whatever it may be for this item. He just drops off, drops off, drops off, and a lot of these cards, let's look at like, well, Telus played not super duper long ago, so the sell-off is probably still happening there, but for a lot of these cards, what happens post-game is, or for even like a ZH again, using him as an example, there's a lot of a sell-off after a game, and this is kinda where the weekly trend trading kinda comes into play, right? ZH was 115,000 coins before the game, right? He's dropped down to 80,000 coins. Now, there's some Champions League games that are coming up later this week, and yes, I know that Champions League games do not count for a lot of these cards upgrades, right? Cause you're not getting in-forms on the weekly, or man-of-the-match cards on a weekly basis for Champions League, but since it is a real-life game that people will get to watch Chelsea play, they'll get to watch Luis Suarez play, the reason why I bought more Suarez today, when he's down here to 120,000 coins is because Suarez is playing well, right? Athletic on Madrid, they play on Tuesday against Bayern Munich. They play on Tuesday against Bayern Munich in the Champions League. Now, of course, I've heard some people saying, why would you buy the card then because he's not gonna get upgraded from a good Champions League performance? That is true, but people do not understand that. People don't get that, and there's a lot of people in this game that just think of once-to-watches, they get upgraded when they have a good game. So if Suarez scores a goal on Tuesday, go back to this graph and watch Suarez go up because he will go up on Tuesday if he scores a goal against Bayern Munich in the Champions League, even though he's not gonna get a special card for that, unless EA's doing something different this year, which they very well could, and then this would be another same way to trade, but they don't historically get team league cards for Champions League performances, and they're not doing man-of-the-matches right now. So this card's still gonna go up if he scores. He's probably gonna rise into game time as well. It's not gonna be a huge rise, but some people just don't understand that stuff. They don't realize that these cards get upgraded only in certain ways, and this card will rise, right? Timo Werner, they play, of course, Champions League this week as well, so just kind of keep an eye on some of these cards, right? Some of these guys that have Champions League, if they're not injured, right? Just be careful with injured players. You know, even if they're playing Europa League, like Spurs are playing Europa League on Tuesday or Wednesday. You know, Bale, let's say Bale today on Sunday, right? This is a very, very hyped-up card right now. This is a card that you would want to sell in the hype, in my opinion, right? Bale's been injured. He's not a guarantee to start. He's not even a guarantee to play. He's probably gonna be on the bench, and people are gonna have a lot of eyes on him. There's gonna be a lot of hype. Does he get in? Maybe. Does he have an impact? Who knows? But a very smart thing to do here, if you bought this card anywhere between 250 and 280, because that's where this guy has been, I would sell this in the hype. He is really rising up into game time. Yes, he has a lot of hype, but the safe way to do it is to sell in the hype with a lot of these cards pre-game. And that's one of the most important things as well. Like we talked about what the Suarez, we saw that he was kind of rising in game, right? You could have bought him Friday for 134 and sold him for 150, like right before the game. And you wouldn't even have to worry about his performance, and you were making not quite 10K a card there. What is, that's almost, that's like 8,000 coins a card if you would have done that. That's a decent trend daily like flipping in, or not, weekly investment that you can make with these cards that you can do almost every week, right? You can literally just sit here since bail is very hyped up. Let's say nothing happens to bail today on Sunday, right? He doesn't get in or he plays 10 minutes and doesn't record a goal and assist or anything like that.  Spurs are gonna have a couple of games coming up in this next week or so. Of course, they've got Premier League games next weekend. They've got Europa League matches midweek. This guy's probably gonna rise back up in price again because there's hype because they're playing. People just like to make that connection between IRL and ones to watch cards. A card in FIFA, this is like the FIFA to IRL connection and people love it, dude. They freaking love these cards. So that's kind of like the major ways that I like to trade with a lot of these cards. Now of course, big time decisions with VAR affects these cards as well. Timo Werner today is a perfect example, right? This Werner card was rising up because he scored that first goal. People saw the goal notification, they saw that he scored, the card started to rise. It went to VAR and there was panic listening, right? Because people were like, oh no, this went to VAR, he might not score. So the price like dipped right down for a really short amount of time. I'm pretty sure that's what happened today. And then he rose back up when the goal was scored or whatever or the goal counted. So if there's ever offside goals, right? Be very, very careful. This is why it's risky, trying to trade with these cards and try to buy them when you get a goal notification. Because then some people try to buy the card right away, sell it like 10, 15 minutes later after everybody else goes and buys it and try to time that perfectly. But you have to be very, very careful with VAR and with offside calls. And especially like no, if you're watching a stream that your stream might not be like right on time. So when you're going to buy the card, it might already be inflated. So just be kind of careful with that. The biggest advice I can give you is this website right here. Sofascore.com, find yourself an app that keeps score. This SofaScore app, I've got it on my phone. I use it all the time. I've got notifications set up on my phone right here so that when guys like Timo Werner score, guys like Swires, basically what I do is I go through this entire wants to watch team and I turn notifications on for each and every player because if they score, and if I'm not on my console, I can quick flip up the companion app and possibly buy a couple cards, especially if it's a really high player, watch them rise 10, 15 minutes later, sell that card, make a few coins that way. That's a way you can kind of be risky with it, but also get goal notifications. Sofascore is the name of this website right here. There's a couple other ones out there. Just make sure that if you're getting an app, we're downloading an app and getting notifications that they are very, very fast, right? They're very fast, very detailed. And check Twitter too, right? Because people are tweeting all the time.   Or something like that. So stay tuned to Twitter and get goal notifications. That's the biggest, if you're going to trade quickly with these, like during a Saturday or Sunday game, that's the biggest advice I can give to you. And again, these cards, they're so fun to trade with and especially this year, it looks like we've got a really nice set of a couple teams here with once to watch set one. We have a lot of strikers, attackers, a lot of midfielders, honestly, when I look at these two squads, we've got a lot of midfielders like center mids, like Thiago, Arthur, Vidal, but we also have a lot of strikers too, right? Rodrigo, David, you've got other attacking players like Ferran Torres in team one. I think this is the most prolific team, Werner, Suarez, Bale, Hakemi actually scores a decent amount of goals. If ZH gets in, that could be pretty interesting too. So these cards are going to be really fun to trade with year round. They're going to be very profitable week in, week out and they're going to get forgotten about. As we head on throughout the year, they're going to get forgotten about, but they're always pretty consistent ways to make coins because they're fluctuating weekly. They're selling and getting low after games. They don't have a good performance. And then of course you can know like, hey, if they have another game coming up soon or you can kind of watch these cards on the promo Friday, promo Fridays, there's a lot of panic selling sometimes. You see a once to watch card getting sold. The next day you know they've got a lead game. Maybe you have a chance to pick up that card at a deal. And then obviously the hyper turns for the next day as a once to watch card would rise up for the game and the potential to score. So that's kind of ways that you can trade these cards. So hopefully this video helps you guys out. A lot of information about once to watches. They're risky, they're fun, but this is like a gambling aspect of even how trading is kind of gambling in some sorts. It's just like you're betting on a real life performance for one of these players for their price to rise and for you to make coins instead of a video game. So it's really interesting, really cool, kind of confusing sometimes. And it's a big potential lose, but also a big potential game. It's like high stakes, right? High stakes trading, very volatile, but very, very fun and enjoyable when you get it right. So if you enjoyed this video and this helped you at all, smash the thumbs up on it. Comment down below if you have any questions and subscribe to train afternoon. It's been Nate, The Foot Accountant. Catch you guys later. Peace.