Okay. It's recording. So in our publication here, right after the chapter on the family of God, we have the subject on the church being the pillar of truth. Okay. But we will take this up next week. I'm going to skip this chapter and go straight to the next chapter here, which is about the church being an army. So these are all the various facets we said that the church, it should have various characteristics as described in God's Word. And that's really interesting. How can you talk about the church being a family on the one hand and then also talk about the church being an army? An army is so different from the way a family is. But God says that these are all the characteristics that he wants in his people, in his body. And we are trying to understand this more from the perspective of the local church as well. So the local church as an army is what we are going to consider for learning now. So the local church as an army, we've already, when we talked about the mission of the church, we said that Jesus said that, you know, I give you the keys of the kingdom and the gates of hell will not prevail against it. So we find that the local church has been bestowed with power and influence very similar to what you see a militant force like the army have. Because if the gates of hell will not prevail against it, you know, we are talking about a very powerful entity. So the church of Jesus Christ, it's not a weak entity, but it's a powerful entity which can engage the powers of darkness and overthrow the powers of darkness. So that is why it's okay to look at the church as the army of God. And rightly so, we find that Paul encourages the believer to put on the full armor of God. So we are engaged in spiritual battle. Are we, when do we engage in spiritual battle? It's a 24 bar 7 thing. And every believer, as long as we're living here on the earth, we are on the mission field 24 bar 7. And there is an enemy against us 24 bar 7. So while we are the family of God, we are also the army of God that should know how to overcome the evil one. Now Jesus has already expressed his intention and given us this mandate of victory. And he said that the gates of hell will not prevail against the church of Jesus Christ. So now it is for us to live this out as God's people and to see the victory against the works of darkness. Now in the writings of Paul, you will find that he uses this kind of war or army language quite often. So Philippians 2, he says he talks to Epaphroditus and he calls this person a fellow soldier along with calling him a brother and fellow worker and other terms. So he calls him a fellow soldier while writing to Timothy. Now he tells Timothy that I want you to wage a good warfare. So with the implication that in the world we have an enemy and we're constantly faced by attacks, challenges that this enemy hurls at us. Who is this enemy? So we've talked about Satan, who is the deceiver. He's the accuser. He's the opposer. He's the intruder. He's the adversary. He is the father of all lies. We've seen the description of Satan and all the things that he can come up with to attack a believer. And the church, however, we just need to be aware of who this enemy is, what his tactics are and at the same time our position of authority and our position of victory. And when we know that the way Paul wrote to Timothy and asked him to wage a good warfare, we will also be able to wage a good warfare. Okay. Yes. Some other terms that Paul uses, he says, fight the good fight of faith. You know, if living as a believer was a cakewalk, you wouldn't use terms like this. There is an enemy to fight. So he's using terminology and reminding us that we are in battle. Fight the good fight of faith. Again, writing to Timothy, he says, end your hardship as a good soldier. Okay. And it reminds us that we need to be committed to the cause that God has called us to and also lead our lives intentionally with focus, with Godly goals and be prepared to face anything that may be heard at us by the enemy. Okay. And while writing to Timothy towards the end of his own life and second Timothy, Paul acknowledges and he says, I have fought the good fight. I have finished the race. I have kept the faith. Okay. So even Paul had this experience of battling it out till the end and who are we fighting against? Paul is quite clear. He says, look, it's not flesh and blood that we are trying to fight, but we are fighting against spiritual forces of wickedness and Satan and his powers of darkness. They are the enemies. So the church has to live with a sense of spiritual militancy. Spiritual militancy is that resolve where we are passionate about overcoming the enemy and we are passionate about being victorious over every scheme of the enemy. We are passionate about resisting the devil. One Peter 5. Peter talks about resist. Be sober. Be vigilant. That's how an army person is or somebody in the defense forces, they are constantly on high alert. Be sober. Be vigilant. Okay. Or have a very, you know, be sober simply means that you're in your right mind. Okay. You're not drunk with wine. Or, you know, you're not in a place where you're not able to make decisions, but be sober. Be in your right mind. Be on high alert. Be vigilant because your adversary, the devil walks about like a roaring lion seeking whom he may devour. That talks about how proactive the enemy is against the believers and against, you know, the church of the Lord Jesus Christ. So that Peter says, resist him. Okay. Resist him. So that is something that we have to learn to do as believers.  The devil is doing this to me. The devil is doing that to me. But a believer who has understood what the Lord Jesus has done on the cross for him or her will walk with a spiritual militancy. So every time you observe some kind of an intrusion, you will know, okay, be sober, be vigilant, resist the devil. We will know how to go against the schemes of the evil one. Right. And that's what we are called to do. And in living this life, you know, carefully and alertly, we are also reminded by Paul, he says, give no place to the devil. So we live our lives in such a way that the enemy has no hold over our lives. Okay, so we have the spiritual armor on. We are alert. We are also told in 2nd Corinthians 211, do not be ignorant of the enemy's devices. Listen, not to say that we have to have an unhealthy curiosity for what Satan does and his schemes are, but just an awareness. Do not be ignorant of the devices of the evil one. So you understand those things and then you know how to resist it. And we know how to fight the spiritual battle because all these enemies are spiritual. So we wrestle against principalities, powers, rulers of darkness, of this age, spiritual hosts of wickedness in the heavenly places. So that's how that is the focus for our spiritual battle. Now, does the enemy want to bring us down, no believer or the church as a whole? Definitely. The enemy's trying his best to get maximum damage, okay, done to the body of Christ. And one of the ways in which he can accomplish that is by attacking shepherds or leaders in the body of Christ. Why? Because you know scripture tells us in Zechariah 13 and verse 7 that if the enemy can strike a shepherd or cause some failure in the life of the shepherd and if one shepherd falls, all the sheep whom he or she were leading, they all get scattered. So he is very strategic in that sense. How can we get maximum damage done to the body of Christ? So he will try to attack in different ways. We as believers, we can be prepared and we can have our guard up and know how to respond or react when certain things happen. So that's more like a response kind of a preparation that you have in place. Even otherwise, you know, you just shield yourself, don't let yourself get into situations where there can be trouble. So in this manner, we can live very, very carefully. Okay. So in addition to that, when we talk about living with spiritual militancy, this chapter here, I'm on page 73, a section that it also talks about how the Great Commission has to do with battling spiritually for souls. Okay. So one is to live sober, live vigilant to resist the works of the devil, to overcome the works of the devil. And when it comes to the Great Commission or winning souls for the kingdom of God, the church has to be spiritually militant, meaning you go after the paths of darkness. You know how to battle against these spiritual forces. And you know, through our prayers, through our worship, we've seen this, you know, how all these things affect the spiritual realm. We can take charge, you know, we can overthrow the paths of darkness and there will be a greater freedom for the gospel to be preached, people's hearts will be more open. So we will be able to take the gospel far and wide. So that's also something the church has to be aware of and use spiritual militancy in order to proclaim the gospel to various people. Okay. Now coming to the next section here, it talks about training believers in this form of spiritual warfare. Obviously, for us to live as a soldier, we need to be told, okay, the awareness has to come in first. And secondly, equipping. So training the believer in spiritual warfare is important. So we have to engage in these things. And as we do that, you know, believers will be in a position where they can put on the whole armor of God. Okay. And whatever be the vials of the wicked one, right. And it's different at different times in our lives for, you know, different people, the challenges are different, right, based on, you know, one second. Sorry. Yeah. So what I'm saying is to be aware of oneself in such a way that you're prepared for whatever the enemy holds at you. And that's not just true for an individual, but also for a local body. Okay. So we understand the schemes of the devil, but we also understand ourselves really well. And that's the way in which we can overcome. Okay. Sorry, Kennedy. I didn't realize you have a question. I just thought it got unmuted by mistake. So that's why I'm muted you. But yeah, I'm reading your question here. It says, how can a local church call for civil disobedience when they're not in the right standing of God's word now that we are an army like in the case of Daniel. Okay. A church call for civil disobedience. Okay. I didn't quite get that, Kennedy. Can we take this question up towards the end if you don't mind? Yes, Kennedy. You're unmuted. Okay. Okay. Fine. Yeah. Thank you. Thank you so much. Okay. So we'll continue then. So yes, equipping believers, training them for spiritual warfare. So that would mean awareness of the enemy, awareness of oneself. And also helping them grow. When Abraham asked that question, I said, okay, we need to trade. We need to equip. So think that prayer, worship. Not everybody will know how to engage. Not everybody will know from the start how to receive answers to prayer or how to engage in spiritual warfare. What results can be sought from that. But when we create that atmosphere, when we provide opportunities in the local church to engage in these things, the people come, they pray, they learn from what is going on and they realize, oh yeah, the power of prayer is working. The power of worship is working. Okay. This is how we pray. This is how we battle the enemy. So just one small example that I want to share is, you know, in the area where I serve, several times we've gone out on these prayer walks and then having times in people's homes where we gather together just for a time of worship, just for a time of intercession, knowing that these are the things that break spiritual strongholds in that territory. So as believers join us for things like this, they are being equipped. They understand, oh, okay, fine. This is how we engage in spiritual warfare cooperatively to share the gospel in the region. Now, in this manner, we can equip them for all other areas. Okay. How to resist the devil? Okay. If this happens, then you go by spiritual weapons that God is giving you, use the word of God. It is written. So equipping of a believer. How do you equip a believer to move with spiritual authority? These are all ways. I'm giving some examples here and we can do that as pastors, as leaders, as mentors. Help believers, help the local church to understand spiritual warfare and use the weapons of warfare. So then they are prepared. They're prepared for daily life. They're prepared for, you know, whatever God is placing on the heart of the local body. Okay. So let's consider the fact that the church, right? The church is supposed to be armed and dangerous. So, you know, Paul again, he talks about the weapons, the weapons of our warfare. And I just mentioned the word of God as one of the weapons, but there are others listed in scripture for us. We can use the name of Jesus, right? We go against the powers of darkness in the name of Jesus. Now, you would recall in Acts 19, when the name of Jesus is used, Paul uses that name to cast out demons and the sons of Sceva. They also try to do the same thing, but it doesn't work. Okay. But the name of Jesus is a weapon given to the body of Christ. It's given to the believer and we can use the name of Jesus for spiritual warfare. Go against the powers of darkness and we will see God's work being accomplished. We can use the word of God. Did Jesus use that when he was being tempted by the devil? The blood of Jesus, right? Overcome by the blood of the Lamb. So what does the blood do for us? I'm redeemed.  So we use the blood of Jesus. We speak about the completed work of the cross. We understand that we are playing in our lives. Our position in Christ Jesus is also our understanding of that and application of that is a weapon that we can carry. Prayer and intercession is something we can use in warfare. We can use praise and worship, also repentance and righteousness. So there are all these spiritual weapons that we can use to destroy the works of darkness and also to bring freedom in our own lives and in the lives of the people around us. So in all these ways, we engage in battle. Obviously, as believers, we may not wake up every day thinking, oh, I am a warrior or I am a soldier or I am in the army. We may not consciously think of it all the time, but what we are saying here is, see, whether we like it or not, we are carrying that authority. And as in when applicable, we can rise up, we can use that authority and we can see the power of God being demonstrated through our lives. So we are engaged in spiritual warfare and we must train believers to move in spiritual warfare. We are anointed for battle. We have talked about how the anointing of the Holy Spirit breaks the yoke. So what brings freedom? It's the power of the Spirit. We are anointing of the Holy Spirit and we are carrying that power as believers. So we must remember that we can function through it and we can see God's kingdom established. And the section here talks about how the local church must intentionally go against the gates of hell. We touched on this also earlier and we said that there are many strongholds.  These can be strongholds of corruption or they can be strongholds of injustice. They can be strongholds of poverty. They can be strongholds of whatever, some form of biases in the society. So whatever strongholds we observe, we are already equipped with the truth of God's word and we are equipped with the anointing of the Holy Spirit on our lives. We are equipped with weapons of warfare. We are equipped with authority, dominion. So we are everything that is required to go against the power of darkness. And we have also seen how a lot of these things in the society have their roots in the spiritual. You have demonic powers instigating several things in our region or in our community. So as believers, we can also intentionally go against whatever God is putting on our hearts. Maybe there is a stronghold of suicide over a city. So how does a believer or a local church engage in this? You might just want to prey on that subject as a community and say, God, we want to see a breakthrough. We do not want to see people committing suicide. We take authority and we go against that spirit of suicide which is working in the lives of the people. We find it in Jesus name, we cast it out in Jesus name.  So what is the target?  Suicide, the spirit of suicide which is operating in the region. And the church militantly is going against it. There is another way of responding which is, if something happens then we will react. But that is not being militant. The church of Jesus Christ can go against the gates of hell because the gates are stationary. Remember we said that. So the mobile entity is the church and the church will go to the gates and destroy the gates. So similarly, if it is a matter of addiction, if it is a matter of some form of crime, it could be a matter of drug abuse. Whatever has a spiritual root to it, as God's people we can engage. We can see those strongholds breaking, getting shattered in the name of Jesus. And that is a privilege that we have as God's people. So we can advance against the gates of hell. Now this is not to say that we don't do things practically. We can also engage in some practical ways of resisting the devil. What about counseling? At the end of the day what is happening? You are taking the truth of God's word in the most simplified way and you are imparting that into people's lives. As you are counseling, you are giving people that compassion of Christ or that understanding. They just want to be heard. It is from the character of God. We are releasing that to the people and that is making a difference. So in practical ways, through spiritual warfare, in different ways we can actually go against the gates of hell. But at the end of the day, the church is engaged in warfare and the church is victorious. So we must never be afraid. God puts something on our hearts and says, I wanted to do something about this area. It might look very daunting. But we are equipped spiritually to take on a spiritual enemy and we must not be afraid. We can engage in a spiritual battle. That is something we must understand. Now talking about the army, we would all agree that the army or the defence forces are about discipline. They are about order. They are about ranks. In a similar way, when it comes to doing life as a church, let's break it down and apply it to the local church. There must be some order. There must be some form of following rank in the body of Christ. Now again when we are saying this, we are not saying go create an hierarchy, a very rigid one and someone is on top and everyone else is under them. That's again not the point. Basically it's order. There are people who are leading and then there are others who are following. There is no rebellion or division or strife in the body of Christ. Things like that. Following rank and order in the prophecy of Joel, Joel talks about how the people of God, they run like mighty men. They climb the wall like men of war. Everyone marches in formation and they do not break ranks. They do not push one another. Everyone marches in his own column. Though they lunge between the weapons, they are not cut down. Joel 2 versus 7 and 8. This is how an army can function effectively. If people are all competing for the position of the commander and nobody is willing to listen, then how will the army take on the enemy? But when there is rank and order, we know so and so is leading. That's chief. They give the instructions. We follow the instructions. There is that discipline and effectiveness in the way things are done. Similarly, even in the local church, if we follow that divine order, there is a blessing in it. There is always a blessing in following divine order. Now again, while we talk about submission, we just want to reiterate that our ultimate submission is to the Lord. We are not advocating some kind of control or dictatorship like an army in the local church. That is not the meaning of what is being said, discipline and divine order. Ultimately, our submission is to the Lord and the way scripture tells us in James 4, we are to submit to God. Then when we resist the devil, he will flee from us. A little more has been added here about being the local church, being the army of God. One is to carry that military mindset. Military mindset is just to be alert. Just to be alert. Every time we notice some intrusion, we go after it. We are like, you can't do this. Enemy, you can't do this. We will not take it sitting down. We will fight against you. We know who we are, we are well-equipped, we are well-trained and you can't do this. Basically, you carry that mindset. Maybe in our regular life, we just go about doing things normally, but as and when attacks come or you hear of a brother or a sister who is going through something, you just move into that mindset and you say, okay devil, I'm not going to leave this. I come against you in the name of Jesus, I resist you. You do engage in battle. Carry that military mindset, but an alert mindset. Military lifestyle is some focus, basically. So Paul, he wrote to Timothy in 2 Timothy 2, verses 3 and 4, he said, end your hardship as a good soldier of Jesus Christ and no one engaged in warfare entangles himself with the affairs of this life. That he may please him who enlisted him as a soldier. So what is Paul telling Timothy? Paul is telling Timothy you need to know that you are born from above and there is a calling on your life. You're living for a mission. Yes, life is happening, everything is there, but we are committed to that lifestyle. We are keeping the focus. We don't entangle ourselves. When you're born from above, you're in the world, but you've never become off the world. We know how to live military lifestyle. Live with focus for the kingdom of God. We continue to serve God while we discharge all the other required duties here. The military discipline, this has to do with not giving the devil any foothold. So whether it is in the area of our spirit maintaining strength of spirit personal strength of the spirit maintaining personal strength of the soul or personal strength of the body in every area. We maintain that the spirit. Why? Because we're told that the adversary he's like a roaring lion. He's just waiting. What's the weakness of the soul? Is there an area of weakness? In some other way, let me get it. When he is so proactive, every believer must recognize that we must give absolutely no place for the devil and at the same time maintain that internal strength as an individual so that we can always be victorious over the enemy. This is applicable even to the church. Everything that I said. The local church keeps rank and order. The local church maintains a military mindset. The local church maintains a military lifestyle and the local church also maintains military discipline. The local church as an army can be very strategic. Since we're talking about warfare and enemy and all that, this strategy is important because we are dealing with a very intelligent enemy. Even the church must be very strategic in the way it overcomes the evil one. Another thought that has been added here in this section is that when the church functions as an army we must remember that not in an army or when war is going on some people get injured. The army generally never lets go of them but they take care of the injured the wounded and most of the times even if there is a prisoner of war somebody has been taken away the army will see how to get that person back. That should also be a part of how we function as a team or a community because when you keep saying army it feels very hard rigid where there's no compassion for anybody. Everybody just gets the job done everybody wins the battle. That's why you are here that is what you are called for but at the same time we do understand that people are growing people are at different levels of maturity within the local body so just the way in an army the wounded are not left behind we must be sensitive and careful to take care of the needs of everyone who is a part of the community. This is about spiritual authority it's about being an army it's about taking on the strongholds of the evil one in the world outside So two challenges to be prepared for whenever we talk about spiritual authority and demons Satan the intention is to create awareness that people can become demon conscious so when that happens we might have to bring them back on track and say no you will be more authority conscious you will be more dominion conscious. Yes demons exist but we have already been equipped with what we need for victory so that can happen people might lose the focus so sometimes it's weird people can become spooky spiritual everything has a demon behind it everything has a spiritual reason behind it but we would need to teach them and say it's not like that give it the right amount of potential then engaging incorrectly so whichever way people are doing that we would correct that so I am just coming back to the chat section over here and Rupa says Victor's mindset true as an army of God we must have Victor's mindset so I will just leave this open for some comments and discussions any thoughts? any questions? Prabhakar has a question here this is with regard to the previous section is it okay that the mentee can be older than the mentor? if the mentee is willing to receive from the mentor that's the most important thing open heart the mentee is older I think it's okay Prabhakar yes sure that's great alright any other questions? Rupa please go ahead it's not a question I wanted to add a small yes yes please go ahead mentorship I think it is not something very formal it happens very informally and it's a connection between two people where each other respect and it's a flow of life from one person to the other it's something not maybe we can make it formal but it's mostly informal I think it's where the mentee accepts the mentor first that person should accept you then the flow of imparting or guiding will happen God has blessed me with many mentors really cherish those relationships it's very beautiful taking that from them that's what I wanted to add and one more thing about being the church the local church being this battle mindset so I just wanted to add we should be always mindful that we are already victors and we are only standing on the promises of God and claiming the victory which is already ours so with that mindset and with God's strength it is easy to win a battle than thinking that we are doing something and striving to gain the victory that's what I learnt I just wanted to add thank you for sharing and it's very encouraging that you have many mentors and it's been a blessing to you just coming back to the chat here Kennedy is reminding us of this question we will take this app civil disobedience yes you are audible I am saying in the case where things are not being taught right or the government is not giving the right direction or they are gaining the truth so how would you advise them both believers and non-believers to resist or to act again is what is being propagated see how would you advise believers and non-believers we can answer that from the word of God we will struggle but the civil disobedience part I didn't get Kennedy this is a case where you are calling for mass action in the case of Daniel they have to refuse eating so how would you how the local church organize that in case of operations for the young ones or for the widows see the local church can instruct its own people to do as the Holy Spirit is leading them to do but I don't think we are here to call for civil disobedience of any sort we can proclaim the truth and if that causes some movement to take place then that's a separate thing it's not like the church is calling people to go against the government yes sure Kennedy thank you I am just reminded of this perhaps sometimes here Charles says shed more light on how to care for the wounded so Charles this is just going back to the family concept of the body of Christ where you understand people's weaknesses and you take care of them in their needs so that's what it means and it's already 1050 so quickly a Christopher says civil disobedience also called passive resistance so I will share my thoughts with you on this I just wanted to say that I am reminded of what is that the Martin Luther movement civil rights movement of the US it was based on a right principle like you don't judge people on the way Martin Luther put it you don't judge people on the colour of his skin but on the content of the character so based on that they just started talking about what is right and then it created the entire movement in the US so the church has such calling people to go against the government I don't see anything working like that because we are instructed in fact we need to honour authority and government but when we speak the truth when we preach the truth and it causes a transformation in people's hearts the civil rights movement is an example the movement just took place because they were fighting for justice that's my understanding and with that we will stop because we have run out of time maybe we can talk about it later in our class thank you everyone God bless you meet again next week so we will just wrap up now maybe Samuel could you just say a word of prayer before we end the class yes thank you heavenly father we come to your presence we take this time to thank you remember you and bless you everything that you have done and you are doing for us we are grateful that you have chosen us to be a part of your great big family we are grateful that you have chosen us you have given us a calling you have orchestrated this day for us where we could come together online and learn about your house about the church about your wish about the power that you have given to the church we thank you for everything that you are doing for us we thank you and we bless person Nancy and her ministry we thank you for her life we dedicate her to you fill her with your spirit as she leads us equips us to be your ministers we thank you for everyone who has been able to attend this call attend today's class bless each and every family here equip us Lord this and everything else we ask you to precious name of Lord Jesus amen amen thank you so much Samuel thank you everyone God bless you have a blessed day bye thank you ma'am thank you thank you bye


There is a famous saying in Tamil that goes like this Unave marindu This translates to there is no better medicine than food But in the present scenario what we have did we have transformed food which is supposed to be a medicine into poison Mindless use of fertilizers and pesticides has reduced the nutrition value in our food and also has damaged the environment around us Although through modern technology and use of fertilizers we have increased the food production and increased the life expectancy of our population the disability adjusted life years is also on the rise There is the increasing prevalence of non-communicable diseases like cancer in our society While talking about this issue what comes to my mind is the silent killer of Kesargad which is none other than Endosulfan See first of all what is Endosulfan? Endosulfan is a pesticide What is meant by a pesticide here? Pesticides are substances that are meant to control pests such as insects, weeds, fungi and other pests So we can say that pesticide is a collective term to represent herbicide, insecticide, nematicide, maluskicide, rottenicide, bactericide and other insect repellent, animal repellent, microbicide, fungi side etc So all these that are used to control the pest are collectively termed as pesticide See Endosulfan is a brown colored solid that may appear in the form of crystals or flakes It has a smell like turpentine but it does not burn It does not occur naturally in the environment Yes this organochlorine insecticide was first introduced in the 1950s This is to control a variety of insects including white flies, apids, leaf hoppers, Colorado potato beetles and cabbage worms So this Endosulfan is a broad spectrum organochlorine This pesticide works as an insecticide and accreside Insecticide means it kills the insects that are detrimental for crops And accreside means it kills the subclass of arachnids which is acre This acre subclass includes ticks and mites See in the year 2011 the Supreme Court of India banned Endosulfan throughout India Now let us see some of its features and the harmful impacts caused by the Endosulfan And let us see why it is banned The first feature is it is relatively persistent and it is semi volatile compound What does this mean? It means that this Endosulfan lasts long in the environment Because they are less likely to get vaporized So this Endosulfan is detected in soil, sediment and water and even in areas where it is not used This is the first feature Secondly it has the potential to bioaccumulate in aquatic and terrestrial organisms Here bioaccumulation refers to the gradual buildup of chemicals in a living organism over time See these are the two major features of the Endosulfan Now let us see what is the issue with this pesticide The main issue is it is toxic by inhalation, skin absorption or ingestion And it causes many health issues Its persistent and bioaccumulating nature further aggravates the problem Due to this it has negative impacts on humans In humans it leads to neurobehavioral disorders, cognitive disorders, hydrocephalus, mental retardation, cancer at anger age and other lifelong illnesses among female children Here what is hydrocephalus? See it is a condition that increases pressure within the head and make the head grow in abnormal size This leads to brain damage and ultimately death Endosulfan causes abnormalities related to male reproductive system also Just look at this image to see the harm caused by this endosulfan It does not stop with this, it also impacts the environment and other organisms It leads to mass death of bees, fishes, birds and also causes congenital deformities in domestic animals See the Burtland report in 1987 defined sustainable development as the idea that human societies must live and meet their needs without compromising the ability of the future generations to meet their own needs See eliminating the use of harmful chemicals like endosulfan is also an important component of sustainable development Let us take effort to conserve our nature to protect our future generation To know more about environment related news and issues, follow Shankara Esakadami's YouTube channel. Thank you


Ronnie Chichot, if you could recommend two books to to someone to read, what would they be? Just two books from any genre. I would say read Dune Okay Frank Herbert's Dune really Understand what Dune is saying Spice is the life Fear is the mind killer Read Dune, another book I would say read Jeff Smith Bone because you everybody needs Some fantasy some amazing Amazingness in their life. Thank you very much for the follow pink QB Salute salute salutations Cheers


all right now the Saudi saying they're going to take action in the future and try to round up anyone who might have been culpable in this action against the Washington Post report is one thing but the financial impact how we respond to all of that is going to be quite another remember we have tens of billions of dollars in state globally this is actually for the time being more important than whatever back and forth we've been having with China Cheshire Krasko is looking into all of that right now Tracy good morning yeah yes defense stocks could be in focus as questions mount for both the United States and Saudi Arabia over the death of journalist Jamal Khashoggi at the Saudi Council consulate in Istanbul earlier this month Saudi Arabia warned it will respond to any quote threats or sanctions against it as its stock market plunged on Monday saw continued volatility this week this following President Trump's warning of severe punishment over Khashoggi's disappearance however just yesterday the president reaffirmed that he does not want to cost us jobs by ending us sales of military equipment to the Saudis they agreed to do this they agreed to spend 450 billion dollars on buying and investing in the United States so I hope we can keep that I hope we don't lose track of that there are plenty of other things we can do the escalating tensions also has some investors concerned that economic sanctions could affect investments linked to Saudi Arabia's public investment fund which is one of the largest in the world with more than 220 billion dollars in stakes around the globe meanwhile oil ended down more than 3% for the week to 6912 a barrel despite the US Saudi stress that maybe of course because of some reports of an increase in oil supplies and we've seen business and political leaders dropping out of the upcoming high profile future investment initiative in Saudi Arabia which highlights the country as a place to do business a number of CEOs including JPMorgan Chase Jamie Diamond Ford chairman Bill Ford will not be attending US Treasury Secretary Steve Mnuchin also canceled his attendance though he will be attending an anti-terror finance meeting with Saudi security officials later this month Neil a number of media outlets including Fox Business CNBC the New York Times Bloomberg CNN and the Financial Times have also withdrawn from the event alright Tracy thank you very very much we do have an update also from King son and who was sometimes you can make this up but anyway the king had said he is ordered his son the prince to revamp the intelligence services which is akin to me you know policing the refrigerator to make sure no one gets into it but that that's where we stand alright let's get the read on the market fall out from all of this Gary Calp on join us Jonas Max Veris and the Stuxwish founder Melissa Armo Melissa contained reaction maybe thinking that there'll be a contained response what do you think honestly I think this is just noise for the market market has much more bigger concerns with the Chinese tariffs and how if that goes into 2019 I think we saw some selling this week but if you look at the selling from last week in the market this week was really a big nothing burger we just were flat this week and really from August until October the market ran up made new highs came back down so we're really trading in that same range in the down in the S&P we were just two months ago which isn't that big of a deal it's not like we've had this huge massive sell-off we're really back at the same price point we were just a few weeks ago so I don't think that this is going to affect the market long term unless it gets blown out of proportion and that's why Trump is being very diplomatic here he didn't rush to conclusions and say the guy's definitely dead and blame the prince we're waiting to see what's happening if there's recordings because that would definitely say what happened and that might be the term since there are and apparently the first time I read this morning was that the CIA has heard or and or looked at at some of them so we don't know for sure on that but I do want to posit with you guys that if it gets severe the president has rightly argued you know we have a lot of big financial commitments with the Saudis 450 billion over the course of the last couple of years 110 billion of that just last year with the defense agreement so a lot's on the line well you've heard the president businessman in chief basically saying we're gonna do business as usual and something you haven't heard from anybody else around the world that we're pulling back from investing with them they're not going to this is about the bucks so I think it's gonna be business as usual as we get farther and farther away from what just happened I think it's gonna be back to all the other things that are affecting the market and I must tell you I just want to add in the markets on the ledge here the Dow is only 5 or 6% off the highs but there's a whole slew of industries at new yearly lows world markets the whole works and if we break the lows that we've seen over the last two weeks I think we've got another big leg down and I'm real worried here I hope we do not break but we're on the verge and could be an economist potentially if a tape comes out you just remember in good markets they'll good markets will ignore bad news in bad markets bad news is look out so I'm watching this is gonna be a big week to two weeks heading into the election yeah but it's turning season Google and Amazon report Thursday night if they if they perform well I mean the market Netflix gaps up 30 bucks on earnings a growth name drops $45 in two days that's what the market's doing right now that continues this and Jonas maybe you're gonna be with us because there are a quick few ways to look at the Saudi for oil to most this point of nothing burger there and ended up not doing much defense stocks originally hit and then they came back so the areas that you think would be quickly hit including the Saudi currency and the Saudi markets which were everything kind of came back right because that's like the 1970s impact of the Saudi Arabia situation there's the oil pipeline is not the problem that oil is gonna go into some market now China where it's not like the old days when we were getting a lot of oil from then they would just cut us off and oil price with skyrocket the pipeline out of Saudi Arabia is cashed to the venture to to the tech companies at this point you know let's not forget Saudi Arabia now is on the way to having the biggest world sovereign wealth fund they have almost 5% stake in Tesla they just give a billion dollars to another another American electric car start up lucid they are a they're turning their oil revenue slowly into an investment fund of epic proportions that keeps Silicon Valley it's one of the major sources we want to be part of that of course we do which is why in some ways presidents not being diplomatic which is possibly good the end of the day investors know Saudi Arabia isn't really the enemy Saudi Arabia is one of the safest places to be a journalist in the world believe it or not they if you go to the APG a committee to protect journalists which is a very excellent site with a database it's almost a thousand journalists killed since 93 it's only one in Saudi Arabia and that was by al-Qaeda in 2004 because I didn't think it's disproportionate nothing against my profession but the one thing I will say this new reticence open forward thinking government Gary has arrested and detain you know a lot of dissidents it has and this is the crown prince of crackdown on his own family and imprison them albeit in a rich problem right but but extracted a hundred billion dollars from my point here is that they're not saying and to all of your point earlier that you know we don't expect that in this region of the world but it is a reminder how this one journalist death tragic though it is has disproportionately skewed the picture look it's a lot of saying of one thing but doing another and drop the news on the 15th page of the newspaper so nobody's really talking about look there's still plenty of bad people still plenty of bad places around the globe but it doesn't want to hear a straw no the hope is is that yes this prince is going to bring the culture up to snuff but then this happens and you know I think I'm going to see you guys a little bit later but I do want to show you something else we're following very very closely this caravan that all of a sudden has ballooned to become a major international crisis at first it was a few hundred now we're told a few thousand now we're told stuck on a bridge not happy being stuck on a bridge and now there's trouble at the border not our border yet the Mexican border with Guatemala and it is getting nasty very very nasty and the president has said either you contain it Mexico or else what does or else mean after this


The smooth particle hydrodynamics, SPH, method was used to predict the effective thermal conductivity of porous media. The accuracy of the simulations was verified against ideal homogenous and multi-layered media. A concise method was also developed to generate unsaturated media using the SPH framework. The results of the simulation showed that the reciprocal of the normalized thermal conductivity and the reciprocal of the saturation are linearly related, which is consistent with the empirical formula proposed by Coat and Conrad. This article was authored by Bing Bai, Yan Wang, Ding Yu Rao, and others.


Well, it is a distinct honor for me this morning to introduce to you and to welcome back to Gustavus, Dr. Michael Blaze, the first Gustavus alumnus to be a presenter at a Nobel conference. While I was gathering some information for this introduction, I contacted some friends and some emeritus faculty and what, the one or two remaining faculty that had Mike in class while he was a student at Gustavus. And to a person, they remembered him. In fact, they remembered him quite well. So I started looking a little deeper, hoping I might find some little story or foundations for a story or two that I might share with you. And as I was talking with his daughters about this, they're kind of perked their interest a little bit, and they thought maybe he'll find something that's a little bit shady here, you know, that we can hold over old dad's head, but they were disappointed. I apparently, but I did not delve into his fraternity activities or a lot or into some of the other extracurricular activities. So maybe I talked with the right, with the wrong people. But so I really didn't, it was kind of disappointing to them, I think. I couldn't come out through with that. What I did find was unanimity, though, amongst these faculty and praising him as a student and a respected person around campus. He spent only three years at Gustavus going, attending the University of Minnesota after three years and transferring some credits back so that he graduated with the class of 1961. Although he did not create any unusual kinds of waves at Gustavus, he certainly has done so as a medical clinician consultant and research scientist. He became involved in immunological research while a medical student in the highly acclaimed immunology laboratory of Robert A. Good, the University of Minnesota. After an intern in residency program, he joined the National Cancer Institute or the National Institutes of Health in 1966, where he has worked for 26 years. Currently, he is head of the cellular immunology section of the metabolism branch and is very active. In the NIH clinical center. His work with rare immunodeficiency diseases in children had earned for him worldwide recognition. But more recently, he has integrated his clinical and research background in immunology with molecular biology and using the tools of molecular biology has been able to help develop gene replacement techniques that may open a new era in medicine where certain genetic diseases may be contained or even conquered. And in the well-known landmark experiment in 1990, Dr. Blaze and colleagues, Dr. French Anderson and Dr. Kenneth Culver, performed the first federally approved use of gene therapy on a human patient. This patient was a four-year-old girl with a denizen, deaminase, or ADA deficiency, a condition that paralyzes the immune system. And I'm sure that Dr. Blaze will discuss some of the results of this historical event. I believe that event also will be there are plans to include some of that the mementos and so on from that event in a history of American medicine being set up at the Smithsonian Institute. He continues his research interests in other immune, immune deficiency disorders, cancer, and AIDS. Dr. Blaze is the author or co-author of over 250 publications. He served as consultant, presented numerous lectures around the world, received a number of prestigious awards, and his active and other professional activities, as indicated in your program. But what is not mentioned in your program, but I think appropriate to emphasize here, is the distinguished alumni citation in medicine that is awarded to him by Gustavus Adolphus College in 1983. His concern for and willingness to contribute to the encouragement of young developing scientists is indicated by his involvement in intern programs. A number of Gustavus students, plus other undergraduate students from across the country, have had the privilege of interning in his lab while participating in the normal volunteer program at NIH, and he has maintained a contact with a number of these persons. And they remember his very warm and considerate and somewhat laid back demeanor, but also his keen interest, his high energy, his knowledge and the competency in his lab. I also would like to extend a hearty welcome to the members of his family who are here with them. This is sort of a double as a homecoming and a family gathering. His wife, Julie, is here as a Gustavus graduate of 1962, his daughter, Elise, a graduate from 1989, Christy, is a currently a student at the University of North Dakota, and his father, Robert, from Minneapolis. His daughters have assured me that dad is just a wonderful speaker. So I'd like you to join me in welcoming Dr. Mike Blaze, who will talk on the topic Gene Therapy, Medicine for the Future. It's really been a special thrill for me to be invited back to the Hill and to be invited to share this podium with the distinguished scholars and scientists that we've already heard. It's extra special for me because my family is here and especially because my dad is here. In all the years I've been in science, he's never heard me give a lecture about what my work is, so if you talk about pressure, we've really got it this morning. As I've been listening with you to the wonderful talks that we've heard yesterday by Dr. Manasaroff and American Gallo, I've been pondering about how to present my story. In these days of high-tech science, advances often take the contribution of many different individuals with a variety of different skills and talents and backgrounds. One part of this team of individuals is the physician scientist. It's our job to take the insights that have been gained from the basic scientists, so wonderfully presented in the last three lectures, and to try to figure out ways to apply these advances in knowledge to the treatment of human disease, that is to help our patients. What I've decided to do this morning is to take you on a quest with me. I'll try to share with you some of the sense of excitement and frustration, some of the advances and retreats and re-advances along the road to try to develop a new kind of therapy for human disease, that is gene therapy. To begin with, if we're going to talk about gene therapy, we should discuss a little bit about genes. Genes are the set of instructions or the blueprints of life. They're the set of instructions used for the assembly and function of all living things. So people have genes, mice, insects, pine trees, wheat seeds, bacterium viruses. All of the instructions that make up the development of each of these different organisms are related to genes, and all of the genes use the same fundamental coding apparatus. In human cells, the genes are located within a cell in the nucleus, and they're arrayed along structures known as the chromosomes, which are made up of long chains of DNA. It's the DNA that contains then the genes that we're going to be talking about. Let's start off with a definition so we can at least begin at the same point about what we're going to say that gene therapy should be. And we're going to call gene therapy the insertion of a gene or genes into human cells to get a new set of instructions to those cells. And you can think of at least two different ways to apply this technology. One would be to repair or correct an abnormal gene that has led to a disease. There are over 4,000 genetic diseases of man. You've all heard of sickle cell disease, juvenile diabetes, cystic fibrosis, and some of the diseases I'll be presenting later on are much rarer than these. But this is potentially a very powerful technology to use this coding information to treat other disorders. As you can also think of providing a new or an enhanced function to a cell. That is, if we could figure it out, we might be able to add resistance to T cells so they can't be infected with the HIV virus. Or we may program a cell to be more effective in attacking and killing cancer. So this is the kind of context that we're talking about for gene therapy. I'm going to pose some questions for you and I'm not going to give you answers to these questions, but I'd like you to think about the implications. Let's assume for a moment that you're all physicians and that you're dedicated to helping your patient. And now we're going to have several situations to think about. Let's assume that you're caring for a child with a disfiguring, extremely painful, and untreatable genetic disease. We may have another situation where the parents of a child with terminal cancer plead with you to help their child. You may have a couple of already had one child die from a disease that was inherited from them and they come to you and ask you to fix them. So that they won't pass that trade along to other children or to their grandchildren. You may have parents come to you with their newborn infant requesting that you give the child a treatment to increase for IQ to 250. You could have a couple come to you and ask that you treat them so their children and their grandchildren will have IQs of 250. A professional mining engineer might come to you and ask that you treat him so that he will be able to work in an environment heavily contaminated with asbestos so that he does not develop cancer. But you could also have a company come to you and ask that you develop a treatment for its employees so that they can work in an environment filled with carcinogens without incurring the liability for that company of inducing cancer. Interesting questions. There are many ideas about where to draw the line for this kind of technology. I think we could probably all agree or most of us will agree that the application of gene therapy for the treatment of a desperately ill child that has no alternative therapy is an appropriate use of this technology. Many of us would feel very uncomfortable with the idea that as a condition of employment you would have to accept gene therapy to make it resistant to something that might be in the environment of your workplace. Well, where do we draw the line and who decides? And all we can say at the moment is that line has not been drawn definitively. But there are some organizations, some structure in place to help us decide. And the principal one in the United States is the Recombinant DNA Advisory Committee at the NIH. And this is a committee that's made up of physicians and scientists.  And they discuss the ramifications both medical, the possibility that we might be successful, but they also discuss the ethical implications and it's this body that must give us permission. So there's someone out there looking out for your interests. There's someone asking these crazy scientists the hard questions and making us justify that what we want to do is within the bounds of at least what society believes is appropriate today. The Food and Drug Administration is also involved in giving approval for these different proposals so that you know that the materials that are being used are appropriate for human use. Well, one of the questions that was raised on that list of questions that I gave you was the issue that we'll talk about saying somatic cell versus germline gene therapy. What does this really mean? We talk about somatic cell gene therapy as the insertion of genes into the diseased tissues of the patient only. So that you try to correct the disease cells but you specifically avoid introducing these exogenous genes into the reproductive tissues of the patient so there's no possibility that they could transmit these genetic alterations to their offspring. That latter technique would be called germline gene therapy. So if you want it to be fixed so your children don't get a disease and you don't transmit it to your grandchildren, the only way we could really do that would be to affect your reproductive tissues and to remove a defective gene or alternatively add something to it. Now it's been the decision of the Recombinant DNA Advisory Committee in this country and in fact in all countries in the world that are considering these kinds of technologies that will restrict all of our efforts at least at the moment to somatic cell gene therapy. But I'm sure in the future there are going to be discussions and that we as informed citizens are going to have to keep aware of these discussions about the potential uses and potential abuses of germline therapy as this becomes technically possible. Well how do we achieve gene transfer without exposing the germline to these exogenous genes? And so I've listed a couple of things here called ex vivo and in vivo treatment. In vivo treatment would mean that we would take the genes and we would infuse them into the patient. Now there are many genetic diseases where you might have to do this procedure and we can talk about it later on but it's a real problem because obviously if you infuse genes they have the opportunity to reach the sperm and the ova. That is they have the opportunity to reach the germ tissues of the individual. So at the moment we're not going to consider doing in vivo therapy. What's the alternative? Well the alternative is something called ex vivo treatment where you remove the diseased tissue from the patient, take it to the laboratory and attest to, insert the corrective genes then in the laboratory and then re-infuse the corrected cells back into the patient. So we're going to focus at least initially on this ex vivo treatment and there are some real constraints now about the kinds of diseases that we can think about treating. What cells can you remove from the body and effectively put back? Well we know that you can do bone marrow transplantation so you can take the bone marrow from someone. Theoretically you can remove skin or some of the cells lining the blood vessels or the immune system cells that they'll emphasize that we've heard about in this conference. It might be possible to remove liver cells, possibly some kidney cells but there are lots of cells that you can't effectively remove.  So we're very restricted. You can't remove all the skeletal muscles from a patient that has muscular dystrophy, fix them and give them back. So this constraint of doing ex vivo therapy severely limits what we can do at this stage in the development of this kind of therapy. Alright now as physicians we're going to think about what are the candidates that are going to meet these requirements that we've talked about. First of all we certainly want to pick a disease that's a very serious and life threatening disorder. This is a new technology, it's not trivial and we don't want to try it on something that really doesn't need extreme kinds of treatment. We obviously have to have a disease where we've isolated the gene. As I said there are more than 4,000 genetic diseases but the number of genetic diseases where we actually have isolated the gene that's responsible for that is a relative handful. It's growing every day and part of this human genome project that you've heard about in the press is to try to map the entire human genome so we have the genes available so we can study them, understand how they work and potentially apply them for treatment. We want a disease where the treatment is not adequate. If you have a perfectly satisfactory treatment there's no sense in taking any potential risks of this kind of new treatment. Some technical issues we want a gene with simple regulation. What does that mean? Well let's say that you were going to try to do gene therapy for diabetes. That you would want to give an insulin gene. You know that the amount of insulin in the body changes drastically with time. It depends on how much carbohydrate you have in your meals. So that would require a gene system that would allow insulin production to respond to those physiologic signals. That's really a tough problem and it's too hard for us to approach just yet. So we want something that we call a housekeeping gene. A gene that's simply been turned on and works at a certain level and doesn't have to be modulated in its level of expression. We want a gene for a single-chain protein. What does that mean? Well a lot of the proteins in our body are actually made up of multiple chains of protein that are coded for by different genes. One example is for instance hemoglobin, the red pigment in your blood cells. Hemoglobin is made up of two different chains. But during development from the time of the fetus to adult there are actually four different hemoglobin molecules that are expressed at different points in differentiation. Well to do gene therapy for a hemoglobin disease you'd have to put your corrective gene in and then figure out how to get to express at the appropriate time in development so that it only came up when it was needed. Now that is also a very difficult problem so we're going to be restricting ourselves to situations where we only have a single chain that we have to worry about. So related to that is we want a disease where the defective gene does not produce the pathologic gene product. What does that mean? Well all of you have heard about sickle cell disease which is a hemoglobin disease predominantly of blacks where the hemoglobin molecule becomes rigid and so the red cells cannot squeeze their way through the capillaries. Now that's a defective gene that produces a defective gene product. So even if I knew how to put the correct hemoglobin gene into those patients I'm going to have to figure out how to get rid of the bad one. So I have two problems and again that's a difficult problem that we're just not going to be ready to handle. And finally as we've already discussed we need a tissue that permits exfivo treatment. And the disease that fit those criteria are best illustrated by Chelsea here one of our patients with severe combined immune deficiency. Severe combined immune deficiency was popularized I think in the press if you remember back a number of years to David the bubble boy who was put in a plastic bubble from the time of birth in Houston where he lived. He was kept in that isolated sterile environment of a plastic bubble until he died at about the age of 12. He was put in that sterile environment because he had no defense system. He had no T cells or B cells and so his immunity basically did not develop and he would have died of overwhelming infection with just a matter of weeks if he was removed from his plastic bubble. Well Chelsea here has a similar problem but we know the gene that causes Chelsea's problem and it's a gene for a protein enzyme called adenosine deaminase or ADA. We know that Chelsea's disease can be cured by bone marrow transplantation and that's very important because now if we can cure her by giving a brother or sister's bone marrow we can also potentially remove her own bone marrow insert a corrective gene into that bone marrow and then give it back to Chelsea. So one of the requirements she would fit this ex vivo treatment model. We also know that the ADA corrected cells in this disease should have a what we call a survival advantage. What that basically means is that the cured cells will ultimately take over from the defective cells in her body.  We don't have to add any extra insults to her like total body irradiation or chemotherapy that's often has to be used with bone marrow transplantation. Now this slide is going to show us the pathway for the chemists in the audience. This is deoxyadenosine which is a toxic substrate that accumulates in the body of these children because they're missing this enzyme adenosine deaminase. And what ADA does is remove this amino group and convert deoxyadenosine to deoxyenosine which can then be excreted in the urine or removed by other catabolic pathways. Now in the absence of ADA this compound which is ordinarily not found in cells accumulates to very high levels. And unfortunately as it continues to accumulate it gets forced along one metabolic pathway in the immune cell specifically. And it becomes phosphorylated to make a compound called deoxy ATP which is a poison and it kills the immune system cells in these children. So basically these kids end up suiciding their own immune system because they can't get rid of this toxic substrate. Now as I mentioned the strategy here is to try to put the corrective gene in the bone marrow stem cell. This slide looks at the development of our immune system and our blood system. So down here in the bottom are all the mature cells that are found circulating in your blood. They have the red cells and the different granulocytes and monocytes and the T and B cells from the immune system. And we know that all of these cell types originate from a particular specific grandmother cell that's found in the bone marrow that we call the bone marrow stem cell. And as you need more lymphocytes the stem cell will differentiate to different progenitor cells which will ultimately give you a mature T cell or B cell and so forth. Now for gene therapy what we would like to do is put the gene up here. That would be the ideal place because if this cell is genetically corrected then it's called upon to give off daughter cells to make red cells or T cells. All of those cells will be genetically corrected. So one treatment should theoretically cure the patient's disease. And so that's what we're going to be focusing on to try to do stem cell gene therapy. Now how are we going to get the gene in? Well there are lots of ways in the laboratory that we have for tuning genes but nature has been working on this problem for several hundred million years. And we might as well try to take advantage of what nature has been doing and nature in fact has infectious genes. Those are the viruses. And so what we're going to try to do is develop a strategy for taking infectious genes from nature and changing them so that they do our business for us without causing disease. And we're going to focus on the retroviruses, something that you heard about extensively from Dr. Gallo yesterday. Now Dr. Gallo showed us a slide similar to this. Let me explain why a retrovirus is particularly interesting for our purposes. If you remember back to that slide that had the reverse tree structure going from a stem cell on down, you have to recognize that each time a cell divides you have the possibility of losing an inserted gene. If you put DNA in there it can be diluted out as a cell goes through multiple steps of division. So what you really want is a gene that will go into the nucleus and stick itself into the chromosome. So as the cell divides and the chromosomes duplicate themselves the new gene will go along with it. So we're looking for a gene insertion process that would integrate. Remember Dr. Gallo told us that retroviruses integrate into the genome. What does that mean? Well here's a retrovirus that binds to the cell surface receptor. And it inserts its RNA into the cell along with some little dots here called reverse transcriptase which convert the RNA molecule into DNA which can then go into the nucleus and it inserts itself randomly into the chromosome of a cell. Then that gene is just like any other gene along that chromosome. It can be transcribed and translated into proteins. In this case the proteins are going to be the virus protein so that this virus can make more viruses. But this is a very attractive feature. This is the ability to integrate because it would suggest that if we can figure out how to use this system for gene transfer we'll be able to integrate the genes into the chromosomes to be able to handle something like the immune system which is actively dividing. Now you heard about retroviruses and they sound nasty things aren't they? I mean HIV is a retrovirus. So what we should do is to try to use the properties of the virus that integrate but get rid of the bad parts. And this is a very simple series of slides that are oversimplified but if you remember Dr. Gallo said that the retroviruses, at least this is a mouse retrovirus called the Maloney-Muring leukemia virus and it only has three genes. It's the simplest of viruses. And it has these things out on the ends that are called the long terminal repeats which Dr. Gallo pointed out are the places where this virus will integrate into the human genome. So we'd like to keep these parts but we want to get rid of the bad genes from the virus. So we're just going to cut them out and throw them away and then glue in the place a gene of interest. Now it's not quite that simple but you got the idea. Now this particular gene is a gene that we've taken from a bacteria. This is a gene that actually encodes for resistance to an antibiotic called Neomycin. Now you can put, so now we have a virus that we're putting a bacterial gene in and let's make it more complicated, let's put another gene in there. We're going to put in the human ADA gene. So now we've made this complex structure which still has the long terminal repeats so it should be able to integrate but there are no viral genes left in there. So it can't produce more viruses and it can't cause disease. So we're going to try to take advantage of this hybrid guy now to insert the ADA gene into some T cells from patients with this disease. Now this is a data slide and let me explain this a little bit. We've taken T cells from our patients and T cells will grow very actively in tissue culture and that's what this shows.  And now we're going to challenge those growing T cells with that toxic substrate, the deoxyadenosine. And the red line here, I'm sorry these are not drawn very well but this line here is what happens to normal T cells. And you have to get out to a very high concentration of deoxyadenosine before you inhibit the growth of the normal T cell. You have to get out to about a thousand units of deoxyadenosine. This is a T cell line made from Jimmy Fox who was my first patient with ADA deficiency and you can see that Jimmy's T cell line is inhibited by only about 3% as much deoxyadenosine as the normal.  And we're going to take this population of cells and we're going to put that ADA virus into it. And lo and behold, here's what happens when you put the ADA gene in using the retrovirus. You can metabolically cure these cells using this technique. Now this was very exciting data that we had back now, seven years ago, but in 1985 and we were wondering, gee, we can cure these cells and we start treating these patients. But we thought before we went into patients that we really ought to step back and think about it a little bit and to try to show that this technology would work in an animal model and particularly in a primate. Now there's a problem here in that we don't have any ADA deficient animals. So we have to figure out some way of testing it in a system that will tell us whether it potentially could work. And since these techniques have never been used in man, we went to non-human primates that would be as close to man as we could do. And we did a bone marrow transplant with this gene therapy and let me work you through this. So we took rhesus or cinemologous monkeys and we isolated their bone marrow and we mixed it with this retrovirus vector to insert the gene into the bone marrow cells. While this was going on in the lab, the monkeys received total body irradiation to kill off any bone marrow that was still there so that when we gave them the bone marrow transplant they would have to get their marrow from the infusion. So that hopefully if the gene went into these cells when these animals recovered they should now be producing human adenosine deaminase. And this is the result from two of our monkeys Bonnie and Clyde.  But here's the effect on the white blood cell count of these animals that got total body irradiation.  And then the bone marrow transplant starts to work and you can see the white count came up to normal. And we got very excited out here at about two months when we started to detect the human ADA protein in the blood cells of this monkey. And we got even more excited when the value started taking off and then our emotions went the other way as we saw this very drastic fall off and finally the disappearance of the human protein in these monkeys. Now this isn't going to work. This is the best we can do for gene therapy. There's no sense in going ahead. And it was a very bad time for us because we couldn't figure out what was going on why it wasn't working for us. And I'd like to, I mean what happened is it didn't work and where do we go? I don't know but let's think about where we might go. We can think about what was the problem and the problem comes back to this initial diagram that I showed you. And we're trying to get the gene in up here in this toticotin bone marrow stem cell. Well one of the things that Dr. Gallo mentioned yesterday about retroviruses is they only insert their genes into cells that are actively dividing. A cell has got to be synthesizing DNA for a retrovirus to insert its gene. And unfortunately this cell is usually just sitting there. It's not actively dividing so it's not susceptible to the gene transfer system that we're using. And what happened in Bonnie and Clyde is that we got the gene way down in here. These cells are very actively dividing because they're actually providing the peripheral cells with the mature blood cells and lymphocytes that we look at.  They'll synapse and be replaced by a more immature cell that never got the gene. So we see this burst of expression of our introduced gene but it disappears. Well we're really frustrated now because we couldn't seem to get the gene in the cell we thought we had to get it into. And then it occurred to me as I was writing a chapter for a textbook and reviewing some of the literature that there might be a way for us to actually go at this cell. I've already showed you that we could cure that cell in the test tube. And so we're going to look to see whether a T cell can be used for gene therapy. Lymphocytes have a number of properties that make them sort of interesting. As you know they're the cells in the immune system. They're present in the peripheral blood so they're very easy to obtain. You don't have to chop out some of these liver to get the appropriate tissue as an example. They're very simple to grow in tissue culture. We know a lot about these cells. They're probably the most widely studied cells in biology. T lymphocytes can actually be very long-lived in the body. One of the examples I often use is that I had my last tetanus shot over 30 years ago. But I'm still immune to tetanus. And it's conceivable that the cells that saw that tetanus antigen 30 years ago are still around. So if I had put a gene in those cells 30 years ago, it might still be in my body and functioning. Finally, T lymphocytes have antigen specificity and they can actually go to deposits of antigen in the body which might be important if we were trying to deliver a gene to a specific problem like a deposit of cancer. So we started looking at lymphocytes and again we've been to animal models. And this is just to remind me to tell you about these studies briefly. We took T cells from a normal mouse. We put the gene for human ADA in that normal mouse. And then we gave the cells to this guy that you've also seen. This is a nude mouse, a mouse that does not have a thymus. So it doesn't have any T cells of its own. So we could follow how long the T cells survive because they should have come from the original donor. And in fact, after a lot of studies in mice and then in monkeys, we showed that in fact T lymphocytes would work. And we can get expression for a long period of time if we put these foreign genes in this cell type. So we were ready to go. Let me read this for you though. One of the questions, if you're talking about using retroviruses in man, you know the prince here is saying it wasn't black magic, it was mead contaminated with somebody's recombinant retrovirus. Okay? We're concerned about the implications of using these modified viruses. They'd never been used in man. And so we started on an odyssey of getting approval for this process. And I just say that this is sort of a flip inside, but we spent seven years of very extensive studies looking at the safety of these retroviruses in a whole variety of animals including about 50 different primates to demonstrate that in fact this procedure was safe. But then we had to convince these guys and this is a review, a list of the public reviews that we went through for our first gene insertion starting in 1987 and finally 18 months later we were authorized to go ahead. Now the first use of gene transfer in man was not to treat ADA deficiency. I really didn't think we'd ever get permission to go into a child. And so we looked for a different population of patients and the first study was done in some patients with cancer and I'll come back and describe that later on. But what it showed us when we did the initial studies in cancer patients is that this procedure was safe and it was effective and so it allowed us to go ahead then and try to treat ADA deficiency. Now, we have another problem.  And for ADA deficiency there are a number of important alternative treatments. This is an incredibly rare disease and I was asked last night how we could justify spending the money to treat such a rare disorder when there are so many people with poverty. And I gave the response that studying rare disease is often very important and let me just say how important this has been. Because these children are so desperate and they're dying within a few months of life, there have been a lot of innovative new treatments introduced for the treatment of severe combining inefficiency. Bone marrow transplantation which was first used to treat SCID as you now know is used to treat all sorts of cancers and other inherited disorders. It's used to treat thousands of people a year. That treatment was developed to treat this disease. Enzyme replacement which is a very important concept in therapy of actually giving the missing enzyme to a patient which has actually been used in ADA deficiency. The point was also proven in this disease that you could give exogenous enzyme to treat a disease. And now as you'll hear gene therapy is also being applied to this disease. So this disease that affects five or six patients in the United States a year has had an enormous impact on the development of new and innovative kinds of therapy. Well the purpose of this slide is just to talk about these alternative therapies and what we can do. The treatment of choice for this disease is bone marrow transplantation if the patient is lucky enough to have a matched sibling donor. Unfortunately because family size is so small in North America, less than a quarter of our patients now will have a brother or sister that match exactly. So we have to look for some other kind of treatment. Those other treatments involve using donors that are unrelated. You've all heard the advertisements for trying to have you come in and have your blood type to be a potential bone marrow donor. There are now several hundred thousand people in North America who have been tissue typed and we're now doing more and more bone marrow transplants from unrelated individuals that happen to match for these tissue antigens. It's still not perfect though and about half of the children that get these other kinds of transplants still die. Enzyme replacement I'm not going to talk about but it was another way of trying to treat this disease and it works very nicely for some children and not so well for others and we don't understand it. But what we decided to do was to take children that don't have a donor and who are not doing very well in this enzyme replacement and try to do gene therapy. Now bone marrow stem cell correction I've already told you we can't figure out how to do it so why do I think that we could go for T cell correction? And I'll explain it on this slide and basically the observation came from those children that were cured. I think we have a slide to drop here. The children that were cured by bone marrow transplantation from a brother or sister. Maybe we won't have a slide drop. Okay if we had children that were treated with this procedure and were cured and now we study those children four or five years after they're cured of bone marrow transplant. What we found was that their red cells and their granulocytes and their platelets and even their B lymphocytes still had the defective gene in them. They were still 88 efficient but the only cell type that took from the donor was the donor T cell. Now if you can cure these kids by giving somebody else's T cells then maybe if you take their own T cells out and put the gene in you can also cure them. So that's the strategy that we've developed for treatment. Let me go through this protocol with you. We take children with this terrible immune deficiency that have been receiving the enzyme treatment and that helps some. We take their lymphocytes and their peripheral blood by a process called leukophoresis and basically that just allows us to collect lymphocytes but we give the red blood cells back so the kids don't get anemic. We take those to the laboratory and we start them to divide by stimulating their T cell receptors with interleukin 2 which is the T cell growth factor and a monoclonal antibody. Once these cells start to divide we can use a retrovirus vector to put the ADA gene in and that's exactly what we do and then we grow the cells up in tissue culture for about ten days and give re-infusions of these now gene corrected cells to the patients. And this is the results on our first old girl that we started treating back in September of 1990. Let me go through this with you. Here we're looking at the number of lymphocytes in her blood and the normal value is up here. So you can see when she was initially diagnosed she had essentially no T lymphocytes in her blood and she had experienced numerous recurrent serious infection by this time. They initially started to treat her with enzyme and you can see that her T cell count came up very nicely and then during the second year of treatment this improvement deteriorated and she started having more infections again and they tried to increase the dose of enzyme and it didn't help and she basically was getting worse. We started looking at her at this time point and we evaluated her immune system very carefully and found that she had severe immune deficiency and we began gene therapy on this date and you can see that within three months of starting treatment that her T cells came back up to normal. Now what about this inserted gene? Is it actually working? This is the level of ADA in the blood of this child actually being made by her own cells. You can see that prior to gene therapy she had essentially no ADA and then each of these arrows represent times of treatment. She comes in for an outpatient treatment and you can see we had the steady increase in ADA until we stopped treating her and then it stayed steady. We've given her a couple of treatments in the last year and her ADA level has stayed in this range. Now to give you a reference this is the value of her father. So now she's gone from having essentially nothing to having a value that's about half as much as her dad. What's it's doing to her immune system? We're going to look at this panel down here. This panel just shows her lymphocytes after we started treatment and we had some bouncing around and finally it's normal. This looks at antibody production to something called an isoglutinin which is, as you know, if you're blood group O you make antibodies to A and B red cells. And we can use those antibodies as a way of determining whether you can make an antibody response normally. This little girl was blood group B so she made antibodies to A type red cells. Before treatment she had essentially none and within three or four months she's making a normal response. Now we started treating a second little girl in January of 1991 and you can see she also had a very nice increase in her lymphocyte count and one from making no isoglutinins to normal response. So this treatment is resulting in improvement of their immune system. The other side of the immune system is the T cell side. We've looked at antibody production and she's getting better. This is a representation of a skin test. All of you have had tuberculin tests put in your arms where you look for a red bump as an indication that you've been exposed to tuberculosis. Well that kind of immunity is very important in protecting us against a number of infections. And if we skin test with things that she should be immune to things like tetanus or diphtheria or some yeast in our environment what we found is that prior to treatment the children could not give positive responses to anything but after we instituted gene therapy they both acquired normal cellular immune responses. If you can drop that slide so let's summarize what we've seen in these children then. We initially wanted to put the gene in this stem cell and the idea was if you could get it in the stem cell then the B cells and the T cells would both be corrected. We couldn't figure it out so we had to step back and look at an alternative treatment and that was putting the gene out here in the mature T cells and it looks like the strategy is working because now their immune system is coming back their T cells are working and they're making antibodies. Now the most important story is how are the kids doing? You know we started with two children and we've treated and the two children are right here our first little girl the four year old and a nine year old and the reason I show this slide is that this four year old only got out of the house to go visit the doctor before we started this treatment. The parents didn't take her in public because they were afraid of exposing her clearly she's being exposed to the public here this is a party we had for the patients and these are my co-workers in this study and their families but the two children were at the NIH for this party the parents enrolled Ashi in kindergarten the following year and last year she went to school with the rest of the kids with snotty noses for the entire year and did wonderfully. So both of our children clinically have done exceptionally well and we couldn't be more pleased. Now I'd like to change gears for just a minute and talk about other applications when I listed on that initial slide for gene therapy we talked about correction of a genetic disease and also the insertion of a gene to provide a new function or property to a cell and the reason why that's important is that this is a very powerful technology and we should be able to use it for treating other diseases and specifically since I'm in the cancer institute we're going to think about treating cancer and I'm just going to show you a couple of examples this is a chest x-ray on the left here of a lady with various serious metastatic disease and these two big balls are big balls of cancer from a kind of skin cancer in her lung Dr. Steve Rosenberg, a colleague of mine at the NIH has been working on ways of trying to make the immune system work better at killing cancer and he treated this lady with immune T-cells that he actually grew from one of these tumor lumps and you can see six weeks later most of those tumors are gone so the immune system can be a very powerful approach to treating cancer unfortunately it doesn't work very often so what we're going to try to do is spend some time figuring out if we can make it work better and I'm just going to give you a couple of examples this is the lung of a mouse that has a cancer in his lung and all this pink stuff is tumor the white areas are air you can see there's not very much air left in this lung there's a lot of cancer there what we're going to do is insert a gene for a cytokine you heard about cytokines yesterday these are molecules that the immune system uses the cells in the immune system talk to each other by secreting these molecules called cytokines and we're going to put a cytokine into this tumor and then give it to another mouse and this is at the same time point what the lung of that mouse looks like first of all you can see all of this air there's not so much tumor but I think you can see even from the back of the hall all of this black stuff or this dark blue stuff around each of these nodules of tumor what that represents are lymphocytes immune T cells are being recruited to the cancer now because the cancer has been modified to produce a factor which activates the immune system and it's our hope that using this approach we're going to be able to figure out how to improve the body's defenses against cancer so that we can use some of these properties of the immune system to help us in fighting off this invader now here's another mouse with two lumps of cancer this is a what we call a wild type or the regular cancer and this is the same tumor but this time we've genetically modified this tumor and let me help you think through this you know penicillin is a great drug because it kills strap and it doesn't kill us I mean it's not like taking chemotherapy for cancer it's very effective against microorganisms and it doesn't hurt us and wouldn't it be nice if we could treat tumors with penicillin well the bacteria are killed by penicillin or antibiotics because of their genes encode for certain things that make them susceptible to antibiotics so if we could put into this tumor the gene that makes it susceptible to an antibiotic we might be able to treat cancer with antibiotics and that's exactly what we've done we've taken a gene from a fungus for an enzyme called cytosine deaminase which actually turns on an antibiotic to kill the bug but in this case it kills the cancer so one can potentially use gene insertion of very unusual things now we're putting a bacterial gene in to a human cell to allow us to treat it with a new kind of pharmaceutical approach now how could we really apply this to cancer treatment in man and here's one way that's going to be starting this fall patients with brain tumor are often desperately ill and one of the problems with brain cancer is often the cancer is in a location that surgically you can't get at you simply can't cut through critical tissues in the brain but you could theoretically put a long needle into the brain area and so we're developing techniques for actually inserting genes for these susceptibility factors into brain tumors so that the gene will be taken up by the dividing brain tumor cell and then we're going to treat with an antibiotic or in this particular model we've taken a gene from a virus called herpes we've put the herpes thymidine kinase gene into tumor cells and this is a rat that's had this treatment done he has a big tumor in this part of his brain and he had the herpes gene put in but the animal was just treated with saline and you can see this huge tumor that's grown out from the rat's brain and we're going to take exactly the same animal but we're going to treat it with the drug the antiviral drug called Ganscyclovir and you can see this litter made animal now all of that tumor has been destroyed both macroscopically and microscopically we've seen no evidence of persistent tumor so now we've been able to develop new ways of inserting genes to help us treat cancer and we really hope that in the next four or five decades that this new kind of treatment is going to revolutionize the practice of medicine and I'd just like to close with acknowledging many of the people that are involved I told you that this took a lot of people to be involved but my fellows in particular Ken Culver and Don Cohen were very important in developing these strategies Steve Rosenberg and Ed Oldfield are the surgical colleagues that I work with for both the neurosurgery and my partner in these studies for the last eight years and I'd like to close with this cartoon that I stole from the Washington Post to try to get some feeling for where this is going there's been a lot of press about gene therapy you have to recognize there have only been two or three patients in the world actually have received this treatment so far but it's such a powerful approach that I'm really sure that it's going to change the way healthcare is delivered around the world within the next few decades thank you