Welcome to The Commentaries, a podcast series from Tan in which you'll learn how to read and understand history's greatest Catholic works from today's greatest Catholic scholars. In every series of The Commentaries, your expert host will be your personal guide to not just read the book, but to live the book, shining the light of its eternal truths into our modern darkness. Visit tancommentaries.com to get your copy of the book and to subscribe for access to all the great reading plans, new episodes, bonus content, and exclusive deals for listeners of The Commentaries. Hello and welcome back. I'm Father Robert Nixon, a monk of the Order of St. Benedict and director of the Institute for Benedictine Studies at the Abbey of the Most Holy Trinity in New Norse or Western Australia. This is the commentary series on The Imitation of Christ, one of the most beloved spiritual books of all time, written by the great Thomas the Campus. Today is Day 16 and we're going to be examining Book 4, chapters 8 through 14 of this wonderful work. But before we get started upon looking at those chapters in detail, let us pray to God. In the name of the Father, and of the Son, and of the Holy Spirit, Amen. O Christ, in bread and wine disguise, hidden from our earthly eyes, but present now in mystery, from death and sin, please set us free. Let us pure and true devotion rule our senses, thoughts, emotions. Let thy blood refresh our soul. Let thy body make us whole. As I mentioned last week, Book 4 of the four books which together comprise The Imitation of Christ deals with the Blessed Sacrament and it does this in a very wonderful way. In chapters 8 to 14 of this book, we're continuing with our exploration of the wonderful mysteries of this Blessed Sacrament and chapter 8 begins with the idea of the oblation of Christ on the cross and of our own resignation. Now this word, oblation, which is a translation of the Latin word, oblazio, means something like gift. It's a word which appears in our current English translation of the Roman canon. So the oblation of Christ on the cross, the gift, the offering of Christ upon the cross and of our own resignation. The theme of this chapter is the kind of unification of self-resignation with the self-offering of Christ on the cross to realize that in sacrificing something of ourselves, in residing something of ourselves, we're uniting ourselves to that wonderful sacrifice of Christ which took place on the hill of Calvary all those years ago. And it begins with Christ speaking, as I willingly offered myself to God my Father for your sins with my hands stretched out upon the cross and my body naked so that nothing remained in me which was not turned into a sacrifice to appease the divine wrath. Even so must you willingly offer yourself to me daily in the mass for a pure and holy oblation together with all your powers and affections as heartily as you are able. What do I require more of you than that you endeavor to resign yourself entirely to me? Whatsoever you give me beside yourself I regard not, for I seek not thy gift, but thy self. And so this is a wonderful imploration Christ is inviting us to participate with him in his sacrifice of the cross to offer our own souls on the altar. And I think a very important part of the mass is what's called the preparation of the gifts. And this involves the kind of offering of what we have of who we are upon the altar in sacrifice to God. And this is not only the priest who's offering himself but every member of the congregation there present. And it's a wonderful exchange. What we offer to Christ is then transformed by the words of consecration into the essence of the divinity itself. So this is part of the mystical union with Christ which takes place in every celebration of the mass. In chapter nine we move on to that we must offer ourselves and all that is ours to God and pray for all. And this is following the same thing in the previous chapter. So this is the disciple now responding to the Lord. And he says, Lord, all things are yours in heaven and earth. I desire to offer myself to you as a voluntary oblation and to remain forever yours. Lord, in the sincerity of my heart I offer myself to you this day to be your servant evermore, to serve you and to become a sacrifice of perpetual praise to you. So as we are present at the celebration of the Eucharist, as we prepare ourselves to receive the body and blood of Christ, we should offer ourselves upon that altar. Say to God, everything I am, everything I have, everything I do, I offer to you. Take it, Lord, purify it, accept it with all its faults and shortcomings and transform it by your holy grace. Chapter 10 tells us that holy communion is not likely to be omitted. And this is very important. It's Christ speaking to us. And it tells us that often a person is hindered by too great a solicitude for obtaining devotion and a certain anxiety about making his confession. Follow herein the counsel of the wise and put away all anxiety and scruple, for it hinders the grace of God and destroys devotion. Leave not the holy communion for every small trouble and vexation, but go quickly to confession and willingly forgive others their offenses against you. And if you have offended anyone, humbly crave pardon and God will readily forgive you. What does this avail you to delay confession for a long time or to put off holy communion? Purge thyself with speed, spit out the venom presently, and make haste to take this remedy. And you shall find it better for you than if you had deferred for a long time. If you defer today for this cause, perhaps tomorrow a greater one will occur. And so you may be hindered for a long time from communion and become all the more unfit. What he's talking about here is scruples in receiving communion. And this was perhaps a greater issue in his own time for many people than it was now. Because of course in receiving communion we're receiving the body and blood, but as we read anyone who receives it unworthily, meaning without the proper disposition or without being in the proper state, is receiving condemnation. This has to be moderated by the realization that none of us are ever truly or properly worthy to receive this wonderful gift. So he's urging us to strike a balance between what are called scruples, which are kind of unhelpful or exaggerated hesitations about participating. And he's not saying that these things don't matter, but rather he's saying if we're conscious of any sin, then we should hasten to confession, to prepare ourselves. And once we have made confession and received absolution, to believe in the efficacy. I mean, in my own experience as a priest I often, you know, it's not common to encounter situations in which people don't seem to believe fully in the efficacy of the sacrament of reconciliation. But once a sin has been confessed and absolved, then trusting in the sacrament of the church, we are truly freed from that sin, and so ready to receive the sacrament of holy communion. That doesn't mean on the other hand that we should, you know, just disregard our own disposition and state of grace. So there needs to be a proper balance. And he talks about that when he is lawfully hindered. So in other words, there are circumstances when a person shouldn't receive communion. He must always have a good will and a pious intention to communicate. And so he shall not lose the fruit of the sacrament. And he says also if a person abstains out of humility, all by reason of some lawful impediment, he is to be commended for his reverence. Continuing then with chapter 11, that the body of Christ and the holy scriptures are most necessary to a faithful soul. So in the celebration of the Mass, we're nourished both by the word and the sacrament of the ignorance. The word in its way is a sacrament as well. So we're receiving God in a number of forms. Firstly, in the species of bread and wine, the true body and blood of Christ. We're also receiving the divine word through the scripture reading and through the other elements in the Mass. Of course, we need to remember that these two are not equal elements, that the body and blood of Christ is infinitely greater than the holy scriptures as important as they are. And I like to compare this between a letter received from a person and the person themselves. Now, are we going to take more notice of the presence of the person themselves and give that person more honor than this letter which we happened to receive from them a couple of weeks ago or whatever? And sometimes in our church today, there can be a tendency towards a type of idolatry of the scriptures, of almost giving them primacy. And I don't know if this came about as an idea that it might be a nice ecumenical thing to do, that it might make the Protestants happy or whatever. But the body and blood is what makes a Mass a Mass. But we should prepare ourselves by being open to the words of holy scripture and in particular also open to the other parts of the Mass, the beautiful prayers which we find in our missile. Chapter 12, that he who is to communicate ought to prepare himself for Christ with great diligence. And this is so important. We need to prepare for Mass each time. We need to pray beforehand to pray and reflect during the Mass. And hopefully during the Mass, there will be sufficient periods of silence for this preparation and prayer to take place. And we read Christ speaking to the disciple, I am the lover of purity and the giver of all holiness. I seek a pure heart and there is the place of my rest. Make ready for me a large upper room furnished. And I shall eat the Passover with you together with my disciples. If you will have me come to you and remain with you, purge out the old leaven and make clean the habitation of your heart.  Sit like a sparrow solitary on the hell-stop and think in your excess and in the bitterness of your soul. For every lover prepares the best and fairest room for his dearly beloved. And hereby is known the affection of him that entertains his beloved. So this preparing our hearts and our souls to receive Christ in the Holy Sacrament is so important. We need to try to put things in order. If we can imagine if we had a guest coming to our house, we would take care of things. And the example he gives of someone receiving a beloved. And you can imagine, you know, in the early stages of a romance and hopefully in married life, hopefully people take care that they're making a fitting dwelling place for the person who they love so much. And Christ, of course, we love above all other things. So can we beautify? Can we put into order? Can we clean up the chambers of our heart and soul so that we're ready to receive this most beloved of guests? In Chapter 13, that a devout soul ought to desire with her whole heart to be united to Christ in this sacrament. And users there the possessive adjective her whole heart enlighten the soul. Anima is a feminine word. And for that reason it's referred to as her. So this, of course, applies to men as well as women. So it's talking about nourishing the desire for union with Christ before we receive the Blessed Sacrament. So this is written in the person of the disciple. And he prays, Who will give me, O Lord, that I may find you alone, that I may open my whole heart to you and enjoy you as my soul desires, and that no man may despise me, nor anything created move me or regard me, but that you alone speak to me and I to you, as the beloved is accustomed to speak to his beloved, and a friend to entertain himself with his friend. This I pray for, this I desire, that I may be wholly united to you, and may withdraw my heart from all created things. And by the holy communion, and often celebrating, may more and more learn to relish heavenly and eternal things. And this is absolutely a beautiful reflection of the ardent desire with which we should receive communion. We should stir up within ourselves a true hunger for this union with our beloved. And this union, of course, leads us to eternal glory. And then we continue in the next chapter with this same theme of the ardent desire of some devout persons to receive the body of Christ. And it speaks about people who have been blessed with this great and ardent desire. It says, many devout persons have been who out of a vehement desire for communion and a sensible love in their hearts could not contain themselves from weeping, but with their whole souls eagerly thirsting to approach, both with the mouth of their heart and their body, to thee, O God, the living fountain, being in no way able to moderate or satisfy their hunger, but by receiving thy body with all joy and spiritual eagerness. O true ardent faith of such persons, being an argument of thy sacred presence. So giving us the example of this multitude of saints who've had experience of this ardent desire to receive holy communion. And as he says, this is a probable argument of thy sacred presence. Now, probable in this case has a slightly different meaning to its usual contemporary meaning. It means as a proven argument of his true presence that people wouldn't have felt this ardent desire if Christ wasn't truly present in the Eucharist. And I think that is something worth reflecting upon and praying also for the grace to burn with this same ardent desire for the Eucharist, which will then impart itself in the form of reverence and awe and guard ourselves against doing anything which might render us unworthy for this wonderful blessing. Well, that brings us to the end of day 16 in our study of the imitation of Christ. Thank you so much for listening and for joining me on this wonderful journey. Next time we'll be discussing book 4, chapters 15 to 18. And until then, may you walk closely with Christ. Amen. This has been an episode of The Commentaries, a podcast brought to you by Tan. To follow the show, study more of the greatest Catholic classics and to support the commentaries and other great free content from Tan. Visit tancommentaries.com to subscribe and use coupon code COM25 to get 25% off your next order, including the imitation of Christ and countless more spiritual works to deepen your interior life and guide you to heaven.


I'm right girls can I ask what you think of daddy's cuts what do you think mommy I reckon it looks like you've got a twinkle in your eye about injuring yourself and you're pretty happy with your war I don't think you've taken this much footage of your kids before in your life but you're pretty proud of these war wounds it's disgusting that's the juicy one yeah that's good to have a touch down every now and then makes you feel a lot makes you feel alive touch down on the concrete oh yeah that's the one there hurts the most because there's a big chunk taken out of it that one there so the box actually not too bad after the fall got a bit of grazing on the handlebars here you can see and it's no longer a 105 it's a it's a 05 Shimano 05 and just on the rear skewer that's been grazed up a bit and the handlebars it's completely you can't really see from that angle yeah there you go crooked handlebars are you okay to be on film well it's been two days since I crushed my bike and I'm wondering how my presence has been around the house you've been an absolute shithead very nice you've been so angry and grumpy and turd pretty much I was empathic for a little while but he actually went for a ride the next morning and that ruined my empathy ruined my chance if you had have actually rested up the day after you got back instead of going for a ride I could have had a lot more empathy but you smashed it up for me and then he'd been a little is that why you've been him I didn't know this now you're opening up on video that's why you've been giving me death stairs no I'm just keeping away from you okay what do you mean I'm not nice so enough of the fun and let's take a look at the crash now but gonna warn you if you're up for seeing like a hardcore crash like me come off my bike and slice myself apart it's probably not the video for you this is more about a lesson that I learned from coming off my bike that I want to share with you right now so welcome to my backyard kids have just been in the pool and I'm sitting here with one of my new favorite beers twoies old Dark Isle and it's hoping me numb the pain that I'm now getting from some of these scratches elbow legs hips are worst but that's covered up at the moment and what I thought I'd do in this video is this first time I've ever captured a crash on my GoPro in fact this is only the second time I've ever come off in a criteria and I guess reflecting on the footage looking at it almost just looks like I've just come off my bike out of nowhere but when you actually slow down the footage you'll see that a rider in front of me has come off his line probably only about four or five inches but because it's happened so rapidly and because I was super close to the wheel whilst going through a bit of a chicane so we were I wasn't a full blown corner but definitely had the bike on an angle I sort of soon as the tyres touched and rubbed I hit the deck really hard so I wanted to break it down and show you in slow mo I've got my computer here in front of me what actually happened and what I've learned from it so I'm just going to press play here and the rider in front of me his name is Armani Drake he's from Pro Racing Sunshine Coast and you'll see as we're going around this slight chicane he tilts his head ever so slightly and as he's tilting his head to the right looking around his rear wheel moves out to the left I'd probably say as you slow down the footage about four to five inches but it happened so quickly and then you can hear the sound of tyres rubbing I'm just over and hit the deck straight away at about 45 46 kilometers an hour and I hit really hot steamy concrete I put the temperature gauge in there for a reason about 34 degrees and it was about what have been what have happened about you about 20 25 minutes into the race and it was a hot and steamy day gets super bright and hot up here on the Sunshine Coast by the time you're hitting 9 30 10 it's like a steamboat out there and I guess I was probably feeling a little bit of fatigue as well first crit in two months and hot human condition it didn't feel like a really hard crit didn't feel like a Glenvale and a windy day nothing like that but I think the heat sort of amplifies your fatigue and perhaps I wasn't concentrating as you can see I sort of don't follow his wheel coming out of the sort of the straight there and then I jump on it put in a bit of effort not thinking clearly too close to the wheel now when I came off I've actually just blame myself I thought I was way too close to the wheel there stupid thing to do and as you'll see I dusted myself off bike was actually okay fell to the left not to the right so I didn't bend the derailleur or anything like that and then just got back up and started riding the first thing a money didn't it just proves what a legendary bloke he was he came up and he said mate I'm so sorry for chopping your wheel he works at a local bike shop here on the Sunshine Coast cycles only said mate bring it in I'll fix up your bar tape I'll pay for whatever and I'm like mate I thought it was my fault so this video isn't really a blame game by any means because I actually originally thought that's my fault too close to world and he thought it was his fault because he came out quite rapidly as we were cornering but only really a short distance I mean five inches isn't a lot but when you're super close to the wheel five inches can be the difference between coming off and and not so in this instance I was too close so ultimately the lesson that I've learned here is in recent times I've really been trying to hone into my criteria skills and one of those is to conserve energy you don't want to be dropping wheels like you saw me do and you want to be getting close enough to the wheel where you're safe but also you can serve in considerable energy and I think some of the better bike riders out there can get up really close and if they get in a situation like that they could probably save themselves my bike handling skills are average they're not elite by any means and perhaps an elite bike rider could have saved himself in that instance or perhaps he wouldn't have even got that close so it's just made me recognize that yes you need to conserve energy yes you need to be close to the wheel but your safety is more important and while I didn't break a bone and I didn't hit my head so I'm super lucky in that regard as my wife pointed out I came home on Sunday I was super energised it's like all these natural drugs in your body they get released when you hit the deck and you hurt yourself quite significantly and yesterday wasn't too bad got up for a ride but then today because I haven't really slept well the last couple of nights I've been an absolute prick and I'm feeling a little bit better now cooling down having a beer and having a chat with you but I know I'm probably gonna be like this tomorrow and the next day and just slowly improve but it's very frustrating my hand here I can hardly put my hand in the sink and wash things you know putting pants on hurts the kids constantly bumping me like just all these small things throughout the day it's very frustrating so you know it's a lesson learned could have been a lot worse I'm lucky it wasn't and the thing is this stuff happens you know bike riding makes you feel like a kid again and that includes getting scabs all over your elbows and your legs so it's not going to stop me from racing a crit I might sit out this one this coming Sunday but there's one in Giraweem which is my local area following Sunday hope you get down for that in fact I hope to film that and I hope to catch you in the next video


So we're going to talk about a story right now That just kind of broke late tonight and is very touching it deals with the Nintendo switch and Satura Iwata You guys have already seen the title of this Essentially it appears that Nintendo intentionally has What appears to be a piece of Satura Iwata embedded on every single Nintendo switch In order to watch over the switch Kind of showing the importance. Mr. Iwata had at Nintendo and to the people who were working on switch at the time But let's let's get into the specifics. So We haven't talked about it on this channel, but hackers have gotten into the Nintendo switch for a while and There was a modern named switchbrew who discovered that the game gulf was in In is on every single switch unit They did a dump of title names from the file system back in July and that's where golf was discovered and Obviously, we also know that the NES emulator flog is on there, you know, ironically or not golf backwards and Not a whole lot was known, you know, if it was playable or not since then we've learned it is playable It's played with joy cons. It seems to have joy cons specific controls. We have an image of it here, but What's interesting here is What the why this is on the system, right? Some people thought maybe it's just a test game They're working on it or to get it ready for potential virtual console in the future or maybe as One of their first games that they'll give away with their online system and in this again A lot of it just felt like it was just a test, right? Every switch unit has it, but it was just a test that it was leftover code and it just stayed in the OS Well, it apparently might not have been just this leftover code that stayed in the OS it appears that golf and the emulator running it flog was Intentionally put on every single switch unit. So here's here's the deal We know that the game itself can be ran on switch and until tonight.  So basically you need a launch unit It's never been connected online and I say that because you need to set your calendar to July 11th Okay, the reason that July 11th is such a specific date is that is the day that Satoru Iwata passed away And once you are have your clock and your date set to July 11th You take off each of the joy cons you hold them up and you guys remember that direct to you motion That Satoru Iwata did in every single Nintendo Direct Hello, this is Satoru Iwata from Nintendo It looks like I'll be delivering the first Nintendo Direct of 2014 Directly to you correct well with each joy con in each one of your hands You do that direct to you motion and it will launch the game And there's video evidence of it if I can if I can find a very good video showing this off I will throw it up in here and give full credits on in the description and all of this information I got from spawnwave who did a video on this? I'll have a link to his video down in the description as well so You have to do a direct, you know Iwata is direct to you motion from the Nintendo Directs It can only be launched in July 11th and it can only be done on systems that have not connected the internet Because once you connect the internet, you can't really mess with the calendar that much So you'll have to wait until next year on July 11th to try this for yourself If you've connected your switch to the internet and if you've updated it Etc. Or if you bought in a new switch unit and it doesn't happen to have have the version 1.0 0.0 Now it's still the game is still there that it's still there on newer versions It has not been patched out of the OS You just can't do anything until July 11th now that that's like a huge nod to Iwata as it is but Game explain found out some additional information So Justin Esperin and I'll have a link down to game explains video as well that goes over this In almost the same deal I'm gonna give to you now But Justin Justin Esperin is a senior associate producer at 8.4 Which is a translation studio that worked on fire emblem echoes and he tweeted out that people in Japan are Calling the golf embedded on switch oma mori and then oma mori is a charm so The idea here is that it's a charm from Satura Iwata who coded the game himself So Satura Iwata coded golf and back in the early days in Nintendo Satura Iwata coded a lot of the early NES games And golf was one of those games that he was the person who did all the code work on it In Japanese culture and oma mori are bodied shrines that for various reasons that if you keep them close to you Are supposed to protect you or give you luck. So the idea here is that this game is This this game that Iwata created that Iwata coded Iwata coded golf is an oma mori And as such was embedded in every single switch unit to watch over them Think about that So you can only launch the game on July 11th the day of his death or the anniversary of his death right now you can only launch it doing the exact motions he is known for in Nintendo Directs and In Japan it's being considered The inference here is that Justin Esperant heard this from people at Nintendo in Japan That this game is only even on the system to have a piece of Iwata watching over it that is think about that a Lot of you guys weren't at this channel back when Satura Iwata passed away. I did a a video on the Importance of Iwata to my life And a little remembrance of him and I'll put a clip of it up in here if I can dig that up, but He was a huge part of my childhood From balloon trip I Played lots of balloon trip. I always fight for those high scores Just the Super Smash Bros. Series the first one in melee. He was a programmer on those games to Kirby and all my wonderful members of games like Kirby's dreamland it's Man, I mean even just now talking about this. I'm tearing up a little bit that This just goes to show you how important Satura Iwata was to the people at Nintendo as important as he was to me and as important as he was to gamers across the world and developers across the world this is Man, I think at times we forget that Nintendo switch was Satura Iwata's baby This was his idea. It was his brainchild. He never got to see it come to fruition and come out but this was in development as something he was pursuing and You know for all of the flak that Iwata has deserved over his run as CEO He didn't always make the best business decisions. There were game droughts. He wasn't perfect He saw Nintendo through the height of success that it's never seen before in the Wii and DS and also saw it through basically blowing that success and tanking the company during the Wii U era but There can be no doubt about Satura Iwata the human being and his impact and the way he Affected people at Nintendo that they would even want to put this game on the system as a little piece of him a small Piece of Satura Iwata for every switch owner to watch over their switches to take care of them to take you may Maybe it even has a deeper meaning to help take care of the people that own it because we know that Nintendo Has done things at least back during the Wii era where they were trying to help with people's health And think about you know even now There's games you buy a Nintendo will hey, maybe you should put this game down you've been playing for a while Nintendo worrying about your well-being and Having Iwata kind of watch over the switch and watch over all of us. It's a very It it hits me right in the heart like it's tugging on my my heart strings right now to think that Nintendo thought so much of him that they did this with every single switch unit regardless of your OS update And it's potential that in the future they they might even advertise Next year on July 11th That you can do this only on that day everyone can play it Maybe we'll have the bugs worked out because it's a little buggy from the people who have been able to play it, but it's man Nintendo Why are you gonna make me what we're gonna make me feel? Sadness and happiness at the same time because as sad as it is this is what has gone now I know every time I turn on my switch I'm gonna be reminded that there's a piece of him in there a piece of his hard work and dedication to the company that Really made my childhood and made most of my adult life Man kudos to you Nintendo and I know it's been a couple years, but again, I'm sorry for your loss in Nintendo But I'm glad that he's still inspiring you guys to this day Anyways folks, I'm Nathaniel awful Jants from Nintendo Prime if you like this video You know what to do and if you dislike the video hit that dislike button If you haven't subscribed already subscribe so you don't miss any of our videos and heck when you do There's a little bell icon you can hit and make sure you see all our videos Because I know some of our subscribers don't get to see every video we make Yeah, I Man I'll just cut you guys in the next one


This just arrived in my mail directly from Nintendo, and it'll cost you nothing if you want to get one. Everything from Nintendo's site is free, and I'm gonna show you how. But on top of that, I'm gonna show you how to take your physical Nintendo Switch games and turn them into free money that you can use on the Switch's eShop to download whatever game you want for free. But on top of that, I'm gonna show you another way to make free money, and then go to Nintendo's website and buy whatever you want for free. I had this arrive at my front door that cost me nothing. Well, actually, that last part isn't exactly true. It was supposed to cost me nothing, but Nintendo screwed me again. That was dramatic. Alright, here's the video. Oh, and stick around to the end. I'm gonna open this, and it'll make sense when you get there. What? Is this common knowledge? I just discovered something today that blew my mind, and I should have been doing this whole time. And I messaged my buddy RGT, and I was like, Did you know about this? And even he was confused. Did you know that when you buy a Switch game physically, and you put it in your Switch, you can click on the game, and then hit my Nintendo Rewards program, and redeem points for the game. I had no idea. And the worst part is, apparently you only have a year to do it. I have hundreds of games, hundreds! That's like 30,000 gold coins I've missed out on. This all started because Triangle Strategy just came out. You can buy a different cover on my Nintendo for it using points. So I went to my Nintendo because I was like, That's kind of sick. I'll take a look at that. And I realized I have like no points. I was like, If I can't afford it after buying this many games, who can? And that's when I started to realize this whole My Nintendo program that I've been ignoring has free stuff. My mind has been shattered. I wanted to go through the tutorial and see what that is with you guys, and then try and redeem as many things as I can that I bought in the last year, and then see what we can buy on My Nintendo. What game is this? NINJA-LA! This video is sponsored by the completely free-to-play Nintendo Switch exclusive game. Since the game launched almost two years ago, they've added so much extra content. Now it's in its ninth season. NINJA-LA has teamed up with Jujutsu Kaizen. This collaboration is filled with costumes, emotes, statues. You can morph into stickers, KO animations, gun bottles and gun weapons. So you use gum to morph into objects and create giant weapons. There's also an in-game tournament. It's a six-hour ranking battle called the Jujutsu Kaizen Cup, open to all regions on April 9th. You can win limited edition prizes, coins, medals and more. If you need even more reason to jump in at the game, I picked it up and started playing it again recently, and it's still a ton of fun. You got all our eight-player battles or team modes. There's so many weapons you can switch between, each with different play styles and special abilities. The strategic flow of battles is so fun, whether you're going for points or knockouts, and they've even added a story mode. Again, this game is only available on our favorite console. It is completely free, meaning you can enjoy without subscribing to Nintendo Switch Online and by going to the eShop and downloading the game with my link below directly supports my channel. Okay, so my Nintendo tutorial reward. We're off to a great start because I can't click on this for some reason, although it is loading. Okay, you can get this. All right, I want this. What is this? Redeem your points for this reward. I don't know what I'm redeeming for, but there's 50 of my points gone. Yay. Okay, my Nintendo home. Earn gold points on eligible items and redeem them on eligible purchases. Okay, so that's another thing too. You can use the gold points to buy more games on the Switch. Think of how many free games I could have had. How do I get rid of this? Not letting me get rid of this! Okay, so I can get a Zelda wallpaper for my phone. Okay, there's a lot of wallpapers for phones. Is there something unique about them? Are they like living wallpapers? I don't know if that's worth 50 points, Nintendo. I don't know what to tell you. My Nintendo store rewards. Oh, this is what we want. Pokemon Legends, Arceus, Pikachu, and Eevee. What? What is this? Mask cable strap. Oh, that's 400! And I have how many? None? How do you get platinum points? Platinum points can be earned by completing missions related to my Nintendo service. Okay, and then gold points are the digital and physical. So you can only get physical items by doing missions? That's a shame because I kind of want that and I kind of want this. These dread posters are sick. I would like to get those. Oh, he's pretty cool, actually. He's a thousand as well. How do I partake in a mission? So I would need to play Pocket Camp and then Fire Emblem Heroes. Collect all now. Oh, I got 20 more. Okay, Nintendo services. Okay, the Poochie Pups are hiding in different spots on Yoshi's Crafted World website. Okay, let's look for Poochies. Can you see any chat? Because I can. Oh, wait, what's this? It's right where... You found a Poochie Pup! Ho! You earned 50 platinum points. Okay, we're getting so close to the poster. By the way, we're going to keep looking for Poochie Pups, but I did want to show you what I meant with this. What you do, you click on that. My Nintendo rewards earn gold points and then you click the account you want the gold points to go to and then you earn points for the software. And just like that, I got 60 gold coins. How does that translate into like dollars? So how much have I been missing? 10 points is 10 cents. So you get 60 cents back, but 60 cents times 500 games is 30,000 cents. So divided by 100, $300 is not much considering how much I bought, but it's not nothing. I doubt I have that many games I bought in the last year. I feel like I've really slowed down on buying games. Does limited run physical carts count? We've got to keep trying to get platinum points because I want those posters. I found one Poochie Pup. What is this website, man? Maybe he's it. Does he count? See like what if that was like really sneaky and like that was one? Where are you? Where are you? Where are you? There! Where are you? Where are you? Where are you? Ooh! There you are! Okay, I'm having too much fun finding these Poochie Pups to scroll down. I'm seeing a theme. There you are. You earned 150 my points. You can head over to there and spend your points. Okay, what are we at? 490!  Link your Facebook account. Oh, I don't want to, but okay. Another account has already been linked. Oh, I've already linked an account to this one. We'll come back to that. Link your Google account. Oh, and Twitter. Ugh. Another account's already been linked. They're making us work for it right now. So I have two accounts. I have my Australian account and I have my US account. I'm trying to do this on my US account because I figured we would have better luck getting the posters sooner and probably at all if we use the US account. Create a Mario Kart Live Home Circuit Racer ID. Oh, no. Start making your Racer ID. Take a photo with your camera. Say cheese. Oh, no. Let's stop the screen recording for a second. I'll close OBS and then we'll use webcam. Look, it's so bad. Okay, this is the worst quality camera. All right, we got to take a nice photo here. Hold on, I got to get the microphone out of the way. Oh, wait. I didn't realize... That's even better. I didn't realize it had a countdown. Banana peel. Nice. Little bit of a bullet bill situation maybe. Borders. Okay, nice. I like this. Maybe with a lemmy up here in the corner. Dude, looking nice. 540. Oh, we're getting close. Oh, I can do it. I can feel it. Find the five hidden stickers on the Super Mario 3D World website. Okay, so this is what they look like. There's a belt. There's a belt right here. This one. I did it. Stickers, stickers, stickers. Where are they? Where are they hiding? Oh, oh, oh. I found one. There's another one. Look at you. Has anyone done this? Seriously? Like, has anyone actually done this? I had no idea this was a thing. And there's the fourth. I didn't think they would hide one on by now. Okay, what's next? Find the five holes that are hidden on the Mario Golf Super Rush website. I feel like we know the drill now. You found a hole. Yeah, I did. Hey, holy, holy, holy, holy, holy, holy. This is such a weird video. There's a hole. Hey, hey, hey, hey. Find the four dice blocks that are hidden on the Mario Party Superstars website. We're just beast-moting this now. I'm legitimately smiling. I'm actually having fun. No, that one's sneaky. I almost didn't see that one. Just so you know, all the effects you've heard are from the editor. Thank you, Zach. Because this was dead quiet for me. 850. Oh, I'm so close. We're kind of tapped out here. Sign in to the Nintendo eShop on a Wii U on the Nintendo 3DS system weekly. Why is there no switch option for that? We've juiced the website for the Nintendo services. We have to turn to the mobile games. So I'm going to download on my phone the Animal Crossing Pocket Camp. Play Store, Animal Crossing, Install. Watch me get addicted to this game. And then my next video is I'm addicted to the Animal Crossing mobile game. Now, how much tutorial stuff am I going to have to go through? We already have KK Slider playing us a little song. And I don't think I can skip it. While he's singing away, I can't remember what's come out in the last year, but I know Monster Hunter Story's true did. This is blowing my mind. How have I not been doing all of this this whole time? You just get 60 points for every game. Or does it go by value of the game? This is when we get into the point where I start realizing that these games came out more than a year ago. And I don't know where the time has come. How is that more than a year old? If Game Builder Garage is more than a year old, I'm going to start making funeral plans because I'm going to be dead soon. 30? Oh, because it was a... Yeah, it was a $30 game. This game's making me actually play it before I can hit the social button. What? Now I got to get him an apple? This game looks pretty good, actually. I might actually play this. I've never played the... I know Kim's played it, but I've never played the app. What else came out in the last year? Oh. Kim has my game. I'm going to have to go get the game from Kim. Oh, hold on. I have to steal it from Kim's switcher. This game is making me do so much stuff. Now I got to craft. Let me link my Twitter. Like indie games will give you points. Oh my God. I just had a thought. This is the closest you can get to being rewarded for playing and doing things in the Nintendo ecosystem. But imagine if they actually implemented achievement systems where you get these coins for achievements. People would spend so much more time playing games on Switch. To earn more of these achievement points. You finish the game, you get like 50 coins or something. Like it's not much on its own, but with how many games you're playing, it all adds up, you know? I got to find more games that came out in the last year. And now there's an update. So maybe the game's finally opened up. While that's happening, I want to see if I can actually buy something off the eShop with all of these points. Okay. So if I wanted to buy like the new triangle strategy using only points, redeem points. So I have $30 worth of points. I mean that pays for half the game. I could buy anything for $30 for free. Like I could probably get this new changing tides with just the coins that I have. Yeah, it would be free. I wouldn't even use all my coins. I'd never really paid attention to it or really acknowledged how many coins I was amassing. Like I knew this system was here, but they're redeeming for physical. I don't know how long that's been a thing.  And there was a Reddit post from a year ago. This has obviously been a thing for a while.  I can link my Twitter. Oh, I can link my Twitter. Why is this so hard? How to link Facebook and Twitter. Why does this need a video? This guy is knowing the whole dang time. This was 2017. I am the Nintendo guy. How was this not communicated with me? Hop over to friends, friends. I don't have a friends tab like you do. Did they get rid of the friends tab? Are you saying am I not at the friends yet? This is how I did it on Android phone as of today, December 2020. And you won't see the bottom screen until you scroll up and it'll show the finder friend at the bottom. Oh my, oh my God. You could scroll up on this page. I thought that was a one and done page right there. It has taken exactly 24 minutes and 29 seconds. But I have officially linked. I got 300 points just for linking the Nintendo app, which I did half an hour ago. I technically had enough points 30 minutes ago. I didn't need to link my Twitter. But I could also link my Facebook and get another 300. Yes. I now have 1750. Hold up a second. I've actually just woke up. I'm filming this. Hopefully in time to cram it into the video because I just found out even more. I have never even pressed this icon, Nintendo switch online. It turns out you get points, more platinum points, just for logging in here, I think every day. If you go to missions and rewards, there's even more missions here that you can do like playing the Monster Hunter Rise demo using the data save cloud. I had no idea. You know what I gotta do now? My Nintendo game card case. What is that? That's just a case. That is lame. We can get a calendar or so kind of lame, but I could set a reminder on the calendar to redeem all the points for the cards at the end of the year, which is handy. I do kind of like this guy. Oh, he's tiny. Oh, that's a pumpkin. I thought that was an apple acrylic panel art. That is pretty cool. But I feel like that's only going to be like this bit.  I did all of this for that. That's sold out too. All you have in stock is a cable clip. Not even the key chain. Nintendo giveth and Nintendo taketh away. Oh, this is a holder for the ID and that is also sold out. So we can't even print out the ID we made earlier and put it in a nice little lanyard.  Well, I guess now I have the points for when they launch something else cool and I'll just have to be quick about spending them. I was so excited for those posters. I felt like I had earned them. Let's see if they're on eBay or something. $80. We can do better. What's this 35? I don't care if I'm buying them from a reseller. I earned these posters. I deserve these posters. I'm buying them.   I cannot make an account because apparently at some point I made an account and it's tied to my phone number. Can you buy this poster set for me with your Makari account? Also, is Makari trustworthy? I trust it over any of the other apps. Okay, cool. Apparently four people have liked this item so we need to snag the deal very fast. You just bought it? Okay, thank you, Kim. I appreciate you. Thank you. All right, apparently the camera cut out while Kim was in the room, but she bought it. I earned it and now I'm getting it. I had to pay $40 for it, but I don't know. They're worth it, right? I'm back. Yeah, okay, I had to pay for mine. You know the truth now. It doesn't change the fact that it would have been free if it was in stock. I know that they do update that store and they add new cool things to it all the time, so still a handy tip to be prepared.  Oh, by the way, this. I got Kim to make that for me. It was for dramatic effect, okay? It's technically not wrong. These at some point did come from Nintendo. I kind of don't want to open them yet because I'm moving house soon. Hopefully that's a long story. I actually haven't even mentioned that on YouTube yet. So I don't really want to hang these up yet. I want to wait. Well, these are completely new. They hadn't even removed this thing from there yet. I don't think they've ever been unfurled. Whoa, it's so cool. All right, these were totally worth it. I gotta be honest, they're not full poster size like I expected, but they're still really sick. I really like them. It's hard to actually get a good idea of what it looks like because all my studio lights are like bouncing off like a rainbow effect, but I think you get the idea. All right, well, thank you, random person on Makari for managing to find all their hidden die blocks and Mario stickers before I did and grabbing the posters and then selling them at a, I guess, made up price since they had no value to begin with. Got to say 35 was reasonable. So thank you for that. Could have been worse, I suppose. And thank all of you for watching the video. I appreciate you a lot. Links down below to all my other channels, my streams, the sponsor. I'll see you in the next one. Love you guys.


All right, why don't we go ahead and start this morning? Thank you all that made it back. As you may have noticed, the tables are a little bit narrower and a little bit more towards the front. So no, your life has not changed that much. It just seems like it. So in case you're wondering where your seat went, hopefully there's still a comfortable and available to you, even if it's not exactly the same as yesterday. We want to go over a little bit of some of the discussion last night in terms of some of the future meetings and such that could spring from this. Also wanted to have some time for anyone that had any big ideas or thoughts that need to be shared in terms of yesterday's program. So why don't we start with that? If there's anyone that has anything major to add that just was not brought up from the six sessions yesterday, I'd love to hear it now. So I don't know, take it. I just want to, I guess this is more in reflection on the priority items that were discussed yesterday. I'd like to just throw out, under the evidence one, the concept around deep phenotyping. I know we brought it up a little bit, but it is what I would call a high hanging fruit and it's one of the harder ones to actually deal with. But it is right now one of the major blocks in translating a lot of what we're doing. We're great at finding a lot of these gene signals and connecting them to diseases, but what we're not doing is taking that and actually validating them. So I would suggest that maybe one of the things that we could think about as a priority area would be trying to focus on deep phenotyping. Is that the way to go about validating them or are there other approaches? Or is that the only way? Obviously not, and I think to the degree that we've talked a lot about the virtual cycle and is there a way to bring some of those back to the bench and have them investigated. And I don't know that we've done very well with that and we've talked about it in this group a lot, but we still haven't been really effective at it. And so thoughts about, and perhaps when we go to sum up this afternoon, thoughts about ways to facilitate that kind of work. I don't know, Jonathan, you're looking very eager. So I was just gonna comment that I was on a study section for sort of functional validation of regulatory types of SNPs. And there are some people doing very innovative work in functional validation of Mendelian-like, sort of protein altering hits. And I think facilitating that type of research would be very helpful. I've been engaging people at UNC to try to do something around that. And what I found with the basic scientists has been largely that they're very interested in gene discovery type applications. So they definitely wanna know all of these interesting, interesting hits in novel genes so they could follow those up, but much less so interested in setting up a nice allelic series like the one that Sharon described yesterday from Fergus Couch where we really need to understand all of the variation in this gene that we already know that is involved in disease. And I found that to be a less tractable or less attractive thing for the basic science folks. Adam, I wonder if you could just, we've heard the term deep phenotyping and I'm not sure we all really know what that means. What does that mean to you? So the way I'm gonna comment this a little bit more from thinking about a clinical application or a commercial application of genes and when I'm thinking about it in that sense, I'm really thinking in terms of understanding mechanism of disease action. So going from gene signal to actually understanding the mechanism of disease. So if we can get a better understanding of the underlying biology, the full pathway and understanding, that gives us an opportunity to actually validate targets for new drugs, for instance, or new molecular diagnostics. I mean, that's kind of the area that I'm thinking we need to do a little bit more exploration in. And similar with John, I think we're saying it's not, this isn't the area that many basic scientists want to get into. It's much more in that transitional pathway and understanding how do we actually move down that pathway of development. So at least that's the way I define it. Jeff may actually be able to add, we've been having these discussions in our discovery group, so. Well, I think the term can mean a lot of things to a lot of people, obviously. And so the focus on the mechanistic aspects makes a lot of sense and as Adam said, we've, and we mentioned yesterday, the, you know, we've got members on the roundtable in the pharmaceutical industry that are extremely interested in mechanistic applications of this work. But I think the other dimension that I think some people in this room would be also interested in is when you make a association between a genetic variant and a characteristic in the electronic health record, for example, why not broaden that to include all of the characteristics associated with that patient and as we've also alluded to, begin to bring into the longitudinal dimension of what happens to individuals with that series of characteristics and those genetic variants so you can begin to really create a bigger picture of the implications of genome variation to prediction and to disease association. So I think it has sort of flavors in both the mechanistic side as well as in the clinical translational side. And I might just know that, you know, I think I've heard the term deep phenotyping used much for a much more careful examination of a patient and it sounds like the way it's being used here is more cellular phenotyping and functional understanding, not, you know, let's dive deep into, you know, every, is it, so it's really both? Because I'm not sure that with GWAS hits, necessarily characterizing the individual more carefully is going to tell you anything more about that particular association since they're common variants, they're tagging something and so I don't know if, you know, how well that will work. Well, it also, I mean, the total body MRI could be deep phenotyping, you know, 100,000 metabolomic profile could be deep phenotyping. So there's a lot, it depends on the goals, I guess, but I do think a more definitive understanding of the functional consequence of a variant would be useful and it'd be useful not only for biology, but in terms of, you know, what we talked about earlier, in terms of trying to shake it and see what's real and what's not and so I think it definitely is not, there's a need for more of that. Jonathan, I was wondering, I know Dan's gonna be next, but when your discussions with your basic science colleagues, were they not interested because there wasn't mechanisms to support the work or were they not interested because it just, that's not what they did, right? I mean, I don't know, I can't speak for them. I think partly it's probably more difficult to get something published in a high profile journal if it's, you know, really functionally looking at a bunch of variants in a gene. And so there's that aspect to it, but. You know, one tension that I sort of sense in this discussion is, you know, are you starting with a variant or a set of variants and then doing deep functional characterization of a deeper understanding of what they do, or are you starting with a human phenotype extracted, say, from the electronic medical record and then trying to understand, you know, what set of variants drive that? And variants can be genetic variants, other omic variants, environmental variants, sociocultural variants, what have you. And so I think that precision phenotyping is one of the major challenges to this field. But I'm not sure what the right way to approach it is, whether it's from, you know, starting from the phenotype or starting from the variant. And I suspect that the right answer is that you should approach it from both ways. I really like this idea of, you know, we've been talking about this forever, that type two diabetes is not one disease, but 25 different diseases. And what does that mean? Well, I think it means that there are subsets that are definable, reproducible, and of some clinical utility. Why would you bother to define a subset if they happen to be, oh, that's interesting, that's associated with this variant rather than that variant? If you define a subset, you define it because they're different in some important way to the patient. Their tempo of disease is different, their risk of adverse events is different, their risk of complications, their risk of responding to a drug is different. So I think that there is great value in thinking about that. We've all thought about it that way, but to sort of call it, and put it into the basket of precision phenomics seems to me to be an interesting challenge. And I would start it with it from the functional, from the individual variant point of view and from the individual patient point of view, but getting these, for lack of a better term, clouds of, or sub-clouds of patients that have common subsets of disease is something we should drive for. But that also fits really well to something else we've talked a lot about, and that is this brings us back to the biology. I mean, it's fundamentally about the biology. Yeah, I don't think yet. And that's, and it's important when you talk about bringing it back to the biology, not to bring it back to sort of traditional 1970s kind of biology, but that plus newer kinds of analytical approaches that'll find those subsets. Well, Dan said just about everything I wanted to say, but to reiterate, and the- That is truly frightening. Yeah, I know. We talked yesterday about the granularity of the phenotype, and as Dan was saying, 25 flavors of diabetes. Well, to the extent that those flavors are therapeutically relevant, or prognostically relevant, which is what you were saying, then I think there actually is utility. Teri Monoglio yesterday dinged me somewhat for, correctly, for saying that, well, there's actually a lot of resilience in the phenotype definition, particularly with GWAS association. But I think as we discover more rare variants, and as we discover more heterogeneity within disease, that we'll find less and less of that resilience, and that the importance of, whether we call it precision phenotyping, deep phenotyping, whether it's at a, you know, a molecular physiologic level, or whether it's at a clinical manifestation level, it's still a granularity of phenotyping that I think is going to be increasingly important. And I might add, just for good measure, Mark, that to the extent that once we have capabilities and reasons to do these deeper phenotyping, then the consistency of how we represent clinical data is going to matter even more than it does now. One of the challenges is we've got a scale effect with regard to the sequencing, and we've identified more biologically interesting things than we've ever had before, but we don't have a scale for following those up at a molecular level. The biologists, you know, they can spend 10 years following up one thing, and yet we've got a million things now that they need to follow up. And so there's a gap in the technology at the molecular side at the moment. I think it's improving with some of the new techniques and technologies, but that's the side that's going to bring this along faster and help us get to the biology faster and link these things into the pathways they're in. Yeah, I think that's an interesting point, and then it raises a different role, perhaps, for NHGRI in the sense that if we're thinking about this sort of bidirectionality or virtuous cycle, however we want to characterize it, if we, in fact, have this target-rich environment of a million things to do, then how do we focus the ones that are most important and prioritize those and get people interested so that they can do the functional studies or whatever? And so what that really reflects is some type of a rapid filtering and prioritization to say these are the ones that we really want to focus on. I might ask my colleague, Mike Payson, to comment a bit on the issue of scaling these things because doing them one at a time is, you know, not feasible as you suggest, and there has been some very innovative work in ENCODE in the past couple of years looking at all GWAS hits at once and saying, you know, gee, there's an awful lot of these that are at DNA-sensitive sites and that sort of thing. Mike, do you want to comment at all? Yeah, so first I'd agree with what I think I'm hearing that today. It's easier to find these candidate associations between variants and disease than it is to understand them. And for some time it's been outside of NHGRIs considered it outside of our purview to follow up on the functional characterization of variants that are found in disease studies. Something that was said openly and available to anybody that has internet access at recent council meeting is where we'd like to renew our functional genomics program and we'd like to add in a new component that would include high throughput functional characterization studies. So those RFA's are not written. I don't know for sure what they will look like and I haven't seen there for any of the applications but it's conceivable that some of the work could move in this direction as sponsored by NHGRI. And Mike, do you see a role for interactions with clinicians? I mean obviously there's a role for interaction with clinicians but what role could you see and are being able to either influence or help to prioritize that sort of thing? Yeah, so in the preliminary discussions that we've had on this, that role is not well defined and I'd say on my part it's not well thought out but we definitely would like this project to have experts in biology, experts in disease as part of the project. So I see opportunity, not well thought out, not well defined again on my part but there's opportunity to work with partners in other areas of science.  So say you had some colleague that wanted to be involved in large scale characterization of function and you've spent decades studying diabetes. How would you help them to sort of come up with the biggest bang for the buck in terms of that disease? Some goes back to the deep phenotyping and this interrogation of genes we've done and the identification of, we'll call them tolerated mutations is such a rich resource that generating additional copies of those through pedigrees or other kinds of things I think provides them a way or us a way of prioritizing some of those. Why aren't these having bigger effects than they have? It's partly because the level we look at but I think more interrogation from a pedigree point of view that's a very efficient way of getting at additional mutations and then there's so much that we know if we just look at the insulin gene. 41 of the amino acids, there are natural mutations that change amino acids that are semi-tolerated. So you can live with them with some treatments and I think identifying those and moving those straight into a molecular pipeline or a functional pipeline will do great things but we can help move those both by what's tolerated and by what we can see at a lower level. Right now we have things that must be having an effect but we're looking at their effect on diabetes as opposed on the flux through a pathway and its influence. And I think that's back to the issue of what deep phenotyping is. I just wanted to add, I've been thinking about this a little bit with ClinGen and I know we've had some preliminary discussions but as we're spending a lot of time assessing variants and looking at the clinical validity of genes, would it be worthwhile for our group to figure out ways of prioritizing and we're really pulling together all the evidence now and identifying the gaps and the variants that look really good and the ones where we need a lot more information on. Do you see a role for ClinGen in this space? Yeah, I mean it's something that's come up a lot as we've tried to develop the sort of standardized ways of evaluating functional evidence and I've Sharon mentioned this yesterday, right? You come across a piece of functional evidence that's been done in a well done fashion but it doesn't quite reach the level of a clinical test to judge whether that variant is truly causing problems and so I think there would be a role for ClinGen to point out places where new functional evidence could be useful, right? Here's a whole group of variants in a gene that could potentially be called benign or called pathogenic if we just had this additional piece of data. Well and I wonder too if it might be very useful, it would be probably pretty easy to say of the 20,000 genes in the genome, 19,000 of them we know so little about but really to kind of find those that almost as you said are kind of teed up what's been described as the half-baked bread and you just need to put it in the oven a little bit longer and if you could figure out where those are or identify G if we only knew X about this particular variant in epilepsy or whatever it might be. That I think would be very useful then of course you need to find the basic science colleagues who will look for X which may not be an easy find. We also have maybe a resource among all these consortia and groups that have been listed here and are assembled here because we've sequenced a lot of those, we phenotype a lot of those and they're already signed up for research projects so I wonder if there's a way to leverage some of that to go back into those individuals and re-enroll them in physiological studies and re-phenotyping, deep phenotyping, precision phenotyping kinds of initiatives. I also wonder if there's any value to thinking about it the other way around. As we get, we clearly don't have enough today but as we get more and more sequences very broadly across the people I wonder if there's also an equal interest in the variants that are never seen. Sort of the holes in the genes that for some reason are never touchable. Those seem to me they may actually be particularly useful for a more basic biologist that go back in and say, well here's an easy way to think about doing a knockout especially with tools like CRISPR around, so maybe building a resource that says where are variants that we've never seen. Yeah, I mean that certainly has happened many times where someone has identified a disease gene association in the mouse and then a month later it's published in humans. So I think there is that discovery starting from the model organism going into disease but we have increasingly the kinds of virtuous cycle examples you were talking about yesterday including in epilepsy and diabetes and other things where the variants from sequencing in human populations are identifying priority variants and then through CRISPR go back and make the mutations in the mice and the nice thing is you can do more than one gene, you can target whole pathways, you can really perturb the system in very directed ways to make that functional connection between variants and biology variants in disease. So I think we're primed for this sort of virtuous cycle. It's just how do you get the right people talking to one another that will develop new tools, which NIGRI's mission is not to do the fundamental biology but maybe to develop new approaches and new tools that will scale that up and I think we're in a prime place to make moves in that direction. This is more of a question related to something that Robert said, I'm wondering are the sequencing programs collecting other types of samples that could be used to explore cytokines, metabolomics, the transcriptome as endophenotypes or to begin to tie the genetic variants to some of these other biological networks, would that be of value? It's a great point. Cesar's not but we certainly could. Yeah, we're doing that, Jeff. I really do believe that that's a great way to just leverage resources. It costs so much to identify these patients and roll them, genotype or sequester genomes not to do that seems like a waste. So we've been doing that, albeit we haven't, we've just been collecting samples and getting consent. So I think that the whole biorepository stuff raises yet another metadata informatics question. So you might have them in your database behind your firewall, but how do we, if people are developing these biorepositories for these samples, how do we actually then annotate them and put them online so that they're shareable? That's broadly, that's a whole nother data format standard, semantic standards issue that would have to be dealt with, but certainly doable. Yeah, and as opposed to the fact that we've declared victory on the storage of the genomic data yesterday, the reality is a storing biological specimens is a huge issue. And so if we're talking about scaling that up to collections on tens, hundreds, thousands, millions of individuals, there really isn't the capacity to do that at the present time. I mean, the advantage of DNA is that you don't need a lot of space to do it. And in fact, filter paper works great, but for a lot of the other things you can't. And then the question is, is there a way to prioritize which things would have the best yield? So much as Stephen is doing in his project for certain of the projects that we're doing like in our obesity institute, and then we're gathering serum and urine, and we're actually, during the surgery, we're getting liver biopsies and adipose tissue, which I think is really relevant for that obesity phenotype, but probably is not so relevant for other things that we're thinking about doing. So is there even a sort of a standard set of biological specimens that you would want to collect and what would be the highest utility? That could be a question that could be studied. So thinking along those lines, I'd like to ask how many groups are collecting RNA samples in their work or considering it? One of the advantages to coding mutations, it's more straightforward to predict what's the target gene and then follow that up. But of course, once you've found that, it's hard to know whether that change in the protein is important or not. The downside of non-coding variants is often you don't know which gene they're connected to, but if you do, you know it's probably changing the expression of that gene, not the function of that gene. So what's nice about that is if you know that a non-coding variant affects gene A, you can find that difference simply in the RNA then and say, well yeah, the expression went down and the expression went up. And then with a single assay, you could look at many genes at once, it's a nice genomic approach. I don't know that any of the major genomic medicine programs are collecting RNA. I think maybe a couple of the CSER programs, remind me, Lucy isn't Chenayan doing some. I believe Michigan, the Michigan group is. That's the one that comes to mind off him. The problem of course with these others, I mean, there is a reason that we've all started with DNA and that's because there's no temporality, at least as far as we know, there's no temporality with DNA. Whereas with all of these other samples, it's not only, A, and we've really looked into the logistics of what does it take to get a serum sample that's actually of value if you wanna do metabolomics, for example, there's a whole problem of how long do you have to get it into the freezer. And then there's the much bigger fundamental problem is, are you sampling at the right timeframe in the biological space? And that adds so many variables. That's not to say it's not worth doing, but it certainly boggles my mind. And it probably would behoove us to think carefully about how and when we would draw those samples so that we would get the best functional information. And again, maybe that's something that we need to discuss in collaboration with those who would use those samples. Yeah, I would just point out that one of the things that I think has been exciting in the last several years, especially in space that I know best, which is places where we're actually linking samples to clinical records or to well phenotype samples, is that those samples actually get used by, they get used for experiments. And the problem with a lot of biobanks in the past is they were collections of samples, none of which ever got used. And so, and it's a very expensive process to collect samples and never ever use them. Well, many thanks to Adam for starting this conversation. Clearly there's a, no seriously. It's obviously it resonates. And it happened to be one of the topics we were talking at the steering committee or whatever it was, the working group, whatever we are. Last night about what's next? And there's a number of next issues that have been brought up yesterday. And one of them was exactly what we're just talking about now and that is how do we bring, you'll really create this circle that I'm not sure how virtuous it is, but that is needed and bringing discovery science back into a lot of what we're looking at. And so I don't know, Terry, you wanna comment a little bit on? Well, so yeah, so one of the things that was raised was gee, we have an opportunity, I think, to bring both basic and clinical scientists to the table in a forum like this. And I'll ask Carol to comment as well on how we might best do that. But it seems as though if we could perhaps invite some of our leading basic science colleagues who are doing work that they feel has clinical applications or could be informed by clinical information, they would be good people to have at the table. And then I guess in some ways we would describe sort of what we have in terms of resources. Plus what kinds of questions are we stumbling up against that we really need help basically from? So could you comment further? No, I think that's right. I think the starting point is to have some folks come who are already trying to do this, the same kind of virtuous cycle thing, have them come as exemplars, sort of describe what the process is, what the barriers are, what the gaps are, what the promises and what the results are, and just sort of use that as a launching point to figure out how to make this, the uptake of this approach more broadly applicable. I think that's the way to start. Start with some small examples where success is obvious and go from there. And then one of the other discussion points that Jeff had brought up was bringing in some of the industry players, like what we're generally done with Geisinger and show really there's a new found notion that if you think of the human as being the discovery start point, the basic research then is actually the follow through, which is a little bit opposite as Carol was saying. We used to do in the animal models, we find the gene there and then try to see if it plays a role. But industry, academia and all these things are now moving from human back around. So I think industry that's doing this maybe Regeneron is one of the examples. Yeah, I would like to advocate to go back to what we had done for GM 1 when we were trying to really organize where we essentially solicited send in a little description of the projects that you're doing in the implementation space for genomic medicine, so that we really have a pretty broad sense and then choose from there what we think are the most informative programs for actual more formal presentation and discussion. And I think that that would be a really nice way to kind of explore that space. Just one addition, once again, thinking about linkages north and south of the border. But my colleague in CIHR, Paul Lasko, who you probably know well ahead of the Institute for Genetics there, has set up a network of looking at functionality of gene function in general for looking at exactly the things that you're talking about and building a network of basic scientists working in yeast, Drosophila, mice, zebrafish and so on. And that network might be an interesting linkage very much like-minded thinking, I think that's going around this table. And that's up and running. Both CIHR and Genome Canada are putting money into that. And Genome Canada has just funded a new platform on Phonomix at the Big Mouse facility in Sick Kids in Toronto. And they're going to be looking at it as well. So it might be some cross-border stuff. Is there a name for that network up here that you- Yes, there is, but I can't remember what it's got. I've forgotten that gene that controls the- So I don't know why I forgot about this, but the office of the director has a U54 program that they're going to make decisions on at council next week on a precision animal model grant. And I think they're planning on two pilot centers. And the whole premise around these centers is to actually do this work starting from variation in human and then being able to model it and take it back to human. So I think looking at those programs that end up being awarded would be another way to bring this in. So we also talked about GM9. Oh, that was GM9. And then there was the scientific meeting. Yeah, do you want to- Do you want me to- Yeah. So sorry, we're getting our act together this morning. Sorry, the Tarian Howard show. So something else we discussed last night was the richness of the discussion around the table of, you know, we can pat ourselves on the back of the Genomic Medicine programs that we heard about and others that maybe we didn't have time to hear about. And wouldn't it be cool if we could have a scientific meeting that would really be devoted to sharing information about those programs and discussing them in a scientific forum like a Keystone meeting or a Cold Spring Harbor meeting or whatever. We're kind of wondering what people thought about that. As you know, none of us needs more meetings to go to, but we- And part of it was, look, it was definitely not to have another meeting because if, and we even talked about, well, if we're going to add one we need to subtract one somehow. But there's a lot of opportunities across even the programs that are represented here that just don't happen. You know, there wasn't a speed dating session at this meeting, for example, not that we want to have one, but the idea of, can we create something where there is these interactions that happen with or without further funding that goes with it? Yeah, I know, I love the idea. And I think that for somebody, this is my first meeting here and UDN is one of the newest, maybe the newest program. And just listening to the discussion and noting what's happening in other programs that actually I was not aware of, maybe I should have been and could have been, has been really wonderful. And I think that if we were going to have such a meeting, I'm sure you would do this, you would organize it around certain themes. And that might, you know, the deep phenotyping, for example, might be a theme that we could bring in the kinds of different points of view on what that would mean. And so forth. So I love the idea and I think it would be great to have allowing for plenty of discussion in the plenty of discussion rather than just a series of PowerPoints. I'll just throw that in there. Yeah, I want to say from the Caesar perspective that we think that would be a very valuable idea as well. And I also want to mention that we do invite people from some of the other networks to attend our in-person meetings. And we would be glad to go to the Ignite meeting or whatever, other Emerge meetings or whatever to talk about Caesar as well. And so we have had those kinds of interactions. I just want to ask not to do it around ASHG because I already have two weeks of pre and post meetings. Well, let's make it a full month then I guess. I think some of this came out of a discussion around, you know, Ignite having, you know, Caesar coming and Emerge and Ignite and Caesar and Ignite and Emerge and blah blah. And how fruitful those have been. And with the number of groups, it's almost impossible to do that in the course of our lifetime, you know. So can we create something that would expedite that? So that's great. I think Tampa in February was what we were talking about. Other comments? Just to comment, we're going to let the, you know, because we do tend to lose some people, some of, none of nobody here, of course, a little bit later in the day. We wanted to be sure to have a robust discussion this morning. And I think too we can let some of the panels go a little bit longer than our if the discussion is robust because really what we need is the discussion amongst us. It's what we all know, not what each of us knows. And so the, you know, the recap at the end could be short changed and we can do some of this follow up, you know, by email in other ways. So. We were talking about the survey. Right, yes. Why don't you mention the survey? Okay. So again, one of the things about summing up the meeting is to try and get a sense of prioritization and we recognize that as we had evidence of this morning that not everybody can sort of instantaneously synthesize, you know, two days of meetings and, you know, come up with a reasonable prioritization. So we're going to use something. Sorry, we didn't warn you guys, I'm going to use a little bit of a strategy and read a by and Jackie about this, but we're going to use a process that we did for GM 7 where we had a post meeting survey that goes out that basically takes sort of the topics that we have agreed upon as a higher priority topic. Send those out. Have you kind of ranked them in a survey monkey or something of that nature? And then we'll use that to, in the final analysis of the meeting. If there are themes that we didn't pick up on or as on reflection you think are more important, there'll be opportunities to enter those in text as well. So we'll be doing that. Yeah, so I have to, keep looking at me, you know, it's like, and now I'd like to introduce Howard McLeod, who will be presenting panel seven, Streamlining Clinical Workflow, Transportability and ClinVar Submissions. And so presenting from there, go ahead.


It's a needle now I can eat it. Needle, needle, needle. I need a needle. Welcome back to Path of Titans today. We're playing on a community server because that's what everybody basically told me to do last time. On there, apparently, you could just like, grow a lot quicker.  So in this server, I think it's called Islander. They've added some mods. So we can be the giganodosaurus as well as some other ones. But really, we're going to meet the giganodosaurus? Of course we are. Heck yeah. And oh, there we are. We could all went wrong somewhere, but let's enter the world. Many hate giga. So it's kill on site. That's a great thing to enter the server on, isn't it? I have abilities. Hide. What does this do? Standard stats with no positive or negative str- Oh, okay, cool. Sweet. I need 900 coins to unlock that. House and charge up the attack to inflict damage based on how long it's held. Oh, I like this. I have got no coins though. I'm pretty sure it is not on this server. Oh no, the KBP for here, it's not. Oh God. Oh, hello. Uh, I don't like the way he's looking at me. It's like Dennis Nedry. All right, all right, all right. Right, is it M4Map? Of course it's M4Map. So where am I going? I'm going towards the northern, oh my God. I'm going all the way over here. Really? So yeah, apparently community servers are better because they have like growths faster and it's like passive growth. So you don't necessarily need to do missions in order to grow. Which is great for me is we can get proper realistic here. Watch this guys. This is what's good about this game as opposed to something like the owl for instance. Because we can do this. Look, not a single thing is on the screen. It's so good. I love it. You really immerse yourself. We can easily switch back. Okay. So just keep on going this way. Oh, I love how there's so many similarities. Like you have to click Z to like move faster. Good God, can they not come up with anything else? Game looks gorgeous though. Look at this man. It's brilliant. You see, I think that's what this game has over other games. Like the aisle is great. Like I think in terms of overall quality, it looks fantastic. However, it's kind of lacking in that depth of game aspect. Whereas Beast of Bermuda, for instance, has a whole like tech tree of stuff you can do. But for me personally, isn't the most visually appealing. However, Path of Titans has kind of a good mix of both hot springs. Oh, yeah, this is nice. Who doesn't want a bit of a hot spring? Oh, there's fish in here as well. Good God. Sulfur fish. Very smelly. God, why is it always raining? I'm playing this game to escape the rain. Dammit, I don't need more of it. I don't know how brittle my bones are.  Come on now. It wants me to migrate to the place where everybody is. They're probably going to kill me. As long as I just enter it, I think that's what it wants, right? As long as I just enter, I'll be good. Sulfur Fields. It's a cruel song from the lost world. Brrrr. Brrrr. Ba ba ba. Ba ba ba. Ba ba ba. What is this?  Can't eat it though. We're not in any area. Entered desolate paths. Collect 25 flowers. Oh, oh, oh. I heard it. Is something also collecting flowers? I do need to hunt to her before, but I mean, I'm not really hungry, so I'm not going to. Also, I've lost you. Oh, yeah! 25 coins! I mean, I- I guess the collecting flowers make sense for something like, I don't know, a herbivore. But can I not like collect bones or something as a carnivore? No. Maybe that's still to come. Does that seem like the right way? Yeah, I don't- I- I wanna follow this. Yeah, if we follow this, we should be good. I know how this goes though. I- I end up going all the way over there and then I die. That's what happens, all the time. Nooooo! Sharp toothed marsh! Ha ha ha ha! No, it's cold really!  I have no idea why they didn't- they didn't put passive growth on in the first place. That makes no sense. Oh! I don't know, was it V for Torquies? Is that the splat though? Oh, okay. I don't know who that is. Ha ha ha ha! Do you know the way? I don't know the way. I mean, I'm going up here. No, this doesn't go for me. It's always best to play ignorant. Ha ha ha ha! Oh, I don't know! Yep, no, I'm good. I'm good, I'm good, I'm good. Ohhhh! Look at that, it's a big T-Rex! Hello! Hello, big T. Good boy.  Ha ha ha ha! I guess that's how, like, the aisle sort of functions isn't it? Like, there's none- there's no collecting. The only growth is literally just killing the other person and making sure you don't die. My God! This game is glorious! Again, it makes more sense if it was bones or eggs or something for a carnival, but flowers? Come on! Maybe I can find flowers around it. Is this, is this like the honey? Oh, it's the hive thing! Oh, this is what I was on before. Man, if I really want to, I can hide everything so I can see it all. Oh, it's so good! I love it! Right, okay. So over here, so I just keep an eye while I get my stamina slowly back. Let's be honest, if something comes out, it's probably going to kill me. Oh, that was a leaf! Okay, almost got scared by it. Right, yeah, I know which one. It's that tree right ahead, okay. It doesn't have, like, a centability, does he? He deliver. Yes! Okay, so I get coins for each one I deliver? I'm a real delivery boy. Gigatosaurus! The flower deliverer! I get paid in pennies. Oh, there he is again. Oh, hopefully he's not aggressive. Oh no, he's collecting things. That's great. Oh, oh God. Oh God, no. No! Oh! Hello. Oh no, I just wanted flowers. I just wanted flowers. You're not very good, are you? Oh God, okay, you're good. I'm sorry, I apologize. I apologize. I'll do it. I'll jump. Oh God, go. Oh, he's too big. Stop it. Matt. My God. Oh, he's got a tail whip attack. Look at you. Aren't you glorious? Yes, I'm now dead. T-Rex I needed to worry about, it was that boy. Well, I think at that point there was literally nothing I could do. I was pretty much guaranteed to die there. Oh, I've got friends. Well, you're lovely. Well, help me with my quest for pine cones, please. Don't eat me. Oh, okay, let's disturb the burrow. That tickles. Oh, there it is. Is it going to kill me though? It looks big enough like it could kill me. Yeah, sweet. Right. Kill three. Paliswanua. What the heck is that? I hear it. I hear something running about. Oh, it's a Thera. Oh, that's fine. Okay. Hello. You want to die? I'm only after this. I was worried for a second there. I thought it was something bigger.  You run funny. No, you. Hello. How do I? A little, little, uh... I mean, I didn't... All right. It's meant to do a little call. I didn't mean to bite. I'm sorry. Oh, my God. There is a giant T-Rex thing over there with a... Oh, wow. I want to see this. This looks amazing. And a Spino. What is going on? Whoa. I feel like I'm Nigerian Marvin. Look at them go. There was a Spino here a second ago, too. Hello. Oh, look, a little baby Alice. Oh, a flower. I'll take that. Thank you. Oh. Oh, that T-Rex is something to be feared. Oh, my God. I got a group invite. Hello. I know what this is, and I've joined. Oh. Wait, we're mix packing. That's bad. I won't tell them if you don't. I don't know what this buff is I'm getting, but I'm just going to leave the T-Rex to eat his food. I'm going to disturb whatever this is. Imagine growing that big. Then you're just dead. Come back here. Come here, come here, come here. No. Oh, my God. Wait, where did he go? Where did he go? Where did he go? There he is. He's running for the flowers. Yeah. There we go. You can eat him if you want to. I'm not hungry. It's killing for sport. Poor rocket guy doesn't even know he's committing any sort of wrong doing by being part of our group. This is fine. This is fine. We should have watched out for that T-Rex because if he gets hungry, we dain. Oh, so once he joined me, my requirement for completing the missions went up. Oh, okay. So I need another nine flowers. So the T-Rex is now sat on the body. Okay. Apparently, the rule is with this server, he needs to sit on the body for 15 minutes. So we've actually got a Giger in our pack. So we're definitely mix packing. But you know, I don't think that the Allo doesn't even know how to talk. It seems to be a common theme. I think maybe they're playing on console or something, maybe. This is safety in here, but at the same time, we do need to do the missions. Hey, that guy didn't body sit for 15 minutes. Oh, you're back? Okay. As long as we know you're there, that's good. Right. Disturb the borough. What's it going to be? Wait, why are you attacking it? Oh, God. Why are you attacking it? We've got to go for things our size. Like this. Oh, no, no. Come back here. Yeah. I did it. Now I can eat it. Oh, you're grabbing the meat chunks from them. Okay. Cool. Oh, my God. The guy's almost dead. Don't really see anything. Oh, can we drink this water? Oh, this is salt water.  Oh, my God.   We're going to let him figure that out when that eventually bites him in the arse. Is this fresh water? Are you drinking fresh water? Oh, my God. Never mind. The guy knows what he's doing. Nobody drank all that salt water just to do this. Again, another thing this has done way better than the aisle is that at least if you die, you don't lose everything. Like all the missions you've done, all the growth. Yeah, they go. But you keep the coins. So next time you play through, you can maybe upgrade quicker. Why? Why did you leave the group? Little Jay. Oh, they could have just logged out, I suppose, maybe. Swear to God. I'm the only one getting this contribution for their flowers. I still don't like that there's a T-Rex here. Like, a huge, absolutely massive T-Rex. And like, there's nothing really here that should be able to sustain him. Aha, yes, more of them. Oh, scallops will do. Does that count as a clam? Yep, that counts as a clam.  There we go. There he is. We'll also check to see if there's anything else in here. No. Thank God. Logging him go, yeah. Ace collecting clams. Stop it. You want a one, you want me. Really? D-d-d-d-d-d-d-d-d-d-d-d. Hahaha. Okay, cool. I'm assuming that poison's just like a thing that's so overtired. Okay, cool. I like the man. It's not like he can kill me. At least it gets you to move around, I suppose. Get to see the sights, the sounds. Fresh air. Okay, hold on. Where do you collect all those? Because there's a lot of them. I'm going to see if I can get any upgrades. Are you sure you want to spend? I don't even know how much I've got. Where does it say? I got 1,000. Ooh. I could have another bite. So my normal bite now has a bleed attached to it. Ooh. Cool. Oh. Hey, oh. What you doing? Hahaha. It's just like next to me. Hahaha. Oh, it's the megalania thing again.  He's gotten bigger. Oh wait. This is you. I best get going. Hi. The giga chin will arise at some point in the near future. Oh, a herby herb. Oh yeah, he's going to dart the other way. He's so small. Bless him. Get him. Wait, what's that? That's a baby T-rex. See that? No, you're too busy facing the... Okay. You want to chase the tiny Ceratopsid?   Oh, damn it. Oh, you found the T-rex, have you? Hahaha.  Oh, bless him. He's running for his life. Let Daddy take care of this. Bleedy, bleedy, boom, boom. Oh, God. Hahaha. Brum. Brum. Yeah, I think he's coming. Oh, yeah, he's dead. Okay. Ready and numb. Really? All right. Brum. Oh my God, it's savage. Brum. There you go. He's dead. Victory screen. Well, hopefully the Megalane will eat good then. All right. Well, you can eat that, I suppose. Wait. Wait, what do you mean? I can eat it. I should be eating it. Damn, dams. No, let me kill it. Damn it.  I need to kill it. All right. Okay. Well, we've got to go somewhere then. We're not going to go to the dangerous Plainy place.  Enter dark woods. Yes. This is what I'm talking about. We've got branches, pine cones, and milk caps. Okay. Let's keep an eye out. Bacon bomb. It's a good little lackey. Let go get the scraps. Yes, master. Oh, hello.  Hello. Okay. Yo, so big. I don't know how you can just sort of glide there and go up and down. Oh, we got loads of growth ready to go. All right. This should be it. I'm going to get like a hundred coins for this, I think. Yes. Boom. Erica played. All I do need is branches though. You're welcome. It was all me. Group disbanded. Interesting. So he left my group after I did all the work. Unless he got killed, he might have got killed actually. Oh, this could be dangerous actually. It was somewhere around here. It was last seen. Oh, now I look like a Giga from the Isle. Almost got legs, which is good. I could also unlock this for a thousand. Charge up the attack and inflict damage based on how long it's held. Yes. So my left click is charge bite and my right click is normal bite. Oh, okay. So I just got... Don't attack me. Let me drink. Is that the crocodile from the beginning? I think it is. He's got the same markings on him. He's just giving me a fish. Oh, there's a big thing over there. What is that? Is that a challenge? Do you think he'll kill me? He looks around about the same size as me though.  There's something waddling towards... What is that? Look at him go.  I'm sorry, my friend. I don't even think I got him. First aerotops would be better. I'm coming for you, baby. Ha!  Oh, how did that not get you? I'm terrible at this. There we go. Oh, there it is. Right. Come here, baby. Oh, that's another chunky. He's hiding. He's just running around in circles around the bush. I don't think so, buddy. Oh, did I get him? Oh, it didn't, but he's bleeding. Is he hiding inside? I need to be careful of him though. I'm on low stamp. This is dangerous territory. Definitely bit. If he's seen the triceratops, he's seen that it's been injured. I did damage to a triceratops. I almost got it. Then I got scared. Let me just get this. And this. Yes. A little bit more growth. Thank you. Damn, I was so close to killing that triceratops. I thought I was just going to kill him before he ran into the cave. They kind of bumped into the Aliso, which I think they did once they ran in, and I think he might have killed one. The triceratops is still here. About tail. And attack that causes light damage. Let's take it. Yes. All of the hotkeys. So now I can go blip. I don't want to get hungry though. I don't want to fight that Aliso, but am I? There's going to be people in the comments like, run away.   You could easily kill that thing. That's how I play these games. There's just too much at stake. That's the problem. Sound like a drum. Or some weird flute. Do we go to the plains over here? Or do we go to the left? There might be chance of survival. Oh, hello dude. You seem pretty big.  Oh, he's charging his tail. Is that a charge of the tail? You're going to swipe? Ooh, okay. This is what I could do. Oh, he can swizzle around. Very clever. Okay. Cool, cool, cool. Not going to go for you. I don't know how dangerous you are.  I could have just imagined like that's how I die. One shot by you Posephalus. Oh, I found it. Oh, okay. More. The more explore, the more XP I get. What is that over there? Death is on its way. That's when we leave. Oh, what? What are you doing this mission? Oh God. It's the Aliso.