The purpose for which God sets us free is yes, so we can enjoy our life. It's so yes, we can Build our families It's so yes, we can build our business Save money stay out of jail Have a great life But the ultimate purpose is so that the message of Jesus can go throughout our life to other people You might be free, but the world you live in today is still in bondage I was reading yesterday and today through my devotional Mark chapter 5 and there's a story about a demon possessed man that all of us know that story having been in Israel last last year we were in Israel Two years ago. So having been in Israel some time ago. I was there. I Was at the Sea of Galilee and And tell you they told me right away when you go to Israel you will be surprised how small the Bible is Everything goes a lot smaller there right Kelly Sea of Galilee doesn't seem like Pacific Ocean When I read I think of Sea of Galilee is like this endless you just never see the the shore It's kind of like Columbia River.  He rebukes the waves He stopped the storm and then he goes to the other side and this was a Gentile area So this was not a Jewish people area and there was these ten little cities or little villages that were there and this man It's a very highlighted story in the Bible because he was so demon possessed. He had 6,000 demons Allegiant a lot of demons. I don't know how they all fit inside of that man But they did and these demons they led this man because one of the first marks of demonic oppression in someone's life is self-destructive behavior He was hurting himself the Bible says he was taking things and cutting this was the first mutilation Self-mutilation. He was cutting his veins. He was cutting himself and we know also is he had a hard time He had a supernatural power. He was ripping chains off He was taking off his clothes running around naked It would almost seem like somebody who had a schizophrenia or somebody who has a mental disorder But in this case it was actually demonic possession Demonic possession you have to understand is that there's few levels of this demonic possession first is it starts with obsession Leads to oppression and then becomes possession a Lot of people they don't realize but the first demonic attack on your life is your obsession Whatever you're obsessed with today. You will become oppressed with tomorrow and Whatever you're oppressed by tomorrow It's a matter of time the devil will get you hooked on that you be possessed by that thing That thing will own you and something happened to this man We don't know how he got hooked on that stuff. We know one thing is that when Jesus came nearby He saw his chance to be free and he didn't wait for Jesus to come to him He pushed through the thousands of demons He went to Jesus and he honestly he fell down and then demons started to manifest Then demons took over and they started to scream and yell and thanks be to God Jesus delivered that man The way he delivered Brian the way he delivered some of you. Maybe you didn't have 6,000 demons But maybe you had 6,000 issues maybe at 6,000 sins maybe had some other stuff But to God be the glory that Jesus still comes into our world Overcoming the storm and everything and when he comes and we run to him He sets us free if you've been set free give God a praise right now If God has done something nobody else can do in your life. I Want you to give God some praise right now If Brian is not the only one in this room that Jesus has raised them back to life Give God some praise right now Maybe you couldn't do it on your own Maybe you've tried everything that the doctors told you to do Like this man, he tried so many different things, but when the man from Nazareth came The demons couldn't stand in his presence and demons can't stand in his presence today and This is that place where this man in a part of the Holy Spirit Jesus Christ is in our midst today Which means the bondages of many years the chains of many decades generational things they bow at his name They bowed at his feet Can somebody say a man and the demons they begged this Jesus they said Don't drive us out of the country We know that you're gonna drive us out of this man We do not want to leave the region. We want to stay in the region We want to dominate the region and Jesus for some reason unknown to us. He permitted He permitted the demons to stay within the region He allowed them to do that and there's a word that says he permitted them because there's God's permissible will and There is God's perfect will Permissible will is what happens in this world. God's perfect will is What God wants to be accomplished on this earth not everything that happens in this world is God's Perfect will and I'm gonna tell you why because when after that Jesus gets asked by the people there Leave this region. Jesus leaves. That's his permissible will. He's not gonna force himself on anyone But when that freed man came to Jesus and says Jesus, I beg you take me with you on your gospel campaign Jesus looked at the man and he says I can't and Now we see God's perfect will he says I want you to go back home and Tell everyone of what God has done this man without a Bible degree Without Bible education this man without a lot of church experience He just recently experienced a drastic and dramatic encounter with God He's going back to the city that is now battling the demons he used to have and Jesus sends him on his own No support system No mentors He sends him with the Holy Spirit and this man's testimony Begins to now impact the region and the scripture says he didn't just go home He went to the cities there and start declaring all that he knew I was naked. I Was mentally not all there. I broke chains. I lived in a graveyard people try to restrain me But there is this man that came through the Sea of Galilee. His name is Jesus When I met him all the thousands of demons were left. My mind was restored. I'm cloth I am a new man and I can tell you one thing because these demons were in that region They were affecting people that testimony started to create a spiritual climate change. I Believe that your testimony changes your region I believe that your testimony changes the climate in our city because see that are demons They are launched in our city. There are demons that are region over the region They'll say I'll leave you and you but I don't want to leave try cities I want to cohabitate here and God sends us back to the city and God says now that I set you free. Don't be silent You might not have a pastoral gift. You might not have a gift of evangelists But when you have a testimony you have a weapon You have a tool for a climate change in your region come on somebody It might not seem like anything to you But it does something in a spiritual world We are delivered. We are set free So that we can be used by God To impact the spiritual climate and the physical climate of the cities we are living in This city. God is concerned for our city from the beginning God punished cities with wrath Jesus wept over the city and The scripture says the spirit of God is upon you and Jesus says you will be witnesses to me He didn't say in in just to individual pockets of people. He says in Jerusalem in Judea and in Samaria Let me paraphrase it in Pasco, Richland and Kenwick and to the rest of the world When the Holy Spirit comes upon us as Christians, it is not only so we stay in a church aquarium It is so that through us yes as weak as we are with the testimony that you and I have They've experienced the power of Jesus the power of God's restoration the power of God's love Don't limit it to just you today through social media today today through the means that we have God says I will use you To impact Pasco, Richland and Kenwick and also through YouTube Instagram Facebook Snapchat and Twitter the rest of the world Come on somebody Hallelujah somebody say hallelujah We have a prayer today for prayer line and I would like to title this message Loosed to be used You are loosed to be used Amen. I love when God uses us. I hate when people use us You feel so Empty afterwards, but God when God uses you you feel so good afterwards You feel refreshed We just came from Arizona and it's a people healed one Youth pastor's wife was trying to get baptized in the Holy Spirit was speaking in tongues for 30 years and That night she got baptized in the Holy Spirit. I have I Have never seen that many people get baptized in that short time and the power of God It's just people were vibrating falling yelling and everything. I love it's Pentecostal, you know, so you stand you like man the more messy chaotic against like yes, Lord I Don't like quiet reminds me of seminary cemeteries. I'm sorry not seminaries. I Wasn't there yet, so I don't know but it's like when you see in the hospitals There's birth and babies is life when there's life. It's loud It's football is loud Hospitals or babies are loud and We've seen about like 30 something people that were healed and and when God uses you it's so beautiful It's so beautiful.  He disregards you use it replenishes you it restores you You feel build up people feel challenged and stretched and we had an incident there when I was there where Unknown to me a young actually an older lady She probably was about to be retired and she wanted to leave her job and join full-time ministry She was a youth leader and the Lord prompted her He wanted her to do that but she was afraid to do that So she gave a challenge to God on the last night of the camp She said that if the preacher is going to preach exactly same message I preach to my youth and he will mention my name It's a sign from God to leave to leave her job and go into ministry and so I'm preaching a message turns out. It's a similar message that she's been telling to her young people and Then there comes a part in the message where I call somebody up and I ask him for their name And the girl said her name is Maricela And I mispronounced it by saying because the lady's name is Merrill Lou So Maricela she tells her name. I think that's her name was Maricela or something with them And so I didn't say Maricela. I mistaken it for Merrill Lou Because I know Merrill Lou from our church. So I call her Merrill Lou.  And so it's like on purpose. I am I completely messed up her name And so she said down everything was fine. And then at the next morning lady comes in and shakes my head And she's crying. She says you have no idea God used you to to confirm my calling and she says you Mistaken the lady's name and she said you had no idea why you did. I was like, well, I know it's just my English She says God used your mistaken name to confirm my calling He said my name is Merrill Lou and I said if God if he the preacher will call my name in a sermon It's a sign. I have to leave my job. I'm like it sucks to be you now But God bless you You are loosed to be used To touch other people's lives because somebody say amen We're going to look at Matthew chapter 21 verse 10 and verse 11 I'm going to read the end of this story about a donkey dad you Probably have heard of and when he had come into Jerusalem all of the city somebody see all of the city Well, somebody say all of Pasco Somebody say all of Richland all of Kenwick Was moved somebody say moved many things shifted Saying Who is this? Verse 11 so the multitude said this is Jesus the prophet from Nazareth of Galilee The beginning of the story in Matthew chapter 21 It tells us about Jesus wanting to go to Jerusalem and he needed a ride Didn't have an account with lifter uber So what he did is he sent to disciples and said I want you to go to the village opposite of you And you will find a donkey if you're reading a King James version.  I Believe that you were born on purpose Maybe your mama and daddy didn't plan you maybe you came as an accident Only to them not to God your birth was planned Your birth was wanted Your birth was expected God anticipated you He designed every single day of your life He used your parents to bring you here, but he is the author and the finisher of your faith can somebody say amen Maybe you never met your biological parents I can tell you one thing that God only used them to bring you here Maybe you never received enough love from them and you're maybe going through something very difficult today Your parents love is just an appetizer and God's love is the main meal God wants your parents to introduce you to him so that you can discover that God is all really that you need He will never let your parents love you so much and care for you so much that you don't need God and Some of your parents. They're like olive garden appetizer Bottomless bottomless salad and some of you some of your parents is like a sushi restaurant appetizer Four leaves sprinkled with some soy sauce or some sauce you're looking at that and it just doesn't fill you up You don't break the plate. You don't curse the restaurant.  I think that the donkey was chained up because I sincerely believe The devil binds people God plans to use see we think it's because they're so bad Perhaps They're so good perhaps Devil knows something about their future. They don't even know you know in the game of football When you get the ball Everybody attacks you you don't have the ball. Everybody's off of your back When you get the ball Somehow the enemy is there To squeeze life out of you.   I believe that you have a purpose I believe that you have a destiny and Satan attacking some of your things that you went through and some of the things that some of you Here right now are fighting and you're simply your whole goal is that I just want to get out of it But I want to tell you that there is a conspiracy that's been developed against you and you're saying and the world tells you It's because you're weak. That's why you're bound perhaps in fact maybe just maybe Perhaps Satan has looked into the calendar and saw something you don't see You remember how many deliverances that we saw here even in our church and the demons said exactly same thing. I Saw his star That's why I'm attacking them or they're gonna be great That's why I'm binding them. See you think you just went through the wars You think you're just struggling with what you're struggling perhaps is the Satan's last attempt To ruin God's plan for your future, but if the donkey got lost so will you come on somebody?   I know you tried I know you've done everything you can but God says For the freedom is set us free You're not gonna die by that rope Satan will be hang by that rope, but you will be loose so you can be used by God somebody say a man When this donkey was loosed somebody say loosed Come on touch yourself say I am loose Jesus have mercy When the donkey was loosed by the disciples I want you to see that disciples did not let the donkey go free the second part after deliverance is Discipleship deliverance has to lead to discipleship because deliverance is God Getting the devil out Discipleship is God keeping the devil out Deliverance is God working for me Discipleship is God working in me It's so important to recognize that if your deliverance does not lead to discipleship Your deliverance Actually makes you a target I've seen this happen with my brother's dog last year had this German Shepherd named April and April was was she had a lot of energy and when we would take April and open the gate in our yard April Gave what we gave her freedom what she wanted. She really wanted freedom. She saw all other dogs and She ran like a bullet She didn't pay attention to the traffic There were cars driving on Sylvester runs through the traffic cars are honking and stopping and she only is concerned about one thing Go and seeing other dogs And I looked at that and I felt like Holy Spirit of lad.   We're gonna bring you to Jesus No, no, no, we're not gonna just bring you to build you a better life We're gonna bring you to Jesus because there is a purpose for your life See sometimes when we get freed, but we don't surround ourselves with right people on our left and on our right Next thing that happens is that we end up under a wheel of a car I've seen this firsthand in Many cases in our church where young people get freed from drugs or other things And they are too impatient to reach their destiny and they don't realize they're not ready yet for their destiny Before there is Jesus riding you into Jerusalem There is a period of disciples walking beside you for a short period Where certain habits get developed where certain characteristics get developed This is where the home groups and mentors and brothers and sisters in Christ knew surrounding and new Kind of environment is so crucial You can't grow bananas in Alaska. Why because of environment God has a potential and a calling in your life But if your environment is wrong even after you've been delivered, it will suffocate everything you got inside of you I Remember a young man who got saved in our church drastically and dramatically saved and Pastor Ilya was discipling him and within few months of his conversion His mama was in Seattle and she was doing her profession involved things not very good bad really bad and Ilya advised the man. I was there this young man got so on fire for God He says I will go to Seattle to see my mom for holiday so I can witness to her for Christ and We were telling him don't go. You're not ready yet. He says no, you don't understand. I love my mom I need to win her to Christ. We said the problem is that your mama is involved in drugs Your whole family does that by coming close to that. You're too vulnerable and he says no I don't need your guys's advice. You don't have a passion and love for the lost as I do and he went and That's where he slipped He never recovered from the fall He's dead now Because he did so much drugs after that that he went mental You saw his story on the news.  He doesn't need people But as he walks in the power of resurrection was being quenched because people were laughing at Jesus And Jesus didn't say I'm gonna prove you wrong. He says everybody get out. It's exactly Bob's is he?  I'm not saying you beat him I'm not saying you heard him You just remove it completely the way sailors did with Jonah and the storm stopped a lot of drama in our life will stop If toxic people will be shown the exit if you don't believe me Remember it was Judas who put Jesus on the cross toxic people close to you will crucify your destiny Are you with me? The second part about discipleship not only we have to disable toxic people and today We are very blessed to have features on our phones that allow us to block people We are so blessed to have features on the social media To block people if you don't use that try it. There's deliverance and freedom in that But the second part that I want you to see in discipleship is not only we disable But we distance ourselves From those people who are deeper in sin than we are in God Now I'm speaking to people who are walking through the process of freedom. I'm speaking to people who want to grow in Christ You may say of that God says for us not to leave the world. It's true But if you are struggling with alcohol and God delivered you from alcohol There are people in your life Who are way more committed to Jack Daniels than you are to Jesus Christ right now And I'm not to guilt-trip you I'm just saying for a time and a season until your roots grow deeper in Jesus than their roots go in tequila create a distance Why because if you surround yourself with them whoever is deeper pulls the other For those of you who say but I've been influencing them in the last 12 months whose music they listen your music or you listen to their music In the last 12 months, how many times they've came to hungry generation versus you came to their parties Be honest with yourself They are way deeper in their stuff than you are in Christ That's why you got to get deeper but to create deep depth with you create a little distance between people who are deep in their stuff God in you is great. He is way bigger than the sin. It's not the God. That's the problem. It's my depth in this God Sin is way weaker, but some people are so sold out to sin that they have an influence over us In the areas we were been delivered from That's why I believe Joseph didn't try to pray for Porty for his wife He knew she saw my stuff.  I'm running from you. Why I gotta create a distance. Why because you can't witness to those things you're tempted by I'm gonna go evangelizing in the club You still got your membership there, honey Let's leave let's leave that We disable we distance and then there is one more we draw closer to people Who are deeper in the Lord than we are? Because if you only run run run, but the Bible says in second Timothy chapter 2 verse 22 It says flee youthful us and run the race with those who call upon the name of the Lord are up your heart God says this race is not by yourself You're not running by yourself with those meaning surround donkey had Peter and John It had some some two disciples walking beside it because Peter and John has been with Jesus longer than the donkey That doesn't mean Peter and John or I'm just using their names. I don't know if it's Peter and John Well, let's just say Peter and John. I'm not saying that they know everything They've had their moments of weaknesses, but they when they walk with the donkey They have a chance to bring this donkey closer to Jesus every person in your life is an elevator They either take you up or they take you down They either bring your clothes to Christ or they're bringing you further from Jesus Christ I know this is Sunday school lesson and I know for some of you. Maybe this is not deep enough But please understand your crowd Creates a cloud over your life Hebrew chapter 12 it says before we run the race. We have to be surrounded. We sing the song. I'm surrounded. I'm surrounded by you That's good But who surrounds your life from your friends because this surrounding We're surrounded by the cloud before we go running Author of Hebrew says make sure you have people on your side and the bleachers that are cheering you on There are witnesses be surrounded by this crowd Why because they create a cloud and influence that motivates you? Challenges you don't be the see on my brethren Bad company corrupts good morals post as that Discipleship is so important for those of us discipling. Can I give a word of advice to a follow disciple makers?  Can somebody say amen? We see deliverance leads to discipleship Let's take one more step further after discipleship disciples of Jesus they bring this donkey they present this donkey And there is one more inside there is instead of sitting on the donkey. They took some garments and they They put it over The donkey's back Why so when Jesus would sit on it it's comfortable So instead of sitting on people Let your example Make it easier for Jesus To use them. I believe your example my example as a leader Puts a cloth over their life and allows Jesus to rest on them More comfortably give them your example Maybe give them some clothes as well That's not bad Give them something, but we are not to Lord over people We are to leave our example on them and our influence and our love and then when Jesus sat on the donkey He says mm-hmm feels comfortable Like as Peter's jacket is there John's jacket is there the rest of disciples his jacket is there the more positive examples people have easier it is for Jesus To Lord over their life Are you with me and we see that Jesus comes now to the donkey and Jesus doesn't say well Disciples I'm taking over he gets on the donkey and he sits upon this donkey There is three levels of knowing the Holy Spirit the first one is when the Holy Spirit is with you He's with everybody who doesn't know Jesus to lead him to Jesus the second one is the Holy Spirit comes to live in you He comes to live in you to develop a good character inside of you And there is a third experience and this is this experience that I want to show it to us today Is that Holy Spirit comes upon us? Somebody say with in and upon Jesus says that the Spirit of God will come upon you and you will be you'll receive power and be my witnesses Holy Spirit upon you. What does that look like? It's surrender Giving control letting him be the Lord of your life Having the Holy Spirit be the boss of your life Not just living inside of me to give me comfort, but he becomes my Lord He sits on me When he sits on you, he's not heavy.   I Almost feel like Jesus set the donkey free through disciples So he can have the donkey all to himself and so he can be now in charge of the donkey I think real freedom is not when God removes the devil. It's when God replaces him I remember reading an exodus Moses comes to Pharaoh and at first when I was younger I used to think that Moses was lying You know how sometimes you want to get something from someone and you you kind of Changed the real reason of why you want to get it when Moses comes to Pharaoh. He says Pharaoh let my people go so they can serve me Come on. I'm like, I read the rest of the book. I know why did God wanted to let them go so they can go to get the promised land That's why God wanted to set them free But I don't think so if God mentioned it I think 18 or 19 times in a period of seven or eight chapters in Exodus so they can serve me So they can worship me. They can serve me. They can worship me. I don't think God was lying I think God wanted to deliver Israel from Egypt so that they could treat him at least to that degree that they've been treating Pharaoh God in fact was saying Pharaoh.  I am their master You terrorize them, but I would bless them and I want them to serve me. They are your slaves I want them to be my sons.  It doesn't say where this evil spirit is gone There is freedom. In fact will freedom is not absence of the devil. It's when God takes the place of the devil But because the devil hurts us we are eager to get him out We seek help to get him out and when we get him out, we don't want to put God there We don't want to give God the same place. We gave the devil. We want to put ourselves there Praise God I have to spend 600 bucks and weed a month I sure I'm not gonna die What if you will continue do what you did with drugs just with a different substance to a different master God didn't set you free so you can be available to you God set you free so he can have you He saw how faithful you were to things that destroy you. He's like I can imagine how faithful he will be to me when I start Blessing him and the moment God get rid of the devil.  I developed some plans. You can really help me out here You know if you change seats on the bus it didn't change where your bus is going Being delivered from Satan so you can be bound by selfishness. You're in a still same bus When you switch the bus and switching the bus is this God gets control He sits on me and he does what he wants When I was in sin, I didn't do what I wanted and when I am in Christ It's the same thing the difference is this is that now I am more alive because he created me and he rains over me You will never be genuinely free until God takes the place your sin used to have That's it kiss freedom. Good.  He will set you free this morning I just feel like many of us we use God to get out of problems But not out of Sodom Kind of like lot you got in trouble Abraham hook me up who hooked the brother up Abraham went or rescued lot only for a lot to go back to Sodom It's kind of like if you have a light on the dashboard and you go to the mechanic instead of solving the problem He said hey, could you remove the light bulb? I really don't like the Christmas lights.   It brought us healing You're not gonna live really for yourself. You can take the train off of the train tracks, and it's free To do what it wants. You know where the train is gonna go nowhere The dog April ran out from the yard. It was free But it was a target. I want to tell you something the safest place Is surrender to Jesus the safest place is to give Jesus the lordship of your life He's tired of being your insurance card. He's definitely tired of being in the trunk as spare tire He says I want to sit on you. I want to rest on you.  He's not heavy His burden is light and his yoke is easy. He's not there to squeeze to torment I came to give life and life more abundantly. He has no religion in his pockets to give you It's not a religious God.  He says I made them He is God When he said on that donkey Something changed about the donkey because the Bible says nobody ever said on that donkey, which means it wasn't trained It wasn't broken, but the presence of Jesus Broke everything that needed to be broken and nicely this donkey carried Jesus into the city If you want to be used by God Get filled with God to the capacity As something happens Nazar, can I borrow you grab this coffee?    Is anybody in this room? The Bible says Jesus walks into the synagogue and he saw sees a man with a withered hand.   Don't worry what you're gonna say Why because the spirit in you? He will tell you what to say Some of you say I don't know a lot of Bible.  This is how we have the Holy Spirit What we watch we're not conscious what we listen to we're not conscious why we got him He's just not resting We're just not full of him We're full of other stuff That's why we can do all the things that Christians people can do and still say I got the Holy Ghost And you say why am I not mindful of needs of people?  It'll be same people will be same boss same work or something about you changes Why because you're conscious of that what you filled with and Once you're conscious you begin to start hearing voices good voices promptings Love you start feeling this no reason This pain in your heart for somebody what is before you judge them?   Hey, but I got hungry general go love, but I speak in tongues what am I the share of our hand up? Well, I'm passion Java gave me a prophecy Yes, I'm gonna be a millionaire A husband is coming The reason why you watch anything you can watch and you have no conviction is for the same reason Marvin walked back and forth And he did not look at the cup Because it's empty some of us locked the Holy Spirit in this safe All our religious preferences He wants to ride on you Sit on me your Holy Spirit Rest on me a Holy Spirit. I Feel a tangible presence of the Holy Spirit in this room right now.   Hold him tight and then just drink him Okay, you don't have to drink it. You can put it put it back nice if you're saying Vlad I Feel like that cup I Want the Holy Spirit to rest in me right now. I want the Holy Spirit to fill me right now I want you to begin to stand to your feet


That's working, yeah. It's been a terrific conference, and Ross is getting the computer hooked up. And the panelists, I think I don't need any introduction really since they've all spoken, and since their names are clearly labeled right there. And while I'm waiting for a, don't you have some kind of high throughput robot that could do that faster, Ross? Never mind. So since this is the penultimate talk in this meeting, I'd like to take the opportunity to thank NHGRI. Eric probably won't thank NHGRI at the end. So in 2003, we were studying a lot of gene expression in the testis, and we were seeing all kinds of transcripts that weren't annotated. And if the slides come up, they're not up there, though. And we were finding a lot of unannotated transcripts, and this is a cartoon that I was using back in that period of time. And we would look at the annotation, which was a wonderful thing when the fly genome was first sequenced. And I went to complain, actually, to Francis Collins. And I said, isn't there something we can do about this? And he said, well, you need to go and talk to Peter Goode. And so I went and talked to Peter. And it turns out that plans were well underway in NHGRI for tackling exactly this kind of a problem that people recognize it. And as usual, I think, NHGRI was kind of ahead of the curve. And I would like to thank them for that. And I really look forward to seeing what happens nine years from now, given the kind of long incubation period for these projects, and then finally seeing them through to fruition like this one. And I also like to have a special shout out for Peter Goode and Elise, because in a lot of modern code meetings, you hear people referring to their job being herding cats. Well, Peter and Elise are the herders of the cat herders. So that's a doubly difficult job, I think. And they've really pulled off a fantastic project. And we're all really excited with the results.  So I think we should give them a round of applause before we move on. What happened? I see it here. We're going to go through the questions that the panelists are posing. And then we're going to take all the questions and have a nice, hopefully good discussion at the end. So my question is here. I mean, like a lot of people, I've just been absolutely stunned by all of these GWAS studies. They're incredible advantages to working on humans. Like you don't have to screen for mutants. They walk into the clinic. And the kind of pie throughput sequencing that we can do now has just opened up all kinds of exciting avenues for research. And pretty much this, I think, is a typical kind of a GWAS result that I've highlighted here, where we know that a particular trait or disease susceptibility is highly heritable. There are few Mendelian kind of things that are easy to get at. And after that, it gets messy really, really fast, where you have a lot of minor, small effect variants. And then you have to get into all kinds of complex combinations and network kind of analyses to kind of get close to getting to finding all of the heritability in these. And so my question, which I have some, at least, potential answers to, which I won't give, because I want to see what other people think, is what can modern code do both now and in the future to help inform these GWAS studies and try and make sense out of these oligogenic phenotypes that are much like what Ross spoke about. So that's my question. And Jason, you're up next, and your slide is the next one. I can just run it, I guess. Is it, I don't know how it's organized. I gave him my, OK, that was it briefly. Hopefully it'll come back. All of the slides are on the same talk. So we were asked to come up with provocative questions. So my question is a very simple one, which do genomic technologies diminish the utility of model organisms? So we heard a little bit, I was really glad to hear Ross's talk earlier today, and actually Eric mentioned at the beginning of his talk that genomic technologies have really increased the accessibility of mammalian cells and human biology to inquiry. And one could think of this, if one thinks of it as a zero-sum game, then I guess you would say that maybe the utility of model organisms is diminished accordingly. So anyway, so I put up some yes and some yes arguments to this question. So with decreasing sequencing costs, many of the advantages that these models were originally chosen for, for example, smaller genome, become less important, right? I mean, if the genome's two orders of magnitude are smaller and the sequencing cost has gone down by 10 orders of magnitude, does it matter as much that the genome is small? Snips and mutations can be readily identified now. And so traditional genetic mapping and screening, in many cases, can be obviated. Improved transgenic methods allow controlled single copy integration into mammalian cells. There's improved knockdown methods for interrogating loss of function in mammalian cell cells. And also barcoding and cell sorting technologies make possible cell-type specificity and highly parallel functional assays. So all of these things are really democratizing to the study of human cells. And the question is, does that make things that we've traditionally done these types of studies in models, right? So the no answers are, there's a lot of obvious no answers. One is you can't control a lot of critical variables in human studies and I wonder whether, you know, whole organism human studies, you can actually control any variable at all. And so that's one, you know, and obviously control of the experimental conditions is a prerequisite of science altogether. Human studies are expensive. Mutants are not often available. Some mutants can't walk into the clinic, right? And the relevance of cultured cells is always a question. So people have these questions all the time about how relevant cultured cells are. And actually this is the one I was happy about with that Ross address, which is that the integration of cell biology, so even if you can do these experiments in cell culture and biochemistry, if you can do experiments in extracts of human cells, it's very difficult to integrate those results with whole organism biology in humans. And models are really good for that, right? Because you can easily, that's where the generation time and things are still extremely relevant is integrating those results. You might get at a cellular level or biochemical level with the whole, how the whole organism behaves. And then even invertebrate models like mice, whole animal studies are slow and difficult. So anyway, these are the two sides of the argument. And I think it may seem like everyone in this room is saying, oh, well, of course not. Models are really important, but this is the debate. I mean, we hear a lot about an emphasis on translational studies, or why can't we look at this directly in humans now? So I think it's something worth explicitly discussing. You wanna do it from there here, it's up to you. Hi. Okay. So I think in a similar way, I think maybe picking up on both Brian's and Jason's components, which is some of the challenges that we're hitting up against in mapping human genes are perhaps more easily addressed in the model organisms. And I think there's both advantages and disadvantages of actually moving to the models. I wanna first show sort of a little bit of that and then sort of talk a little bit about the challenges ahead. So the advantage of the flies, as we heard very eloquently in Ross's talk, is that you can actually map the interactions. In other words, having these very short generation times is something that genomic technologies cannot get around. In other words, you can make the double and the triple and the quadruple knockouts and make crosses specifically based on your hypothesis of interest. So you can go to higher order disease models, which is a lot of where these, a sort of the technology of being able to study these regulatory networks gets us to in the sense that it exhibits sort of these interactions between multiple loci. And also it's also where the challenges of these single locus and additive models of human disease are getting us at in the sense that a lot of the misinheritability might actually be sitting at the interactions. So basically that all of these higher order aspects might actually be more easily addressed in the model organisms. So again, the rapid crosses to actually isolate the genetic contributions in a controlled environment, the rich information of the regulatory network, but again, this is something where the human side of things is very rapidly catching up and then the ability to dissect these rare variants in different contexts. Now some of the disadvantages is that the genes that underlie the disease might actually not always be conserved. The networks themselves, i.e. the interactions, even if the primary genes are conserved, the ways that they interact might actually be different. And number three, the phenotypes themselves might not be available in the fly. So basically constructing these models for human disease is a challenge. The second aspect is we're struggling a lot with regulatory mutations, namely mutations that fall in non-coding regions that are not immediately sort of associated with a gene, or that are certainly associated with a gene, but in a complex way that depends on the specific regulatory element. So mapping these regulatory regions to mouse can be certainly possible, and within mammals, most of the regulatory elements are in fact conserved. However, if you go beyond mammals, if you go to flies and worms, all the regulatory components, the specific regulatory elements, are actually not conserved. So I think that's a big disadvantage in the sense that sort of testing the specific regulatory functions of these non-coding variants might actually not be possible. And then the interactors themselves can be distinct. So again, we have many challenges ahead, many opportunities to address some of these questions of whether the genes, the networks, and the phenotypes are conserved. I think the modern code, the current phase of modern code has a lot of opportunity. And to that effect, we can, for example, look at, we can basically ask, are the genes themselves that are associated with disease that come from, for example, OMIM, or from the NHGRI GWAS catalog, or from the cancer gene sensors, how many of them have actually orthologous genes? And you can see that a small fraction of them do, actually substantial fraction, I should say. And then how many of the diseases themselves have orthologous relationships? So I think that the current mapping of orthologous genes at least gives us some opportunity that this may be relevant. Number two, if you actually ask for the functional enrichments, are the functions themselves conserved, then what we're finding is that for a large number of categories, what we're actually finding is that the diseases indeed have functional enrichments associated with the fly genes. And again, that's very encouraging. And lastly, if you actually look at the genetic interaction network of fly, many of these diseases actually are sort of revealing other diseases that they're connected to. Again, giving us a handle for actually studying relationships between these diseases. So what I want to, I guess, end with is that there are many challenges ahead, but I think a lot of the work that Modern Code is setting up right now sort of can sort of perhaps bridge some of these challenges. But again, I think the discussion will cover a lot of that. Oh, I remember my question. My question was, and I think yours is gonna be similar. What's the difference in going after disease between basic approaches to, or basic research approaches to disease versus translational or therapeutic approaches? And I think the best way I can illustrate this is in an example. Because there isn't, I think there's an underlying assumption in most of the meetings I go to, including this one, that, as I mentioned, identifying mechanism means identifying therapeutics. And I think that's not always the case. And there are many, this is a discussion to go for a long time, but let me explain the difference. For example, my dad had quadruple bypass surgery about 20 years ago, almost 20 years ago, and he just got back from a cruise from Alaska, okay? So what causes heart disease? We really still don't understand the mechanisms that drive disease, and that's why we have difficulty, even identifying risk factors for it. But it doesn't matter because you can bypass it and you can get on with life, all right? And so that's an empirical approach to the disease and it works, and in fact, this past year, heart disease is now the second leading killer of Americans because of bypass surgery, whereas cancer has now taken its place as number one.   And that is a mindset that I think really is quite different from what we're used to. I certainly had to move towards that in the things that we're interested in. And in going to the modeling and so on, I would actually turn the case on its head and say not our model organisms being marginalized by network analysis and so on. I'd actually turn it around and say to date what has network analysis done to treat major diseases that had market success on rare diseases, and of course being a little harsher than I anticipated here. But the truth is, for example, with the drugs we've been developing, our assumption is not that those drugs are even addressing the tumor directly, all of the activity. So I showed you some of the pathways that it's acting on, but I actually suspect that some of the effects of the drugs we're developing are on other, either neighboring tissues, on the metabolism of the fly, and so on. The network analysts that I've worked with to date have really thought of these networks as sort of standalone networks, and they have not considered, because at the moment it's essentially not possible to consider the complexity of the animal. And while it's easy to put that aside and say, well, that's something to sort of deal with, again, if I go back empirically and ask, rational drug discovery, how well has it worked as opposed to phenotypic drug discovery? We have spent a lot of money on rational drug discovery, but the outcome has been mixed, harsher than I expected, but whatever. Well, I guess I would take quite a different perspective because I'm not willing to say that we're just gonna do medicine empirically for forever, we're never gonna understand, and I really think it's a matter of perspective. If you go back a set of five or 10 years, 20 or 30 years, I mean, could you imagine if we didn't know that DNA was a genetic material now? I mean, fundamental research has a massive impact on medicine over longer periods of time. You can't get away from that. It's inevitably over a long-term driven, most of the advances in medicine. And we mostly, we're just at the very, very beginning of understanding metazolean organisms, so this process is just gonna repeat itself again and again. I think the biggest problem right now is that people think they can understand metazones without getting into the full complexity of tissues, their 3D structure, all the different cell types. You can't just grind these things up, you can't just put them in a dish, and I'm sorry, but in IPS cells, can it just be a useless model of disease in 95% of the diseases because they depend on structure and interactions of cells, all of which are lost when you just have one cell. And you see this in mutants. I mean, most trisophila mutants have non-autonomous interactions. You see it's studying stem cells, which I do. If you just have the stem cell and don't know about the niche, just forget about understanding it because it's a property of multiple interacting systems. So we just have to start loving the complexity, which is, I guess, one of Ross's terms, love metazone multicellular 3D complexity. And the sooner people get that in their heads and just start thinking that way and working that way and using our fantastic technology to now, in effect, have that kind of genome information on each one of those cells. And you know how they're all interacting and what's close to what and what's far. That's what's gonna be the wave of the future. And then, step by step, we'll fundamentally understand how groups of cells work and then how tissues work. And it won't be any harder looking at the human genome and seeing some changes to predict what the phenotype is than if somebody brought you in a yeast karyotype and there was a hiss mutation and you'd be able to predict what that phenotype is. There's, it's not impossible to understand metazones by fundamental biology. So we'd like to open things up now on that very strong last set of comments. So if you wanna go to the microphones and while people are doing that, I mean, one of the things that I think came across in all of these questions was this idea of complexity and that we have to embrace it and we're being faced with that continually. And I think that as more genomic medicine starts making its way into the mainstream that that's gonna be increasingly seen as important to embrace that complexity. Yeah, to continue to echo some of the remarks that have been made here, I want to go back to little older days and see what the reaction today is. You will recall not too far away and quite recently just yesterday, there was this adage that the animal models really tell us about the possibilities but not the actualities because we might be able to study a phenomena polygenically as two people mentioned today. But in real life, it is not just polygenic phenomena. Phenomena is polyfactorial as you just mentioned. Are we anywhere away from that kind of adage that the animal model really, really tell us what can happen will really not tell us what really happened. So we will have to go back to ourselves, clinical trials or what our experiments with ourselves to find the arrived at the conclusion which affects us. Comments? So I guess I can start. But so clearly there are all kinds of factors, right?  There's a lot of complexity and not only in the genome but in the interaction between the genome and the environment. And we really don't have very good models for that even in the model organisms right now. Although I think that that's changing, that especially now that we can sequence so many different genotypes, we can start to set up especially designed populations of model organisms with that you could seed a population cage for example with some of Ross's potential tumor promoting mutations and essentially select for a tumor phenotype or then try and use these populations to screen for efficacy of some of the drugs and kind of really build models for personalized medicine using these model organisms. And I don't see any other place you can do that other than using cell lines. And I completely agree that cell lines while they have a lot of wonderful properties, I mean they're not organisms and it completely ignores physiology. So if you- If you let me hang myself to the wall and you with me, you made the comment that we don't have good models. Let me make the proposition that we will never have good models which would be able to give us real prediction about what is happening to us. So that's one point you can remark on that. What is missing, what is often called the reality check is that the environment within which we live cannot be reproduced in models. Maybe tomorrow we'll be very smart about system biology but I am personally not hopeful that we will not soon end the limitation of our ability to reproduce what occurs in nature. So if I can just step in on this. Okay, and again there's many threads going here and I'm sort of choosing which one to address but to address the no good models comment. I think that was your comment. So for example in mouse, mouse metabolism and we've all been told this but in stepping into the diabetes field I've really come to appreciate it. Mouse metabolism is utterly unlike human metabolism in just astonishing and fundamental ways. For example, if you feed a person or even a fly a high sugar diet they'll become diabetic. That's not true in a mouse. You have to go to a high fat diet and then if you take a rat and feed it a high sugar diet then it's fine. So the difference is even in fundamental processes even across mammals is striking, okay.  But to follow up on the second part of your earlier point which is the, so that's one thing is that at the end of the day it has to be tried in people and the best you can do with model systems is to increase the odds that you'll have success in the clinics. You'll never know until it goes into a person and then to sort of riff off that point and what you started with. And I completely agree with Alan. I'm 100% behind the idea that eventually our ability to model things more and more sophisticated in ways and understanding the mechanisms behind things is where it all has to go, okay. To me that's a tomorrow versus a today issue but we don't disagree otherwise. And I think Alan would agree with that. But let me just- I agree with you. I think we are making great progress. I'm very hopeful. But I think we need to be increasingly, as we advance we need to be increasingly more critical. Right, but exactly and the point I wanna bring out is this, yes I agree. And the point I wanted to bring out because this is a point that we often don't see in our basic research world, is that for example in the 1980s, spending per year on R&D by pharma was in the range of $2 to $3 billion total, okay. Last year it was in excess of $80 billion. So now let's review the success of that which is the only thing that matters. Everything else is talk, right. It comes down to new composition of matter, drugs and related things that go into the clinics and actually help people live longer, right. And as you may know, cancer for example is a terrible example of this because five year survival rates for cancer from 1950 to today has moved only slightly which is disturbing to think about. If you look at, so in 1996 which is an echo of drug discovery done in the 80s there were 53 new drugs introduced into the marketplace based on that level of spending. In the past decade that number has hovered around typically between 10 and 15. New drugs introduced in the marketplace per year despite the fact that spending has jumped probably 15 fold. The difference between the 80s and then the 90s onward and we all remember when all our buddies went into pharmaceutical companies and did rational drug discovery, right. The idea is you're gonna go into drug companies, you're gonna identify the mechanism of the disease and then you're gonna hit that with femtomolar specificity and the disease was gonna yield to this. That's the outcome of that result, okay. And a lot of it is exactly what Alan is saying which is we were probably naive in thinking that we could model things to a useful level. I don't care if it's a complete level, I don't care, the only matter is if it's a useful level and clearly we have not been able to do that and that has cost the pharmaceutical companies dearly to the point where they're all facing patent cliffs and they're all merging and so on and so forth and it's because the PhDs went in there and essentially changed the paradigm from phenotypic screening to rational drug discovery. So I think a bigger question would be and it goes to something you were talking about is are we ready for rational drug discovery or do we need to just do the basic research, move along those ways and in terms of actually generating treatments, emphasize phenotypic screening. It will only increase our odds, it's not gonna be perfect, fly models, for example, clearly are gonna have failures but increase those odds is we can't get worse than we have now and that's really the point that I wanted to bring forward. This is a point that we don't see, we just sort of think that by studying mechanism we're helping people today and that's simply not been proven to be the case yet. I think the burden of proof is on us. So I did, I mean one of the things that I think is interesting about model organisms is that it gives us an idea of how certain mechanisms have evolved over time and the impact that those have in the biology, particularly, I mean cancer is an obvious example maybe of that is how those evolutionary changes that may be functional in one organism may be mechanisms that are selected for for certain types of diseases. So I think understanding those mechanisms in another organism is important because it gives insight to what mechanisms may later on be selective or advantage, some type of advantage for later diseases. So one can think of evolutionary change in many different scales. So you can think of it at the level of sort of fly versus human but you can also think of it at the level of sort of within mammals or even within primates or within human and I think each of these levels can tell you different things. For example, looking within the human population you can find loci that have been selected across the history of humans and very frequently they have been selected for one thing and they're now associated with the disease associated with something else and I think these connections, as you say, are indeed very useful. So in mapping genes within mammals or between flies, worms and human what we're finding is one to many and many to many paralogous relationships that are indeed connecting pathways that were previously isolated. We saw a beautiful example at the time course yesterday when you compare fly and worm, the developmental time course where you see these sort of almost duplication of late embryo into pupa which again sort of may suggest connections there between pathways. So I agree this is something that can be exploited to a level that goes beyond just drug discovery but also very much into basic mechanism of pathways that were previously isolated or disconnected and connected that way. Can I just say something too? I mean I think you don't have to look at the problem just at the level of genes. I think the mammalian tissues that are very poorly understood even at the cellular level until recently there were not really accurate knowledge even of this where the stem cells are, how those tissues were new and in fact there are actually many cell types in mammalian tissues and human tissues that are not yet described and model organisms can really help you in finding these things. So for example like my lab has worked on the fruit fly ovary where in the course of we and others found a number of cell types that were not classically described by histologists. We can now look into the mouse ovary where the somatic cells are very, very poorly characterized and so we don't even know the cell of origin of a lot of ovarian cancers. By correct, just by correctly identifying the somatic cell types and what they actually do in this very parallel process that you see in a mammalian ovary or a fly ovary you can get tremendously useful information like the origin of cancer. There's just an awful lot of straightforward things that can be done with model organisms to advance our understanding of mammals. I think another aspect to touch upon is just this extreme pleiotropy of many different genes. The fact that you may be studying one gene in one cell type that's associated with a particular function and then if you look at how that gene behaves in a different cell type that function can be very, very different. So when we're looking at genome-wide association studies that map organismal phenotypes to loci, I think a step of translation of that into not only the relevant pathways but also the relevant cell types that actually might be involved in different pathways I think is another component of complexity that you're bringing up. Okay, maybe speak up a word for the mouse as a halfway house, old platitudes. It's hard to study the nervous system or immunity and yeast and it's even hard to study it in Drosophila. For example, the marvelous things we've heard about about cancer chemotherapy on the basis of genetic networks, really beautiful but one of the newest, most exciting cancer therapies came out of the study of mouse immune system and inhibition of inhibitors of T cells. Similarly, the patterning of neurons as studied for instance in the retina classic studies is coming out of studies of mouse and vertebrate models and talking about complexity depending on whom you believe they're between 40 and 80 different kinds of amocrine neurons in the retina period and what they are. I don't think you could find that out from Drosophila or even worm, thanks. Well, there was this kind of old concept that for any particular question that you might have there's a perfect model organism out there someplace that you can study it in. And I think that all of these kinds of discussions about what can and can't be done in a mouse or in a fruit fly or in a rat, what that really means is that we have to kind of have a collection of model organisms that we can pose these questions to. So we need flies and we need worms and we need zebrafish and we need mouse and perhaps we need some to develop some of the emerging models that look particularly promising. Hopefully there's in tough budget times there's still enough money around to occasionally take a particularly surprising result that an investigator has discovered a new system for something and develop that to see if it can't kind of join the mainstream of the model organism community. I guess I actually had a different point to make but first I have to strongly disagree with Sherm's point which is even for things that may seem to be more complex in mice and humans, I mean the basic rules as we've discovered over and over and over again are often still applicable to the model organisms and more easy to discover in the model organisms. So though I agree there's more complexity in mammals, it's not that you can't learn significant and important things about those pathways in humans. In the model organisms of course just to raise the somewhat humorous example which is a few months ago learning that flies that don't get enough sex drink more. It's probably not for exactly the same reasons but you know. And I'm sure you're not talking about yourself personally. No, no. But just to amplify your point though and you are right we have to and I think I had mentioned this in my talk you have to be smart about what and maybe this is your point about matching problem to organism there are plenty of problems that are not well modeled in flies and I think that's an important point to make and you pointed out some of them. You're right, I'm always surprised to see some of the ones you can but flies are limited in for example looking at nervous system details and so on and a lot of times it's the details that matter. So I actually would agree with that. No I think there's certainly. But the point I wanted to make or question I wanted to raise at least I don't know from the last couple of days but mostly many years of thinking about these issues and this really expands on Allen's point and others about complexity. For me if we look at yesterday's panel discussion there was, we were talking about how really it's for monocode and specifically in code and the focus of these projects which is the nucleus. It's the same thing, it's the same point that Allen was making with respect to tissues. It's not just about the 2D linear order of genes and what binds where. It's about the 3D dynamics of the processes that we're studying. So you can take the same principle, go down to the molecular level of it's about how proteins, how atoms interact and then continue to move up. It's about how the molecules interact. It's about how nuclear organization works and how things 3D structure and the endemics at the cell level, at the tissue level and backed all the way up to environment organisms. And for me at least the complexity of those so many levels of interactions absolutely requires model organism studies because we will not distinguish. And I think, I can't remember who it was who raised the issue about it. I mean in human studies it's great except that everyone including like for example my genetically identical twins who are epigenetically different. There is no control. I think that was Jason's point. Even in the case of twins, genetically identical twins it's not a controlled situation because each has experienced a different environment. So I think my point is just that I don't really see how we can solve a lot of these problems just in terms of human biology and human disease without really thinking holistically about that whole spectrum of structure, architecture and complex interactions. So I think everybody agrees with that. Does anybody disagree with that? Yeah, very good. So I've been told we have time for one more question. So please. I'm here from FlyBase and we've done a lot of work over the years to make the information generated by the fly community more accessible to the fly community and we are starting to think about and be strongly concerned with how do we make all of this model organism information more accessible to the larger biomedical community? What sort of approach should we be taking? I can actually press a little bit of that. So the question is how can we make FlyBase accessible to the general community? First I have to say I love FlyBase. It is really beautifully designed. It's simple and so on. And on that point, many of my colleagues who are not fly people have actually gone onto FlyBase, looked up their gene of interest and then come to me and said, oh, I found this and so on and so forth. So usually a million disease workers and mouse workers and so on, they have a question about a particular gene as do flies have it and so on. And I have to say they've apparently been able to easily go on there and navigate through. So I think it's actually well designed. That's easier. Go ahead, you were about to follow up, I think. Oh, okay. So I think that FlyBase and mod and code data in general, speaking also of worms, that it ought to be incredibly useful to people that are in the clinic. And a lot of times, I think that they can go and find what they want in these databases. But a lot of times they have some difficulty. And I think that when we've gone through the effort, for example, of making, Manolis making these and also Mark making all of these lists of orthologs, if you could have a portal into some of these model organism datasets from some of the ones that people in the clinic are used to looking at, that would be great. So if you could go from whatever site you happen to be in and be able to essentially query FlyBase or to query the mod and code data in the new encode DCC, which hopefully will happen, that you would be able to enter an ortholog list and get some of the model organism data kind of spewed back at you. I mean, I think that that would be kind of a minimal step that we need to make sure happens for making it easier for clinicians to get it at model organism data. I think what you need to do is go beyond just the genes as the point of comparison. So for example, the gene data would still be there, but that's fairly low down in the hierarchy and genes do a whole variety of things in different contexts, which often doesn't come across very well in these databases. So maybe if you had more cell type and tissue type organization and show what the gene, like show what is an insulin producing cell in a fly? What major pathways and genes does it use? And that to a clinician or to someone in another system who's interested in that kind of a cell, that gives them a much more useful entree into what's similar or different with their system than if you just say this one gene, that this sulfonial real receptor is conserved between mammals and Frosophila, which it is by the way, very highly conserved. I think that's a really good point. And I believe FlyBase is actually working on something like that to be able to query FlyBase by human disease, right? We are, we are working on that. So I mean those kinds of things I think could be incredibly useful and maybe in the future if you could do something like being able to query by some kind of a sub-network model or something like that, that would be great. I guess we're finished. So thanks everybody.


So we have 15 seconds. I'll dance a little bit. Yeah, so I'm going to talk about interviewing because it's something I'm super passionate about. I was really happy we had a talk this morning about recruiting because with a great recruiter you can build a great team. And so I have a very particular set of skills. And part of that is because we were 35 people when I got to Puppet and now we're 470. And I've done more than 200 interviews face-to-face and that doesn't count screening and all that other junk that goes with recruiting and finding the right people. I'm Mike Stonkey. I'm a director of engineering at Puppet. You should follow me on Twitter. That's Stanma and Matt Stratton's been pimping that all week and I'm pretty happy about that. I wrote a book a while back. I started the Apple project and again I work at Puppet. So the first thing you need to do to interview is to dole out responsibilities to a team. You should have six, eight, ten people doing interviews and they should all be there for a different reason. They need to find out why that candidate's there. What do you need out of that candidate? What makes them successful? And every person needs to be digging into a different area. We also use a tool called a scorecard and a job description. Scorecard is internal. I want to know what the outcomes are for hiring somebody. Why do I need this person in my organization? The job description goes outbound. It's just stuff like, hey, you need to have X number of years doing blah, blah, blah, blah. Turns out I don't actually care if you have those number of years. I care that you can do the thing I need you to do. And that's what that scorecard is. And everybody on the interview team needs to get together and know about that scorecard and kind of understand it and be able to say, here's the parts I'm digging in for.  I don't care how many piano tuners there are in New York City. I don't care why manhole covers around. I do care that you can do actualwork.com. So, get together with your team and pair on a problem. Do a bug. Find something to work on that's real. And then you get to culture. And people say I want to measure culture. Culture is not about hanging out. If I can drink with you, that doesn't have anything to do with culture.  You can find friends. You don't need to interview them. What you should do is find somebody that works the way you want to work. Do they solve problems the way you need to solve problems? Do they share your values you have as a team or as a company? I like transparency above everything else just about. And so if you're not a great communicator and not open about everything, if you want to keep things close to the vest, you're not going to be on my team. And I am totally okay with that. So, don't hire somebody to do a job they've already done. They'll leave or they'll get bored and they won't be happy. Make them stretch a little bit. Get them into the next thing that makes them just a little better. One thing I really try to find out is do they have 10 years experience or do they have one year experience 10 times? This is something you'll dig into with a technical interview during the actual work.com pairing. So, you should try and dig in and have your technical people say yeah, this person actually was learning for 10 years straight or no, they kind of didn't. Have people done great things or have they stood next to someone who did great things? If people say we a lot during interviews, you need to find out are they always good at trying to really give credit where credit to do or are they just standing close to somebody else who kind of did some awesome, awesome stuff? I also want to know, what do you want out of this job that you're not getting currently? What fulfills you? What motivation do you have? Why do you want to come talk to me about Puppet? I don't I mean, I want to know that so much to start with that can be a 10 minute conversation. My only technical question I usually ask is what's difficult about distributed systems? That can be a 10 or 15 minute conversation. It can be 10 or 15 seconds depending on who you are. And I like conversational interviews versus like question, answer, question, answer. So, the more conversational the better, usually.    Tell me about a time you did something else. And then I also like to know what drives you? Tell me something you're proud of that you've worked on. Sometimes people pull up something from their home infrastructure or their drone or like something they're doing at home. Sometimes it's about a massive project they've rolled out at web scale. And it's great. I love to hear about it no matter what. When you're interviewing, you get a few different types of candidates.  You get the one word answer. This is the person who's like, yes, no, I have done that. Those interviews go very long and they're not very fun. Afterwards, the six, eight people get together gladiator style. We vote yes or no. And then we go around the room and talk about it. And we have a discussion. And one no doesn't necessarily override a yes or one yes doesn't override a no. It's still a discussion. Remember, those six or eight people are there evaluating on different criteria. And the interview should also get a rating, not just the candidate. How well did you do with that interview? This is how you get better. You have to figure out what went wrong in this interview. What was this candidate cheated out of?  Because sometimes you do. So in a quick summary here, you basically need to be able to dig deep. And that means like keep asking questions to find the answers of what you need because sometimes they just stay really shallow. Do a group vote, rate your own interview, hold a retrospective on it and trust your gut. The few times I've gone against my gut, I will say that I have definitely regretted it. Sometimes your gut just means good things when you're interviewing. And please prepare. Those people have come in and tried really hard to be a great candidate for you. The recruiters have worked their butts off to get them there. Please prepare for your interview. Don't just walk in and read the resume across the table. Thanks.


Hello everyone, I'm Lisa, I'm a researcher in the CWI Cortology Group and I'm very happy to present the work, Glow Complexity Vipsuter Random Functions in AC012. This is joint work with my wonderful co-authors, Iled Baal, Jeffo, Kutun, Nifkeboa, Iwai, Shain, Peter Schott. So let's start at the beginning. Recall that a pseudo-random function is a keyed function that looks like a truly random function. The difference of a picture-rand function is that we require security only to hold for random inputs instead of chosen inputs. And the security notion we consider here is sub-exponential security. So security against circuits of a sub-exponential size that have one over-sub-exponential advantage. And why is that, why is that the security notion we aim for? Well, for quasi-polynomial security you get a completely different landscape, as you will also see in the later slide, and exponential security is often just too hard. Fertile sub-exponential security is also what you, kind of what you get from standard assumptions such as discrete log, factoring, learning with errors. Vipsuter Random Functions have many applications, for example, towards secure communication where the parties after one-time setup can use the Vipsuter Random Function evaluated on random inputs as a one-time pan. Vipsuter Random Functions can also be used as identification where a party can show knowledge of the shared key by replying to random challenges. The question we reconsider in this work is, what is the lowest complexity class we can hope to construct Vipsuter Random Functions in? This question is at the intersection of many interesting areas. First, if you can have a big PRF in the low complexity class, it typically gives you efficient metric key primitives, for example, highly parallelizable stream ciphers and simple message authentication codes. Second, it has implications to learning theory, which asks the questions of which functions can be learned efficiently through plug box success. And if a complexity class contains a weak PRF, then this class cannot be learned under the uniform distribution, so it gives limitations in learning theory. Third, the existence of low complexity symmetric objects has been related to the existence of high-end cryptography. For example, constant locality, BRGs gives constant overhead secure computation. The low complexity classes we focus on in this work are variants of AC0. So AC0 is the complexity class of circuits with end and or gates of polynomial fan in and constant depth, as you can see here in the slide. And we will consider also AC0 on top of parities, where additionally to the end and or gates, there is a layer of X or gates allowed at the bottom. And more generally, we will consider AC0 mod 2, where the X or gates are just allowed at arbitrary layers. And finally, that's not the focus of our work, but it will also come up. So I'll mention here is AC0, where their arbitrary mod gates, so mod 2, mod 3, and so on, allowed at arbitrary layers. Here you can see an overview of our previous work. If you want to look at it more thoroughly, you can pause or go to our paper. But what I want to stress is the following. First, there are basically two approaches to constructing weak PRFs. One is to build on standard assumptions like factoring, decision of Diffie Hillman, learning of errors. And the other one is to put forward new assumptions for which known attacks can be ruled out or plausibly do not apply. So heuristic here basically means not used in previous work, but might become standard in the future. And in this work, we followed the heuristic approach. And the second thing I want to mention is, if you look at the orange parts here, we know that in AC0, there cannot exist weak PRFs with better than quasi polynomial security by the famous result of Lineal Mansour and NISA. And on the other hand, we know that above AC0 mod 2, there exists even strong PRFs, so we do have kind of constructions of strong PRFs. So in this work, we focus on the area in between where so far there's only one candidate weak PRF with more than quasi polynomial security as you can see here. So let's take a closer look at the area in between, starting with AC0 mod 2. So as you already saw on the last slide, if you're fast enough, in the recent work we brought forward the candidate weak PRF computed by an XNF formula, which is basically DNF, where instead of disjunctions, you have XORs. And what we show in this work is that you can go even lower to sparse F2 polynomials, so similar to XNF formula, but without negation in the inputs. Going to AC0 on top of parities, there was a candidate weak PRF brought forward by a caveat all in 2014. But unfortunately, it was shown later that their candidate can be broken in quasi polynomial time by so-called algebraic or rational degree attack that I will explain in a bit more detail later. In this work, we show how we can fix this candidate and bring forward a new candidate weak PRF in AC0 on top of parities, the only one currently known that plausibly has sub-exponential security. So let's start with the candidate weak PRF computed by sparse F2 polynomials. The starting point is the previous candidate in AC0 mode 2. As you can see here, the candidate is an XOR of Ns, where the N terms are increasingly biased towards zero. And the intuition behind this construction, very roughly, is that the more samples one sees, the more of these terms will kick in, meaning that given very few samples, these are indistinguishable from random because of the low degree, the low order N terms. And the more samples are given out, the more noise by the higher degree terms will be added. And this candidate, if you write it in a different way, can also be viewed as learning parity with variable density noise, where if you see it like this, you can think of the higher degree terms corresponding to the sparse noise. And the outer XOR is important to ensure that linear attacks fail.  And as already mentioned, the X and F formula is basically sparse multivariate F2 polynomial in inputs and in negation. So what we wanted to do in this work is getting rid of the negation part. So how can we do this? The idea is quite simply, namely, instead of letting the key decide which variable to negate or not negate, is to let the key decide which variable to choose from a set of possible variables. And of course, the simplest attempt, the first attempt that you would try out, is just take two variables. So add another copy of variables to X, and then for each term decide between Xijk and Xijk prime. Unfortunately, it does not work. There's a simple attack with this, because the problem is that the problem is that both Xijk and Xijk prime are zero with too large probability with probability one fourth. And if that happens, the whole end term will be cancelled out. And this is also public when you know the input. And this is what happens for random input, which you get to see for BPRFs. And now the solution is also still quite straightforward. You can circumvent this by not choosing between two, but by choosing between sufficiently many than this, that all of them are zero will happen only with very, very small probability. And this attack does no longer apply. So then instead of Xijk, X or the key, what we will do is having the key pick which of the terms X, which of the variables Xijk to pick. And we can indeed show that this candidate, as the candidate before provably resists linear attacks up to two to the B samples, if now W and B are chosen large enough. And the analysis for this is similar to the previous analysis, but more involved due to the structure. So what you can see here is that the extra layers in the top. So the next question we ask in this work is, what if you allow the X or layer only in the bottom? So what if you go to AC0 on top of parities? As I mentioned before, we're not the first who consider this question. So let's take a look at a candidate construction from 2014. So on the slide, you see the BPRFs here with keys SNK. And the design paradigm is as follows. G is chosen such that it is a function in AC0 that is not to bias. So it has constant bias and it's also called the drives function. And then K is used to hide the heavy Fourier coefficients that we know G has because of the result of linear Mansour and Nissan. And finally, the bias is removed to get from a constant bias BPRF to random BPRF by adding a parity of X with a fresh part of the secret key S. This way of achieving a BPRF can also be viewed as learning parity with simple deterministic noise, where here the noise function is determined by the function, the public function G and the secret key K. This candidate can be shown to resist linear attacks based on a simple combinatorial conjecture. The problem is that it can be broken in quasi-polynomial time by so-called algebraic or rational degree attack, as was shown by Bogdanov and Rosen in 2017. In order to see how we overcome this issue, let's take a look at so-called algebraic or rational degree attacks. The idea behind this attack is that if one can find a low-degree quasi-polynomial H such that G times H equals zero or G plus one times H equals zero, then given input-output pairs, one can solve for H given n to the degree of H samples. So for H with logarithmic degree, this gives an attacking quasi-polynomial time. We call that the AC series circuit in the construction of Akavia et al. is of the following form. Now Bogdanov and Rosen observed that it always holds G plus one times GI equals zero for any of the inner n-terms GI. Therefore, the candidate VKF of Akavia has rational degree logarithmic in the security parameter and can therefore be broken by a rational degree attack in quasi-polynomial time. Furthermore, this is inherent for DIN apps because either at least one of the n's has low fan-in resulting in low rational degree or the function is very biased towards zero and the corresponding candidate could therefore be broken by a linear attack. So how to overcome this? The idea is to consider the two cases of the rational degree attack separately. So call the minimal degree of H such that G times H equals zero, the primal rational degree, and call the minimal degree of H prime such that G plus one times H prime is zero, the dual rational degree of T. And with this, if we reconsider the function from the slide before, a bit more general, just a disjunction of functions, then with the same observation, it's a bit less straightforward than what you saw on the slide before, but it's still very easy to see that the disjunctions in some sense don't increase the dual rational degree. They don't help increasing the rational degree by increasing the dual rational degree because the dual rational degree is just the minimum of the dual rational degrees of all its terms. But on the other hand, what we show in this work, what we can provably show is that it does something to the primal rational degree. Namely what it does, if all the terms are independent, so operate on disjoint set of variables, then the primal rational degree is the sum of all the primal rational degrees of the underlying terms. And so this alone doesn't give much because the rational degree is the minimum of the primal rational degree and the dual rational degree. But now if we look at an N term, it's very easy to see that this just behaves dual to the or. And so there we have that the primal rational degree is not increased, but the dual rational degree is now the sum of the dual rational degrees of all the G line. So by the previous slide, we noted the or increases the primal rational degree and the end increases the dual rational degree. So we can provably increase the rational degree, which is the minimum of the primal and the dual rational degree, just by adding sufficiently many alternating layers. It turns out that we only have to add one more layer compared to the function of a caveat at all. And again, we have to choose the fan in such that the function is not too biased. And this candidate now has high rational degree by the considerations before because we have the end and the or of sufficiently high fan in, so the two outer layers. And further, it again plausibly resists linear attacks based on a combinatorial conjecture. So that was our first candidate. Note here that the parities are secret, whereas the AC series circuit is public. So the next question we considered in the work is, in some sense, can you do the other way around? Can you get a weak pair F in AC0 on top of public parities? So why do we care about this? The motivation of having a weak pair F in AC0 on top of public parities is that it would give a weak pair F that is pseudo random on random code words. This would directly imply a stateless symmetric encryption scheme with decryption circuit fully in AC0 just by plugging in the big pair F and encryption scheme I presented earlier. This is something that we do not currently know to exist. In their work, a caveat all brought forward a conjecture regarding functions in AC0 on top of parities saying that every function in this class has a heavy Fourier coefficient, meaning of size one over quasi polynomial. We strengthened their conjecture by saying that this heavy Fourier coefficient stems from some low order Fourier coefficient by applying a transpose of the linear mapping describing the mode two layer. Similar to a caveat all for their original conjecture, we show that this is provably true if M is a random map independently of the AC0 circuit G and if G is a DNF or CNF independently of the map M. Our strengthening would imply that no weak pair F in AC0 on top of public parities with better than quasi polynomial security can exist. This conjecture together with our weak pair F candidate has also implications to linear IPPP which is the conjecture that the inner product mode two cannot be computed in AC0 on top of parities. Namely, if there exists a weak pair F on top of parities but there does not exist a weak pair F on top of public parities then we show that linear IPP must indeed be true. Finally, in our paper we asked how the existence of weak pair F in AC0 mode two relates to other assumptions. A caveat all already showed that weak pairs on top of parities imply learning parity with noise with high noise rate if indeed every function in AC0 on top of parities has a heavy 4E coefficient. We in some sense strengthened their style by showing that weak pairs in all of AC0 mode two imply learning parity with noise for a specific code and noise rate where our implication holds unconditionally. Further, we show that weak pair Fs that fall into the variable density learning parity with noise framework which includes our candidate weak pair of computed by sparse F2 polynomials imply public encryption under an additional conjecture. This conjecture basically says that if there exists some code that is hard to go with respect to some noise rate then almost all codes are. It is an interesting open question whether this result can be shown unconditionally and or extended to AC0 mode two more generally. To summarize, in this paper we brought forward new candidate weak pair Fs with sub-exponential security. Our first candidate weak pair F is computed by sparse F2 polynomials. It fits into the variable density learning parity with noise framework. It provably resists linear attacks and it also has provably high rational a degree so it's not susceptible to algebraic attacks. Our second result is a candidate weak pair of an AC0 on top of parities. This is the currently only standing candidate which can be conjectured to have full sub-exponential security. This candidate is within the learning parity with simple noise framework. It plausibly resists linear attacks and it has a provably high rational degree. With this I would like to end. Thank you very much for your attention and I hope you got interested and will look up more in the paper. Thank you.