here we go. So we're continuing with John chapter 10, and the Lord Jesus is talking about Him being the good shepherd. And so we learn quite a few things there about the shepherd and about the Lord Jesus himself laying down certain things there as to what a shepherd should do and so on. And especially when the Lord talks about Himself as a good shepherd and also when He says that He is not like the higherling, so we learn from that as well, what we should not be like. Okay, so let's read from verse 11 where he says, I am the good shepherd. The good shepherd gives his life for the sheep. Okay, so he's talking about the sacrificial ministry or the sacrificial way in which the relationship between the shepherd and the sheep. The good shepherd gives his life for the sheep. Verse 12, but a higherling, he who is not the shepherd, one who does not own the sheep, sees the wolf coming and leaves the sheep and flees and the wolf catches the sheep and scatters them. So he's talking about in the face of danger. This is what a higherling does because a higherling does not have a sense of ownership about the sheep and therefore he does not care and leaves the sheep and flees. Verse 13, the higherling flees because he is a higherling and does not care about the sheep. Again, the Lord says, verse 14, I am the good shepherd and I know my sheep and am known by my own. As the Father knows me, even so I know the Father and I lay down my life for the sheep. Another sheep I have, which are not of this fold, them also I must bring and they will hear my voice and there will be one flock and one shepherd. Therefore, my Father loves me because I lay down my life that I may take it again. No one takes it from me and so on. And let's go on to verse 25 and Jesus, this is in response to the question where they say, you know, how long do you keep us in doubt if you are the Christ? Tell us plainly and he says, I told you and you do not believe the works that I do in my Father's name, they bear witness of me. Verse 26, but you do not believe because you are not of my sheep. As I said to you, my sheep hear my voice and I know them and they follow me. And I give them eternal life and they shall never perish. Neither shall anyone snatch them out of my hand. My Father who has given them to me is greater than all and no one is able to snatch them out of my Father's hand. I and my Father are one. Okay, right. So we learn several things here about the good shepherd, the fact that the good shepherd speaks to the sheep, especially in verse 16 and also in verse 14 he says, you know, I am the good shepherd, I know my sheep and I'm known by my sheep. And he lays down his life for the sheep and he says, Verse 27, my sheep hear my voice and I know them and they follow me. Okay, right. So he's talking about the sheep knowing, the sheep interacting, speaking, the shepherd knowing and the shepherd interacting, talking to the sheep, the shepherd leading the sheep and then also talks about how the shepherd or the sheep know the voice of the shepherd and how the sheep follow the voice of the shepherd. So the good shepherd cares, the good shepherd protects the sheep, nurtures the sheep, gathers the sheep and so on. And we saw earlier in the ministry gift of the teacher, the Lord Jesus being an example that he was moved with compassion. When was he moved with compassion? When he saw that the people were like sheep without shepherd. When he saw and then he was moved with compassion and you see the verse after that, in the same verse in verse 634 that he began to teach them. He began to minister to them. He began to serve them, teach them, gather them together. And in fact, he was being the shepherd. So these are some insights that we get about the Lord being the shepherd. Similarly, we learn quite a bit from here, the hard attitude of the shepherd, that the shepherd cares for the sheep, that the shepherd protects the sheep. The shepherd has a sense of ownership about the sheep. Of course, the Lord Jesus, being the creator and being the one who has purchased everyone by the precious blood, so he owns in that sense, he owns the sheep, the ones who are purchased, they are his purchased possessions. And as human shepherds, we are overseers of the flock because he is the chief shepherd and the flock belong to God. So these are some things that we learn from these verses that the Lord Jesus being our example. Okay, so we see some references in the Old Testament as well about the connection between the sheep and the shepherd. Jeremiah 3 and verse 15, and I will give you shepherds according to my heart. This is what God says, and who will feed you with knowledge and understanding. You see that the Lord, when he had compassion on the people, when he saw that they were like sheep without shepherd, he started teaching them. He started teaching them words where obviously spirit and life, he knew the deepest needs and he immediately went about satisfying that or addressing that deepest need. So he started teaching them. So similarly, the shepherd, the Lord saying, and I will give you shepherds, who will shepherd Israel, and he's referring to the spiritual leaders who will feed with knowledge and understanding, feed with knowledge and understanding. Chapter 23 and verse 4, I will set up shepherds over them who will feed them, and they, the flock shall fear no more, nor be dismayed, nor shall they be lacking, says the Lord. So what do we draw from that? The inside that we get is that the shepherd teaches or feeds the sheep, nurtures the sheep with wisdom, with understanding, with knowledge, and that results in the flock not being fearful because they have grown in faith, not being fearful, not being disappointed or dismayed because they have grown in faith and because of the knowledge and understanding, they are grounded, rooted in something that is stronger and it says, nor shall they be lacking. They will not lack anything because of the chief shepherd, because of the words of life that feeds, that spiritually feeds and nourishes the people. So these are some things that we get when we look at what are the practical things that the shepherd or the roles and responsibilities of the shepherd, which Paul writes to Timothy, then we, when we put these together, then we understand, okay, this is what the, as a shepherd, as an overseer, this is what one is supposed to be doing, this is how one is supposed to be ministering as a shepherd, right? Okay, so in Numbers 27, we see, let's just go there, Numbers 27 and it's about Moses, the Lord instructing Moses to lay hands and pray over Joshua. Numbers 27, okay. Okay, Numbers 27 and we read from verse 15, then Moses spoke to the Lord saying, let the Lord, the God of the spirits of all flesh, set a man over the congregation who may go out before them and go in before them, who may lead them out and bring them in that the congregation of the Lord may not be like sheep, which have no shepherd, right?  So we see here, the Lord saying, you know, take Joshua the son of none, but the real need is this, verse 17, that the congregation, that the congregation of the Lord, that the people of the Lord may not be like a sheep which have no shepherd. So he's talking about a person who would lead the people of God, a person who would lead by example, who would lead the people of God into the promise of God, into the destiny of God, which is what Joshua did. He took them into the promised land. He took them into the destiny that God had for these people and he did that. So he heard from God, he got the strategies from God, he heard God's instruction, he received, he obeyed, and of course there were challenges and through it all, he led the congregation of the Lord, as Moses referred to the children of Israel, all the tribes, he led them into battle, he led them into their destinies. Okay, another place very interesting that we see again is in Ezekiel, which talks about the shepherd or what a shepherd should not do. Again, it talks about the irresponsible shepherds and also the true shepherd. Okay, so Ezekiel 34, I think we can just quickly go through Ezekiel 34. Okay, if you're there, verse one, and the word of the Lord came to me saying, Son of man, prophesy against the shepherds of Israel, prophesy and say to them, thus says the Lord God to the shepherds, woe to the shepherds of Israel who feed themselves, should not the shepherds feed the flocks.  The week you have not strengthened, nor have you healed those who were sick, nor bound up the broken, nor brought back what was driven away, nor sought what was lost, but with force and cruelty you have ruled them. So they were scattered because there was no shepherd and they became food for all the beasts of the field when they were scattered. My sheep wandered through all the mountains and on every high hill, yes, my flock was scattered over the whole face of the earth and no one was seeking or searching for them. Therefore you shepherds hear the word of the Lord and we see some harsh things that the Lord says. As I live, says the Lord God, surely because my flock became a prey and my flock became food for every beast of the field because there was no shepherd nor did my shepherds search for my flock, but the shepherds fed themselves and did not feed my flock. Therefore, oh shepherds hear the word of the Lord, thus says the Lord God, behold I am against the shepherds and I will require my flock at their hand. I will cause them to cease feeding the sheep and the shepherds shall feed themselves no more, for I will deliver my flock from their mouths that they may no longer be food for them. So some real warning there and some very strong words from the Lord, a prophetic instruction that Jeremiah delivers and this is what he receives that says that these are the faults of the shepherd. They have not looked out or they have not carried out what they were supposed to do. They have looked after or they have fed themselves. They are just making themselves the priority. The life is centered around them and this is what they did not do. They did not strengthen the weak. They did not heal those who were sick. The broken, they have not bound and they did not bring back what was lost or gather the lost, but look at this, but with force and cruelty you have ruled them. You see the similar thing in the instruction laid out by Peter as well. Peter says that not by compulsion, not by dishonest gain and not as being lords over those who were interested. So here the Lord says by force and cruelty you have ruled them and he says that they have scattered and you have not gathered so they have become prey for all kinds of the beast and they become food and the Lord is saying, you know, I will require my flock at their hand. Again the Lord saying these are, this flock is mine. So I think that's a realization for every minister of God, for every pastor, for every shepherd that the flock is the lords and with that in mind when we interact or minister we will realize that the flock is the Lord. The flock belongs to the Lord and therefore I need to hold myself accountable. I need to do those things, serve in such a way that I give account and it's not a count to any person, any human being but it's the Lord Himself says I will require of the Lord of the flock from their hand. So it's something extremely serious and so here time and again and I think the instruction is of course it's applicable for every minister but more so for the shepherd, more so for the shepherd because here's the flock and the shepherd, the shepherd is interacting and maybe on a regular basis and interacting with the people on a regular basis and there is this tendency to either become because of the family reality, to try to rule, to try to boss over, maybe it's a cultural thing, maybe it's a wrong example in ministry, whatever it is. We look at scripture and we realize that we come to the understanding that this is how the Lord looks at this whole thing of serving His people. So this is what the Lord wants and he says that they shall, I will cause them to cease feeding the sheep which means that that's again a very strong word. One thing is that he is saying I will require from their hand, I need to receive, they need to be accountable. The other thing is that I will cause them, if this continues, I will cause them to cease feeding the sheep. So which means the end of, or the slowly, the influence, the serving and everything just comes to a stop because there is abuse and there is manipulation and force and cruelty. Okay, verse 11, for thus says the Lord God, indeed I myself will search for my sheep and seek them out and we see that in Luke 15 about the Good Shepherd, about how the Shepherd leaves the 99 and goes after the one which is lost. We see that in the parable. For thus says the Lord God, indeed I myself will search for my sheep, seek them out as a shepherd seeks out his flock on the day he is among his scattered sheep, so will I seek out my sheep and deliver them from all the places where they were scattered on a cloudy and dark day and I will bring them out from the peoples and gather them from the countries and bring them to their own land. I will feed them on the mountains of Israel in the valleys and in all the inhabited places of the country. I will feed them in good pasture and their foals shall be on the high mountains of Israel and so on. They lie down and feed in good pasture. I will feed my flock and I will make them lie down, says the Lord.  And then he addresses the flock also, and says, and as for you, oh my flock, thus says the Lord God, behold, I shall judge between the sheep and sheep, between rams and goats.   Therefore, thus says the Lord God, behold, I myself will judge between the fat and lean sheep, because you have pushed with side and shoulder and buttered all the weak ones with your horns and scattered them abroad. Therefore, I will save my flock and they shall no longer be a prey and I will judge between sheep and sheep and I will establish one shepherd over them and he shall feed them, my servant David, he shall feed them and be their shepherd and I the Lord, I the Lord will be their God and my servant David, a prince among them and I the Lord have spoken. So, a word of a prophetic declaration there, like referring to the ministry, the descendant of David referring to the Lord. So we see that here that the Lord comes down on the shepherd and then he says, I myself will do this as a good shepherd and so we have that as an example that he will bind up what is broken, seek that was lost and so on. And he also judges between the sheep, I will judge between the sheep, he says. So we see all that mentioned here. Another reference that we can go to is Psalm 23, which we all know, Psalm 23, where the psalmist declares and he says, the Lord is my shepherd, I shall not want, he makes me to lie down in green pastures, he leads me beside the still waters, he restores my soul, he leads me in the paths of righteousness for his name's sake.  So we see the reference to the good shepherd here that the Lord is the good shepherd, the Lord is the shepherd and so because of that the psalmist saying, I will not be in any kind of, I will not lack anything, I will not be in want and these are some of the things. So we understand that as the Lord Jesus, as he ministered as the good shepherd and we see the example there and we draw a lot of insights on what needs to be done and what should not be done. And we see it's again a serious thing. And yes, we can apply this for all the ministry gifts and we can apply this for anyone who is serving, who's in any kind of spiritual ministry or spiritual leadership and we can definitely apply this, but also specifically for the shepherd, for the one who is called to the ministry of the pastor or the pastoral ministry. Any thoughts, any questions before we move on? We're going to look at some instructions in 1 Timothy, 2 Timothy and Titus where Paul writes and again that is also something that is, it's a broad thing for every minister, but if you notice, the instruction is for, specifically for people who are overseers in a church, in Ephesus and who are spiritual leaders looking after the people. So we're going to look at that. So any questions so far? No? All good? Okay, fine, fine. Let's get going. Let's look at 1 Timothy and right. So the more I read about each of these gifts and the more we see the Lord Jesus being the example, you realize that he walked in it for a reason that we might follow him as well. And here we see the seriousness with which he looks at the one who is ministering. He's saying, I will require the hand, I will require of the flock at his hand. So the seriousness with which he sees this. Also the fact that the way the Lord looks at his people, whom he considers as his flock, we see that someone who are precious, someone he cares about, and he knows he sees the need, he sees the broken, and he sees the condition, the hurting, the broken, the ones who are lost, the ones who are seeking, and the fact that the Lord's heart goes out and the Lord expects the minister, they expect the one who's called to a place of spiritual leadership. Well, the call is exciting with the call is all that. Many times we tend to think it's about us.  Well, yes, we've been faithful in seeking him, probably faithful in equipping ourselves, whatever, but the fact is the call comes from him. So that's one thing. But the other aspect is that invitation is so that we might serve. The word minister itself is the one who serves, that we might serve and serve in this manner, while it might go against popular trends, it might, I'm sure it definitely goes against some of the maybe unhealthy toxic things that are happening in churchianity. But this is scripture. And this is the Lord's expectation. And this is the Lord's yardstick for the minister. So anytime we attempted to think that it's about me, it's all about me, then that thing is shattered. We realize that it's not that, and every time we think that, okay, I'm in a position of leadership, therefore, I can call the shots. And of course, we have to lead, we have to be firm, we have to, all that is true with the vision and all that. But this is the expectation from the Lord that we serve with compassion, that we serve with the flock in mind and what is good and what is beneficial, that we esteem others better than ourselves and not look out for our own benefit, but for the benefit of others as well. And all that comes together. And the fact that the sense of ownership, you can misuse, it can go both ways. We'll say, okay, this is the flock that God has given me. Yes, true. But with that sense of ownership, also, you carry a great responsibility. With that sense of ownership, you also carry the mantle, which means that you serve in a way that is honorable. You serve in a way that honors God and also honors the people of God. So all this, I think it's wonderful that the Lord has put this down, very simple, very clear. So while we might be tempted by it, this is how the pastor next door does it. Or this is how they talk about in the pastor's fellowship. Or this is how popular culture and tradition is in this people group. Well, this is what the Lord looks at. This is what is close to his heart. And it's good that we defer to that and refer and fall back to that standard rather than anything else. Okay, so let's look at 1st Timothy and Paul writing to Timothy, and he's, he looks down and he says, these are the qualities, these are the qualifications. Well, if somebody wants to serve, it's a good thing. But these are some things that we want that person to have. These are some things that should need to be developed in that person, right? Okay, so let's look at 1st Timothy chapter 3 and says, this is a faithful saying. If a man desires the position of a bishop, he desires a good work. Okay, so Bishop, the understanding, we might come from a background where the word bishop brings up all kinds of things to our mind. Maybe it brings a certain uniform, it brings a certain headgear, all that. The fact is that the word bishop simply means overseer, right? Presbyter, overseer, shepherd. So, you know, we need to keep that in mind. I'm just speaking, I'm just, you know, taking out that verse here. It's the old King James refers to it as over, I'm sorry, the modern King James translates this word as an overseer.  And that is all there is to it. And then we realize, and if you look at it, right, it's not a title again, because it's a role, it's a responsibility. And he says here, you know, it's a good work, it's a good work. And one thing is that we see that, well, it's Timothy, who is actually overseeing the spiritual work, okay, who's pastoring this church. And here is Paul laying down some instructions for what are the qualifications for a bishop and overseer. So it's definitely not a title, right? It's a responsibility. It defines the work more than anything, right? So this is a faithful saying if a man desires to do the push for the position of a bishop, he desires a good work and wife, temperate, sober minded, of good behavior, hospitable, able to teach, not given to wine, not violent, not greedy for money, but gentle, not quarrelsome, not covetous.  For if a man does not know how to rule his own house, how will he take care of the church of God? Not a novice, meaning someone who's inexperienced or new to the work, lest being puffed up with pride, he fall into the same condemnation as the devil. Moreover, he must have a good testimony among those who are outside lest he fall into the approach and the snare of the devil. So this is for someone who is a bishop, who is seeking to do a bishop obviously overseeing these were people who were doing the spiritual work of leading people, teaching people, prayer, ministering and so on. Then the other list of qualifications he gives us for Deacon, the ones who are, Diaconos, the Greek word, the ones who take care of the business matters of the church. So for that also you see a similar qualification and it'll be good for us to go through that. Likewise, Deacons must be reverent and not double-tongued, not given to much wine, not greedy for money, holding the mystery of the faith with a pure conscience. But let these also first be tested. Okay, so we're saying they cannot be a novice, cannot be someone new or maybe a new believer, someone not mature. Let them first be tested and then let them serve as Deacons being found blameless. Likewise, their wives must be reverent, not slanderers, temperate, faithful in all things. Let Deacons be the husbands of one wife, ruling their children and their own houses well, for those who have served well as Deacons obtain for themselves a good standing and great boldness in the faith which is in Christ Jesus. So we see all these qualifications being mentioned here and one of the things mentioned here again is not a novice, sorry, not a novice, not someone who is new, not someone who's inexperienced, unless they fall into pride or they become arrogant and that becomes the downfall. So he's saying, set them up for success, set them up so that they thrive and do their work well and make sure. So one of the ways to do that is to test and of course testing would mean maybe a time of seeing them serve but not appointing them as a spiritual leader, seeing them serve as one among everyone and not really appointing them, not really laying hands and saying, okay, here's so-and-so and we are appointing them as a leader but seeing them serve and then that'll give an opportunity to correct as well, that'll give an opportunity for the person to change and so it's like they might do the work but not really carry the damage of not doing the work, not really inflict or create a lot of confusion. So let them be tested and he says, let them serve and being found, being found blameless, so let them first be tested. Along with that we see Timothy, Paul writing to Timothy and he's saying, because we see that Timothy is also actually, he's overseeing that particular, he's doing, he's shepherding rather, the flock of God in Ephesus and so we see some of the instructions that Paul gives to Timothy would apply to the pastoral work as well, the pastoral ministry as well. So right from the beginning he says his instruction about the doctrine, about the purpose of the commandment and the focus to be on the teaching and what he would teach and not giving heed to fables, genealogies which would create dispute and which would not result in godly edification. So that's another thing and the thing is it makes sense because the Lord says, he will feed the people with wisdom, will feed the people with knowledge and instruction and understanding and so if that is what is the objective or the end result then obviously it doesn't make sense to treat what is being taught lightly, to be, to ensure that these are words that will nurture and so Paul, again and again he would say, hold on to those patterns of the sound words that you heard from me and you commit these to others as well. So he would reiterate those instructions. So it makes sense because the end result is this, this is what is wanted, this is what is required and words or the teaching which are chord with godliness and teaching doctrine with a chord with godliness will result in that along with that of course when you lead by example. So he's saying verse 2 that charge some, remain in emphasis that you may charge some that they teach no other doctrine nor give heed to fables and endless genealogies which cause disputes rather than godly edification which is in faith. Now the purpose of the commandment is love from a pure heart from a good conscience and from sincere faith from which some having strayed have turned aside to idle talk. So they are desiring goes on to say they are desiring to be teachers but they don't understand nor what they say the things that they affirm and it has the law has to be used lawfully. Okay, so if it is to just to gain reputation, it is just to, if it is to just to gain social standing and then the motive is wrong and you know what is being taught is not given that importance and the weightage and it results in a group of people not really ending up how they should be right. So he goes on maybe if you look at verse 18 this charge I commit to you son Timothy according to the prophecies previously made concerning you that by them you may wage the good warfare having faith and a good conscience which some having rejected concerning the faith have shipwrecked. So you have faith and you are nourished in the words of God but also you know have a good conscience right which means that you know you're sensitive you're not searing your conscience you're not you know shutting your conscience down based on your motive or your wrong or not ending up in wrong actions and and justifying it you know when that that is when we sear our consciences right when we do something and when we try to justify it and we go against the voice of the spirit then our conscience gets seared you know like Hebrews 3 we see that the sin causes deception right exalt one yourself exalt one another while it is called day and do not be deceived by sin which which causes a hardening right so so this is the thing and then he also lays down certain instructions um inverse uh verse six sorry chapter four and also versus one onwards it's again it's about wrong doctrines and let's just go through that now this spirit expressly says that in the latter times some will depart from the faith giving heed to deceiving spirits and doctrines of demons speaking lies in hypocrisy having their own conscience stirred with a hot iron and you know these are some teachings forbidding to marry commanding to abstain from foods which God created to be received with thanksgiving by those who believe and know the truth okay some of those things right for every creature is good and nothing is to be refused if it is received with thanksgiving for it to sanctify by the word of God and prayer okay verse six um if you instruct the brethren in these things you will be a good minister of Jesus Christ okay if you instruct your the brethren the the ones who are there if you instruct the flock in other words um you will be a good minister nourished in the words of faith and of the good doctrine which you have carefully followed so these are again some instructions to Timothy say saying you will be a good minister nourished in uh faith nourished in these words and also the good doctrine which you have carefully followed reject profane and old wives fables and exercise yourself towards godliness okay not only are you discerning and accepting but you also need to you know surgically reject those things which are not in accord with godliness right and exercise yourself towards godliness then he says bodily exercise profits a little but godliness is profitable in all things having promise of the life that now is and that which is to come this is a faithful saying and worthy of all acceptance for to this end we both labor and suffer reproach because we trust in the living god who is the savior of all men especially those who believe these things command and teach okay so there are certain things that um he says you know you command so it's a mixture of commanding and teaching so commanding is no don't do it teaching is let me explain why you should not do it you know let me explain why it is bad that command and teach right um versus 12 to 16 I think we just look at that and then we'll close um let no one despise your youth but be an example to the believers in word in conduct in love in spirit in faith in purity okay so he mentions uh six things your word in conduct in love in spirit in faith in purity till I come give attention to reading to exhortation to doctrine okay do not neglect the gift that is in you which was given to you by prophecy with the laying on of the hands of the eldership meditate on these things give yourself entirely to them that your progress may be evident to all take heed to yourself and to the doctrine continue in them for in doing this you will save both yourself and those who hear you for in doing this you will save both yourself and those who um hear you okay um they're saying uh so not just the doctrine but be an example in all these ways in all these six ways word conduct love uh in purity in faith in spirit and also talks about you know what happened what he received from the Holy Spirit you know the gift of which was given to you bright by prophecy uh with the laying on of hands of the eldership probably at the time of commissioning him laying on our hands of the eldership don't don't neglect that gift don't neglect that uh teaching uh be strong give yourself um to to reading to exhortation so all this says that you know it goes with uh the responsibilities or the manner in which one can prepare for spiritual leadership leadership and especially of that of the pastoral ministry right so we um uh learn so much from here okay so we'll um we'll stop here um and then we'll continue in the next class uh I'm just going to shut down the recording here um


Keir ron nil, nil draw today. What did you make of the performance? Yeah, tough game against the league leaders, but I thought we battled well and played full ball with me code and obviously we were going to every game wanting to win. I got three points but in hindsight if we look back and take a step back, a point against the league leaders is not the worst result ever. Like you said, clean sheet, taking pride moments from being able to get clean sheet against top of the league at home, a point well deserved. Yeah, I think so. I think we had a few chances to win the game as well. But yeah, I think the back five and up did our job defensively and obviously we kept them out when we kept them quiet for large periods of the game and we did our jobs really. But like I said, we want to win every game, but we're happy with that one today. Are you unbeaten now? Can you take some momentum from that, like you said? It's a draw well earned, but just taking momentum game to game. Yeah, absolutely. We want to keep the streak up, we live as a game, especially at home with the big crowd behind us. Yeah, we want to go into every game as strong as we can and look, we're playing the league leaders today, but we had no fear. We had no fear against them and we wanted to bring the game to them and I'm trying to get to win, but obviously we fell short, but the point was good enough. Yeah, we've had a busy festive period. I know we've got a couple more games to go, but what do you make of all the games we've had over the Christmas and festive period? Yeah, it's a short turnaround. I'm kind of getting used to it myself. That's probably the first time I've played as many games in a short period of time. You don't really do it back home in Ireland, so I'm getting accustomed to that, but I think we're doing well. We're doing the right things off the pitch as well, rest and recover, so we'll be ready for the next match. How do the next game, you do that the goal, rest and recover, and just go again? Yeah, absolutely. It's a very fast turnaround in this one. So we can't be doing too much on the pitch, it'll be more tactical stuff. And when you're at home doing the right things as well, rest and recover.


Okay. Hello again. Thank you for being here. Now we have Robert Partica and this is the vice president of the Polish Linux user group and also owner of the Bobson company and in his talk, The Power to Change, he will ask a question and hopefully answer the question if there is a market for open source. Thank you for being here. Hi everyone. Thank you that you joined me here for this short talk. I will try not to get into the light, at least until I start to make funny faces on the shadow. So the talk is about what I call The Power to Change and I want to convince you that it's possible, it's in your power to shape the world and shape the future because as we all know, the best way to predict future is to create the future by yourself. And of course the best way is to do this according to your own ideas and your own beliefs. Before I start the talk about this, I want to introduce a little myself because you may wonder what this redhead guy, which is a little old, come here, talk to young people and behave like he knows something. As everybody knows, young people know that the old people don't know anything at all about the world. So I begin in the times with the computers, in the primary school, it was 4th grade of the primary school and it was time, who knows what the Amstrad is, or ZX Spectrum. Hi, we are from the same age. It was age of the dinosaurs in the computers. Then there was a big stone coming from the heaven and the era of the modern computer become. In those days, I start to love computers. I start to learn programming. When I get to the university, I found my company, which is called as my stage name, Bobson, which was my nickname for a long time on the demo scene, where I was making open source, not knowing that I'm making open source because everybody knows that the roots of the open source are in the demo scene where everybody shared the source without any license at all. What's the license? So I invented the company, which was invented. I found the company. It will be nice to invent the company. But no, it wasn't that. I found the company, Bobson, and we started to create software and we even started to create software and send software exactly in the open source way, not knowing that it's open source. It was about a year later when I started to get into the Linux and find out, okay, we're doing this exactly as the license said, so why not doing this more? Nowadays, we change the direction of the company. We are no longer the company about the software itself. We become a research company, which are more into the hardware also, but we're based on the open hardware. And we found a funding solution for the people if they have ID, but they don't know how to do this, what they need in the software, what they need in the hardware. We're creating the documentation for them, the prototypes, and preparing the whole documentation for the production. And they get it also, based on the approach from the open source and freedom it gets. So is there market for open source? The shortest answer I can give you as an example from my 70 years of and what's happening now is I landed yesterday in Poland coming back from Sweden from the client. I slept for hours, come here to make a lecture, and I was wanting to stay for a whole three days, but I cannot because the projects which are open source in my company needs my attention, I need to go back. So the short answer is definitely yes, there is a market, but it's not unicorn, it's not something which is only happening good for you because it's open source, but about that a little later. So what's the market? Because everybody tells, okay, there is a market for open source, what's the numbers? That's the information you can get from the Wikipedia. I use those ones because once on the conference about the open source in the Microsoft, we have a little argument because they were having a little different data, and I ask about the source, and it appears because some of the data are from the Gartner that their source was also Gartner. So I ask, okay, if this is Gartner, can I see this report? No, you can't because we pay for it and the agreement don't allow us to show this data. Nice way to get data for presentation from the report, which I cannot show to you because it's top secret report, but I present you the one number, one figure which is from this report. That's why you decide to use only the data which you can check by yourself. Linux share nowadays for this month is about 2.11 to 2.33 of desktops based on the calculation from the usage in the Internet. And those two figures are different because there are two different organization which was measured this. Embedded system, Android Ubuntu and so on, it's about 30%, and those data are already a little aged because this company didn't provide new data for it, so it can be even more now. You can find it on the Wikipedia page. The deeper in the wood, the better. Web servers, 36% or almost 57%. Mind frame, it should be now about 50% because it's prediction from the 2008. And supercomputers, we even don't need to talk about supercomputers. They even sometimes don't know what Windows is. When we look at the technologies of other type of the processors, so not the processors about the PC, so not the internal AMD, but other architecture like M56 or processors which are REM, it's also like almost nobody use the Windows because what for? If you go to the science facilities like Polish facility about the space agency, it's also if you are not a user of Linux, how you want to work with us, that's a question you can get. If you are a student and you don't know Linux at all, you have problem to become an astronomist. And also how much Linux kernel will cost, that's also data from the Wikipedia. With the model of the CACOMO, they estimate that it will be 612 million. European Union make its own estimation. I think it's twice the price from the USA. Something like that if we count also the difference in the currency comparison. So it's quite a lot of money. I think there are maybe two companies in the world now which can afford to spend such kind of money for the developed kernel, maybe three. If we don't count companies which don't do IT at all. I think everybody can name those companies. One have the amount of money in the bank which can cover whole USA debt. So they probably can do this. But I don't think other IT companies can afford such amount of money. So that's the potential which is in the open source world. We don't talk any longer about a bunch of guys which are hippies and they want to develop software but normally they sell carrots because they need to make money for living. They making software because they want to and they want to make money on it. As I told in the abstract which you can read probably on the web page of the QTcon, I told that I will tell you a little about rules to follow and rules to break. Rules to follow is a little more because unfortunately we live in the society or fortunately we live in the society which comes with the rules. So first one, I was really thinking which one should be first and I tell that it's love, it's the first rule which you should follow. And there are two things. First thing, do what you love. If you're doing what you love, you're never working and you really like this what you're doing. But secondly, you have families probably, you have girlfriends, never allow that you're working. It's my 17 years experience as an owner of the company. Never allow work. Cover your life. Have family, have friends, go sometime out. It will make your work better. You will like to come back to work because I want to go out from these people. I want to do something. Holidays all the time are not good. So that's the first and probably primary rule which you follow. But then it's if you're really into being open, don't act only like being open but doing something else. It's quite often that the developers say, okay, I like open source, I want to do open source, but I want to make money so I need to do closed source. If you really believe that the open source is something good. And from my experience, I can tell you that it's also a good business model. It will not solve all problems for you because in every business model, you need to find the client, you need to find something he will want to buy. But follow the ideas you believe to. Because on the other hand, it's something like I'm a Christian but I'm not going to church because why for? Really are you Christian and you're not going to church? So are you really Christian or church or in other places where parts of the Christians go? So follow your ideas and think out of the box because the problem of modern companies quite often is that they are so into how we are ready to arrange something. They are like dinosaurs or scapals from the stone. It's like we have our way of work. It's slow, it's unaffective.  So try to think about the finding solution. It's like you need to try to think because usually people think that way that oh I have a problem or my country have a problem, my city have a problem, my friend have a problem, girlfriend have a problem, child, dog, cat and whatever else have a problem. Don't think about this as a problem. For fierce is a challenge. For second every problem society especially have is a potential for its opportunity for you. If you solve it you probably can make a money on it because everybody should remember that in the rules of open source, in the four freedoms there is nothing about not getting money for it. It's even exactly told by the stalemate. It's not free beer. It's free as a freedom as a freedom of speech. And it's even better if you do money on it because if you do money on the open source you prove that it's good concept for business model. And the more companies start to do this the more people will believe in that because the problem of the small companies for instance is that they just don't believe in that. They don't especially if they are not IT they cannot judge the quality of the product. So how they judge the quality of the product first the size of the supplier. Secondly the price. Usually people if don't know how was the quality the highest price the better. I want the computer which one the best one which one is the best one. I think this with the highest price is the best one. That's how you sell computer as a hardware to the person which has no idea about the quality of the hardware but won't have something best. If you give him something which is really best but it is cheaper than the highest price in the shop he will feel that he's not treated well by you. It's the way the people think. We cannot do anything about that. The usually best way to change the shape the way your boss act is to change the boss because you have the power to change the boss for instance. Next thing law. We live in the countries the countries has law you need to follow this law. We have the 78 I think as I could remember open source licenses which can be used which are approved as open source licenses but you need to know how to apply them to the law which is in your country because quite often the way of applying so for instance if it's need to be signed by two sides or not is depending of the law in your country. Get good lawyer spend some money for the for the lawyer because he will help you in a many situation because for instance the lawyers of your contractor may want to shape the way of how you signed the license how it will be written that at the end it will be not open source license. I have now in fact such exchanging of the changes in the agreement because the contractor on the other side is changing all the time the whole agreement that in fact the open license stop becoming open license. Next thing is you need to pay taxes but you don't need to pay the biggest possible taxes so also get the lawyer he will tell you what to do and you need to that probably in maybe few years they will solve this problem because it's opportunity to make a good money maybe they will do this open source also. Rules to break I choose only two because we don't have one hour for for talk and usually if I choose more than we talking for about one and a half hours I choose only two. First one the IPR intellectual property right what the hell is that for first how you can make a property or something which even don't exist because its property can be to this chair if I have this chair nobody else have this chair even if there is a lot more chairs here but what's the who tell me what's the most overused word by the people which are into IPR piracy yes piracy as I know in the law piracy it's an act of encounter other ship in the in the sea or in the it can be also applied to the to the fly jet but mainly it's about the ship so I'm into fighting with the piracy we can send all our warfare which which is in on the sea to fight the peer pirates in the Africa no problem for that but don't don't even start to talk with people which use this word in the way of intellectual property rights in field rent because it's not this word has the meaning in the law in the international law and there is only one meaning for this word in the international law you can find it also in the vikipedia what's the what's the real mean on the piracy so but you make a software and okay it's your software so what to do with that I don't stop making the problem from this that somebody gets your software if you make it open source it's okay somebody has my software it's even good because it's start to become popular the more the better you in fact break the break the mind problem which the close source companies have they spent a lot of money for fighting people which copy their software and those people sometimes copy this because they just don't have money to do to do anything find the other way to make money on this what you're doing and second it's the old corporate approach to client or corporate old corporate approach to client is of course they behave like they want to kiss your ass when you are when you want to buy something and they totally forget about you when when you already done this and secondly when you read agreement or license for instance from microsoft it's like you should pray to us we thanks that we allow you to install this on only one computer and use this only by by you because if you give this software to your friend on your computer only to use then you break the law quite often I only win with the competitors because I threat people I my approach to the client is exactly what the rules of open source say it's your partner it's not your enemy which you quite often can read that the famous famous sentence before you buy the dvd with the movie as they called legally and first thing which you see you will not download the movies I didn't download this I just buy it why you show it to me so don't don't approach that way to the client approach as a he's your partner talk to him like a partner and then it they usually even don't use their rights which becomes from the open source license and they probably will come to you for the changes because you made this software or you made this software working for them because quite often open source software it's like for everything so it's for maybe not for nothing but it's not really doing what the client wants to so you what you're selling is your work what is work it's energy in time and this is what you should be paid off if you don't working for somebody why you should get a money so how to earn money because I'm talking that it's possible to earn money as I told we for instance searching solutions for the client so we use open source components we use open hardware but client which is not it corporation or they are totally not into it or they even don't want to be it they want the solution if it's open source it's even better for them so they will give you another point because you give them more right more possibilities to to use the the solution than the others with the close a close hardware and close source but you selling them knowledge so the in short the because we have only I think few minutes left four minutes okay in short it's you need to find the you don't selling the software you you're selling knowledge you're selling approach to the client sometimes client wants something in the box so you just putting the copy of Ubuntu with the t-shirt into the box and you're selling this and you're earning money you of course don't selling license for the Ubuntu you're selling the plastic of the CD and the fiber of the of the t-shirt but you're selling this and people like to have box the software is the best selling air in the box you you're buying the game and you have such box with the air inside because there is only paper with the code for the download so if you want to sell air it's just make software boxes and put it in your shop you can find you can for instance use the donations for create software which is probably needed on the market but one one company will not not pay for it but several will probably do if you go to them and tell okay we starting to have such project we need such grant from you this is what you will get from this find client which needs something which is not on the market and nobody will from the big companies will do this for them because sometimes big companies even okay we will do this for you five five million grants why because it's we don't want to write it but we will never tell you that we will not not going to do this for you we will just make a price such high that you will never pay for that so there are there are places in the software designing and software creation where the where you can apply your rules and your ideas and make money on it because as I told open source is for first not about giving to everybody it's about giving to your client in the business model you may do this that you give this for everybody but it's your choice so you need to find the way if it's good for you also to give it to everybody if you have another approach like software as a service with your instant support which will get you money from it and then it's even better give this to everybody because everybody if it's good software or if it's good hardware everybody will attach new code to this so you gaining from the from the giving this to everybody else but you need to always think about it but the the the thing is that you can make a money on it you can charge for it you can tell you need to pay for my work and secondly you you are only giving this to your client if this client will decide okay i'm going with this public because it's open source and i can do this according to the law it it's his choice quite often he is not going to do this because the solution which is exactly for him working only in his environment in a way he has a company organized and everybody else do this differently so nobody will even want this software. Samsung was complaining once on our conference in Poland that they published the code for the drivers for the TV screens and there is a very small amount of people which even download this it may happen making something open source don't mean that you become a famous because if it's software about the about the screens what to do i was about to tell you last about about not least but if somebody wants to know about the approach of the in company which is needed to have then we can do this offstage or in the question and of course if you want to contact with me don't hesitate just write email ask questions tell that i told stupid things also if you want to i will not send something back in the pocket to your house because of that so it's feel free if you go to the web page don't be surprised there is only a logo and the click for the contact because we're changing web page and because of amount of open source project we have now i didn't don't define our check yet for the what's the copywriter is done so that's all from me hope you feel that you have power to change because you do and if there are any questions then please now yeah thank you very much robot let's do a five minutes question answers if there any any questions okay just a moment thank you first pitch once again and i would like to know you you told that you do a lot of uh let's say consulting in order to help your clients to empower the infrastructure workflow whatever so yeah so can you share some insights on what part of your revenue comes from consulting compared to what comes from software development itself just an estimate you mean the amount of money comes from now a day it's in fact half and half so it's half from the software development which is in fact not only software development because we always make a consulting for the architecture and for the design so it's not only write the code according to the specification even if you know that it will never work so because that's what quite often happened uh through in the on the market but we always consult the the solution with the client and second part of the income is from the research in the mostly hardware projects and okay thank you do you believe do you believe consulting will stay around for quite a while yeah i in fact when we decide the answer maybe maybe this will be not answer for your question but then just tell me but when we when we decide that okay we we want to do something new so we i was having friends which was which was great electronic guys and i was always liking to also play with the electronic when i was young so we decided okay we are going to be something right like a research facility also and the next day i pronounced this to my business partners that we are going to do this we was having the first client for it so i think it will stay because we are in fact we have as i told you 50 percent of the income is from this and i don't do any active selling work from now so i think it can even overcome the software designing okay especially that you have a little more things possible to do when you are integrator consultant and so on then only software designer you always need to design some software in it because of course hardware now don't work without the software but okay thanks thanks for being clear any more questions in the audience oh over there does your company sell software to other companies for example or does it mostly produce software is which is relevant for companies or is it also software for like end users people mostly we do the software for the web applications nowadays and some software for the mobiles in most cases is that we are subcontractor or that there is a software company which wants to have something or there is a company which creating a bigger solution and they need software which they cannot produce because they are not company which making software sometimes but it's a rather minority we do software for the companies which are totally not from the from the designing something for the others they just want something for themselves but we always provide this in the there is for first we always have striped rule in the agreement that the open source components are open source and are provided as open source and secondly we give sla for for our software but it's additionally to the normal license of the software which is one of the open source usually it's even not gpl but rather the mit or or similar we have 78 open source licenses to use which are open source so there is you can choose a lot thank you any more questions else i would say thank you very much again thank you also to the ones it was nice to be here


Well, good morning and thanks. As you've heard until recently, our analytic tools allowed us to find gene variants or mutations that greatly affected a person's characteristic or their risk of disease. And non-genetic factors that have little effect on risk of disease in these kinds of these kinds of mutations, for example, hereditary polyposis in which individuals develop a number of polyps in their colon, and they have a greatly increased risk of colon cancer. So we are going to talk today about more recent tools, genome-wide association studies. And my job, as I understand it, is to give a little bit of an overview about causation models, thinking about genes and environment. And then I'll discuss an example of complex disease, etiology, cancer. Okay. So first, to look at causal models and inferences, inferences we can make from study populations. So what I'm trying to depict here is really a continuum of causation, where environment, rather than looking at nature or nurture, which historically people have concentrated on and had debates about nature or nurture, that really this is nature and nurture, that both are important, it's a matter of degree. So on the left side of the continuum, there's more a genetic effect where variation in the genes affects disease risk of the trait that we're studying. On the other end of the spectrum, our environmental factors, our nurture, and they have a greater impact on disease risk or on the characteristic we're studying. So the conditions that we've considered or found today, the kinds of genes that we found, are ones that are primarily due to genetic factors, such as Huntington's disease and cystic fibrosis, then environmental factors have little impact on risk. Now on the other end of the spectrum, are things that are largely environmental if we think of extreme exposures to ionizing radiation or airplane accidents or things like that. Those are things that are largely environmental in nature. Most of the common diseases fall somewhere on the spectrum. So for example, in cancer, there are a number of conditions called hereditary, cancer susceptibility syndromes, and those genes cause a greatly increased risk of cancer, but they're not deterministic. There's other factors as well. So the vast majority of what we're looking at then are somewhere in the middle of this spectrum. So just to take an example of height, that both genetic factors and environmental factors are nutrition, affect a person's ultimate height. So what we're really looking at when we study populations, it will cause a difference in height among individuals. Another one I'm trying to depict is that this is a population in which people are homogeneous genetically for genes related to height. So when we study both nutrition and height in this population and genetic factors, what we'll find is that it's nutrition largely that affects a person's ultimate height because there is no variation in genetics, so we aren't able to find that. In this case, in populations where, in which nutrition is adequate for development of height, for example, in the U.S., what we'll find, most of the variation in height in the population will be due to genetic factors. And finally, when in populations in which there is a lot of variation in nutrition that affects height and genetic variation, we will be able to find both factors. So the point of this small section is that we have a causal model here where both genes and environment affected height, but we can only find it, whether what we find depends on the population study. So if there's little or no variation in the genetic factors, we won't be able to find that. Likewise, if nutrition or environmental factors are somewhat homogeneous, we won't be able to find that. What this means practically is that you can find differences amongst studies or different populations that may indeed be true differences. Differences in study results from populations are sometimes viewed as errors or inconsistencies due to study design, or in fact, they may be real differences because of the nature of the populations that are studying. So I wanted to turn to an example of multifactorial models in complex diseases in cancer. Because I think when we've studied, we've seen people that have a greatly increased risk of cancer or other common diseases, and then we wonder what underlies the other risk. So what this is depicting, it actually is a group of, in this case, a group of women who have breast cancer. And we know that mutations in genes such as BRCA1 and BRCA2 cause a greatly increased risk of breast cancer and other cancers. But what is less clear, or we also know, that only 5 to 10 percent of breast cancers can be ascribed to a known inherited factor such as mutations in BRCA1 or BRCA2. And that's true for all cancers, that there's a small proportion that can be explained by strong risk factors. We go back to the end of the genetics end of the continuum. These others are sometimes, so what might be causing cancer in the 9 out of 10 women in this picture who don't have a known inherited factor? These are also often referred to as sporadic cancers, but they still likely have an inherited component to them. Most cancers come from random mutations that develop in the cells in the body. Cancer is inherently a genetic condition because it's due to genetic changes in the cells. But there are changes that accumulate over a person's lifetime. They're not inherited changes. So let's look at some of the mechanisms underlying both those changes and how they may be repaired or maintained. So just as a quick review that we're really talking about are changes in the double-strand or single-strand DNA. These are the nucleotides that Dr. Collins talked about. And in nucleotides or genes, genes are read in the cell to produce proteins. So if there's a mutation in a nucleotide, then that may result in an altered protein that then has a decreased efficiency or doesn't function at all. And go back to the BRCA-1 and BRCA-2 example. Many of the mutations that cause a greatly increased risk of breast cancer cause a protein that is shortened. So it's a protein that doesn't work properly in the cell. So those actually knowing the mutation, the type of mutation that someone has in those genes can predict something about their cancer risk. So thinking about the changes in the cells, that as I mentioned earlier, cancer is inherently a genetic condition that results from many changes in the cells. And this is depicting normal, this is cells life as it goes along and is replicating. And basically cancer results from cells result from many changes that allow uncontrolled cell proliferation. So the control, the normal control is lost. And what's thought is that then inherited mutations, people who have inherited cancer risk have a jumpstart on this process so that they require either able to accumulate mutations faster because of the changes or may have inherited an important mutation in this process. So cancer arises from a series of mutations in a single cell that then allow the cell to proliferate. Okay, so let's look at what might have gone wrong then for these nine women. So these are some of the factors that can affect cancer development and progression. And they're oncogenes, which are genes that promote cancer development when they're changed or mutated. Tumor suppressor genes actually would normally help control cell growth. And so when those are changed or mutated, the cell no longer has that control, but that control is altered. So that's another type of gene that may affect, will affect developing cancer. There's also a class of genes called cancer metabolism genes and carcinogen metabolism genes. If you think about the exposures that we're subject to every day and, for example, tobacco smoke that carcinogens can do their damage by getting into the cell and causing genetic changes. So the efficiency of getting those exposures into the cells and also getting the toxins out will affect the amount of damage that can be done in the cell. And finally there, that our body has immune surveillance for abnormal cells. And so some, many of the abnormal cells are found by the body and destroyed through immune surveillance. So I just want to look at one example of a tumor suppressor gene, which is DNA repair proficiency. So our cells actually, there's damage to our DNA occurring all the time. And estimates are about 1,000 to a million DNA modification events per cell per day. And that may sound like a lot, but when you think that we have 6 billion nucleotides in our cells, it's a small proportion of that. So clearly we have something that allows us, allows our bodies to repair this damage so that it doesn't accumulate and doesn't cause early cancer or early death. So this, so the damage to the cell can be done by both endogenous mechanisms. So through normal cell processes or also through exogenous mechanisms such as exposures. Exposures to ionizing radiation, exposures to tobacco smoke, different kinds of exposures. And normally these, the damage that's done from the endogenous exposures and exogenous exposures is repaired. And we've been talking about the DNA in the nucleus so far, but there's also DNA in the mitochondria in the cell. So we have a, so it's repaired and then normal metabolism goes on. Well, if these changes go on unrepaired, there's some pathology cell, that abnormal cell that has some pathology. And that can result, as we talked about in cancer, and can also result in two, two ways for the body to control, control damage. Kind of at the end point, senescence, the cell basically goes into a dormant state, a permanent, permanently dormant state and can't replicate. And then apoptosis is cell death, so programmed cell death. So it's a way, kind of an end way for the body to protect itself from the DNA damage. So actually I want to talk a little bit more about these repair mechanisms, because I think that those can illustrate some of the complexity that we talk about when we talk about multiple genes or multifactorial diseases, multiple genes having small effects. So for example, there's different kinds of DNA damage depending on the exposures. And there's two types are single strand damage, which is just a one strand of the double helix, and then there's also double strand damage. And if we think of the single strand damage, there's three types of repair. So if there's one base, if we think of the nucleotide, there's one base can be damaged. And there's, for example, endogenous, damage to endogenous exposures tends to be single base damage. And there's also damage to environmental exposures such as components of tobacco smoke. So there's under this rubric of repair, there underlies many pathways. I got the one minute signal so I'll speed up. So basically the complexity in DNA repair is under this area right here. So there are multiple pathways depending on the type of damage that's done. And I'll skip this slide. This was just to show actually some, a little bit of the complexity of genes that affect the lifespan and that a lot of those are due to DNA repair, dune DNA repair. So to conclude, what we learned about disease theology in population-based studies depends on the populations that we studied, as well as the measurements that we include in the study. So differing results may represent real differences in populations, or they may be due to design issues, that there may be differences in study design that affect the results. And finding the same results in several populations reinforces the finding that it may be real, which we hear a lot about in genome-wide association studies. And I've also tried here to illustrate the kind of a complexity of disease theology can lead to very complex pathogenic pathways, which result in many genes having small effects. And that these complex pathways account for most of the common diseases that we see in the population. And finally, that both nature and nurture are important to consider. Studying one without the context of the other may lead to erroneous or incomplete results.  At your tables for the reporters are microphones, since we're doing this for a webcast. If you're going to ask a question, please turn your microphone on. The little red light comes on around the top of the microphone. And then when you're done, turn it off. But we definitely want to start a conversation around this stuff. Dr. Harris has started off trying to show us very much the complexity of the relationship between environment and genes. And especially as it goes down to the biochemical pathways that are life. So we'll start with your questions for Dr. Harris and then we'll move on. Hi. I have a question. Could you just tell us who you are? Sure. I'm Joanna Schaffhausen. I'm from ABC News. I work in the medical unit. I have a question about the model of the building up of the mutations leading to the development of cancer. It seems like with a lot of diseases, not just cancer, that they come in two forms. One, an early onset that appears to be really strongly genetic. And then the later onset, which seems to be much less strongly genetic, at least that we know of so far. Is it similar for things like Alzheimer's disease or Parkinson's, this idea that, you know, it's a building up of the mutations and the people with the genetics have this head start? Or would it be a different model for other types of diseases? Yeah. So yes, part of, for most diseases that are of adult onset, if you look hard enough, you can find instances with early onset severe disease that tends to be highly heritable. So for Alzheimer's disease, for instance, there are pedigrees where individuals are coming down with a disease in their 30s and 40s. They're inherited in a dominant fashion. And that are mutations generally in Precinellin 1 or Precinellin 2 or in the beta-amyloid protein. But most late onset Alzheimer's individuals do not have mutations in those genes. They tend to have a variation in ApoE called ApoE4. I don't know that in that instance you can draw, though, the mechanistic conclusion about a buildup of mutations. We know that cancer is coming about as a consequence of a buildup of mutations. With Alzheimer's disease, it's more like you're building up some kind of toxic product that gives rise to the tangles and the plaques that you see under the microscope, which appear to be sort of insoluble proteins. And presumably in the early onset form, that gets going very rapidly and leads to the pathology at an early age, whereas in older onset form it's not quite as bad and so it takes longer before the symptoms start to appear. But actually, can we back up? There was one slide here, Emily, that I thought we ought to dwell on for a minute, because while this is the National Cancer Institute slide, so it must be right, I'm actually going to take some issue with the caption here. So what they're talking about here by identifying one of the 10 people with breast cancer is to say that there are instances, kind of like your question, where breast cancer is strongly inherited. A woman who has a BRCA1 or a BRCA2 mutation is presumably what's being depicted here. But that's not to say that the other nine women with breast cancer have no hereditary contribution to the fact that they've developed the disease, because we know that in those other nine women, family history was probably a predictive factor of their risk collectively. It's just that in those other nine women, the genetic factors, the heritable factors were much weaker, and until recently, were not identifiable. I am aware there is a breast cancer genome-wide association study under review, which has identified genes that are playing a role in those other nine women at a very high level of statistical confidence. I don't know when that paper will come out, but you'll be hearing about it, I suspect, in the next month or two. And in a way, this is a bit of a fine distinction that is probably not going to hold up between highly heritable and not so heritable. This is going to be an indication of hereditability from things that are really deterministic, like high-intensity disease. If you have a mutation, you can get that on the screen. So things that have a very low odds ratio, if you can hear about odds ratio, if they want, they don't want to tweak your risk. They kind of will get everything over to you. With the breast cancer example, the women who don't have the, who don't inherit the BRCA genes, oh, Judy Foreman from the Boston Globe and other places, do the sporadic cases also end up with damage to the BRCA genes? We're in the house here, very early, who actually runs the database for BRCA1 mutations. Do you want to answer that question? What's the frequency of somatic mutations? So the answer is that the kind of mutations that we're used to where the DNA actually is, the DNA for the gene is damaged so that the gene doesn't function anymore, doesn't happen very often in sporadic breast cancers. There are cases where the genes turned off by something called epigenetic changes where the gene state is methylated and the gene is shut off, but if we go in and sequence it, it looks perfectly normal. So is that what you're getting at? So there's multiple pathways, obviously, to breast cancer. Even in the sporadic cases, they don't include necessarily the BRCA. Correct. Yeah. There are other tumor suppressor genes where they were found in inherited families, colon cancer is a great example, where mutations were found in inherited colon cancer families and then when we looked at the sporadic cases that most of the population, the same genes were mutated in tumors, but it wasn't the case for the BRCA1 and 2 gene. I'd like to reinforce something that Dr. Collins said about these so-called sporadic cases, that the point of showing that the talking about DNA repair is that that may be one of the many mechanisms that is affected by genetic variations, the efficiency of DNA repair that may underline the so-called sporadic cases and may put individuals at increased risk because they can't quite as efficiently repair DNA damage that causes, that leads to the mutations in cancer. We know that to be the case, for instance, in hereditary non-polyposis colon cancer, which is a fairly strongly inherited form of colon cancer, where the mutations are in the genes that make the proteins that normally act as the spell checker when you're copying DNA. And if your spell checker isn't working, you make more mistakes, you get colon and uterine cancer as a result. David Brown with the Washington Post. Can you say something about the usefulness of populations with extremely homogeneous genetic backgrounds and whether, first of all, how available they are, how you know, how you can test their homogeneity, and are they useful to attribute the function of the environment or are they useful for identifying the rare exception to the homogeneity? That's a great question, and I'm not sure we completely have defined the answer experimentally, but clearly populations that have been derived from a small set of founders and have remained as a group because of the absence of outbreeding, the Amish, for instance, or people who live in Finland who are often the subject of studies because of having descended from maybe only about 2,000 people that moved into Finland about 2,000 years ago. Those are populations that are particularly revealing for rare recessive conditions. Remember, a recessive disease comes about because both parents carry a rare mutation and then they each pass that on to the child who then has two copies of it and develops the disease in a circumstance where you have a limited number of founders the likelihood of having a child that has, in fact, inherited the same mutation from both parents goes up. That's the consequence of inbreeding. So there are lots of diseases of the recessive sort that have been characterized in populations like the Amish or the Finns or the Mennonites or the Ashkenazi, which reflect, I think, that population structure. I guess some of us thought maybe when it came to common disease, looking for variations that were going to predispose to diabetes, for instance, that it would also be more successful to look in a relatively homogeneous population because they would have less of a diverse spectrum of gene contributions. So far that hasn't really panned out. And I think it hasn't panned out because the things we are finding are, in fact, quite common variants. And that means even with a few thousand founders, you have essentially the same spectrum of genetic variation as if you had a few million. A few thousand is enough, basically, to be a pretty good snapshot of the rest of the population. In terms of environment, oftentimes the populations that are genetically constricted are also environmentally more homogeneous because they have stayed together in one place and they're likely to have, many times, same cultural practices. So that is a potential advantage of doing this kind of study, although it doesn't help you so much in terms of disaggregating genes and environment if they're both basically different than you'd see in a general population. I think the bottom line is for common diseases, it's not clear that it has made a huge difference to focus on those special populations as opposed to looking at a more outbred group. I think you did this, Teri Manolio. You did get the idea, though, that if you have limited genetic variability, you are more likely to pick up environmental influences on a disease than if you have much more genetic variability. So that is helpful. And likewise, if you have a group that lives in a very constrained environment, you're more likely to pick up the genetic contributions. Hi, Dr. Collins, could you go over again just briefly the notion of the SNPs traveling together in neighborhoods just boiling, boiled down? Oh, okay. Oh, sorry, Meredith Wadman with Nature. Yeah, it's coming. I was just giving a very quick overview. This will be repeated probably at least twice because I think Teri will say something about it, too.