Hello, everyone, and welcome to Navigating the Skies, a session on leadership. And as it's the first day here at the World Economic Forum, welcome to the annual meeting of new champions, and to everyone here in the room, but also at home, watching on the live stream. That's not for me, but for our guests coming up. I'm James Chow, the editor-at-large at China US Focus, and also a World Health Organization, Goodwill Ambassador. So here today, we're here going to be talking about leadership. It's a term that's used, and I think sometimes overused in many different contexts. But what we're going to try and use this time for together is to break it down to unpack it. So we begin to understand what leadership means in our own context, our own communities, and what it could mean to all of you when you go back to your own homes after this conference. We have a fantastic, unique story, which is Samantha Freeben, who this year was promoted to wing commander in the Royal Australian Air Force. She's one of only about 40 such women in that role, and there are only 700 pilots. So she really is not only at the top of her game, but she's one of the finest of the finest in the world today. Samantha started her journey when she went on a plane trip to Hamilton Island. She was born in Victoria in Australia. And in those days, pre-911, you could go into the cockpit and see for yourself what it was like. And the pilot turned around, and he saw her, and he says, what would you like to be one day? And she said, a pilot. So please join me in welcoming pilot and wing commander, Samantha Freeben. Thank you, James, and thank you, everyone. Thank you. So when you hear the words military, pilot, and leader, are there faces that you picture? Are there people that you imagine? I wonder how many of you, prior to that lovely introduction, would have pictured somebody like me. Because I stand before you as all of those things, and yet in many of our societies, and in our cultures, and in our organisations, I would represent none of them. Imagine if you will, the story of a little eight-year-old girl in her school class when a pilot came to talk to the school about their job. They were in the military. They had these green, flying suit coveralls on, and they had these very impressive patches. And they told the class that they would fly really low and really fast, and they had travelled the world. And because they were in the military, they were an officer, and that made them a leader. And being a leader was really important. And the pilot asked the class, who here wants to be a pilot? And a number of hands were immediately raised. And the pilot looked at the class and thought, oh, there's lots of boys here. Do any girls want to be a pilot? And eventually, one very brave little eight-year-old girl raised her hand. And the pilot asked her, would you like to be a pilot? And she replied, no, it's too dangerous, and girls can't do it. And I wonder how many of you had made some assumptions, perhaps, about that little eight-year-old girl and about that pilot. That was actually only a few years ago, and I was the pilot. And I look at this little eight-year-old girl who's growing up in an Australian society, and I just marvel that my upbringing had none of those limitations. I had an incredibly supportive family.   And I had that dream, and I was allowed to realize my dream. So I joined the military, and I joined the military to be a pilot because they had the fastest aircraft. And I have learned a number of lessons on leadership. And the way I've navigated my leadership journey has been through flying in the highlands of Papua New Guinea where my crew tried to sell me off as a bride. I was offered two pigs. I've learned my leadership lessons playing the crash victim for a helicopter paramedic search and rescue exercise where I was covered in prosthetic theater makeup to make it look as though I had real injuries. I've learned my lessons on leadership by flying into combat, flying in and out of hostile environments. And I've even learned my lessons on leadership, flying missions to Antarctica where we landed on a runway made of ice. And I was once told that a mile of highway can take you one mile down the road. But a mile of runway, well, that can take you anywhere. And it has. It hasn't always been smooth air. It has had some turbulence. I could fly a plane when I was 16 before I was even allowed to drive a car in Australia. And that was me with my dream. I had a dream as a little girl. I worked hard for that dream. And ultimately I achieved my dream. But it did come at a price. In the early years of my career, I found myself as a young woman in a very male dominated environment. And I stuck out. And the lessons of communication, the lessons of diversity and inclusion, and the lessons of decision making were really about to begin for me. The first one happened when I was under training and we flew a tactical mission in the C-130. It was a low level tactical mission and we flew quite aggressively and very low.  It just doesn't sound like you can. And I was a little dumbfounded at the start and I asked him to please explain further.  He's down the back of the aircraft in the cargo compartment. He can't see what is happening up the front. All he can do with his helmet on is hear and listen the way I'm running and commanding the crew. And he recited my crew brief to me and then he recited it again and this time his voice was lower, slower and louder. It just didn't sound like I knew what I was doing. And he was right. In that environment, my style of communication was ineffective. I was the captain of an aircraft and my crew needed to know that not just what I was saying was good, but when it comes to communication, it's how you say it. It's where you say it. It's when you say it and it's who you're saying it to. So I changed. And then I kept trying to change and fit in. Has anyone else ever felt like this? Where you know deep down who you are and what you wanna be, but your environment doesn't really let you shine. And that all changed for me in October 2002, when I was one of the first crews to fly the humanitarian evacuation mission from the Bali bombing in Indonesia. As a crew, we were called into work and we didn't know why. We chatted quite excitedly about this mysterious mission that we were going to go on. And then the news broke and the news broke to say that there had been terrorist attacks and terrorist bombs had gone off in Bali. And as a crew, we fell silent. Our mission brief had very displeasing answers to questions like, will there be more attacks? Possibly. Will we be attacked? Possibly. Will we carry weapons for self-defense? Negative. This is a humanitarian evacuation mission. And so we took off and we landed safely in Denpasar. And the sight on arrival was really confronting. If you can imagine, these people were on a beach holiday. They were wearing shorts, they were wearing singlets, they were wearing summer dresses.  The ensuing fire, it melted their hair, it melted their clothes, and it melted their skin. And it took a while for us to be able to evacuate them back to safety. But eventually, we were able to take off. And during the take-off, my navigator lent over and he held my hand. First up, I thought, oh, that's a bit weird. But I looked at his eyes and just, he was shocked, he was confused, he was sad. So we just held hands for the majority of that flight home. During our mission debrief, we sat in a circle and our executive commander conducted the debrief. And at the end, he asked the crew, would anybody here like psychological support or perhaps speak to a chaplain to overcome what you've done today? And I looked around the crew and no one did or said anything. Not the navigator who had clearly been affected by that mission, not the captain who was the leader of the crew. I was literally the most junior person on that crew and I knew I needed a lot of therapy to process what I'd just seen. So I raised my hand. And we all received the psychological support whether we wanted it or not. But that debriefing technique that our supervisor employed to not fill the silence, it allowed me to raise my hand and it allowed that the difference that I could bring could actually be a value that I could add. And there are lots of techniques like this that the military have. Another one is decision making. I was always taught that it doesn't matter what decision you make, it will be wrong a minute later because time moves forward, information changes and a decision is only as good as the moment with which you can make it. And because of that, in my environment, where time effective and efficient decision making is no more important than when you are airborne with a time critical, high pressure dynamic environment, decision making can't be left a chance. So we're taught it. It's a process and we use a framework. The framework that I like to use, I'll share with you, it's a combination of a couple but it works well for me and it's called Grady. You have to gather the information and you have to gather the information from as many people as you can. And in hierarchical organizations, in my experience, you need to start from the most junior person before you move to the most senior person. And that's because without even meaning to, the more senior person will inevitably influence an outcome or set a tone. When you review the information, have you gathered it from as many avenues as possible? Are you making a decision on behalf of a demographic that you don't represent? Have you heard their voice? Review where you've sourced your information from? You have to analyze. And a good technique in analyzing to prevent group think is to appoint somebody to be the devil's advocate who's only job in the decision making process is to pick holes in everybody else's ideas. But then somebody has to decide. And that is the role of the leader, the decision maker. And my technique with my crew to ensure they understood the decision had been made is to simply say, crew, the decision is what? You then have to set the wheels in motion to implement the decision. But one of the most important aspects because a decision is only as good as the time with which it is made is you have to evaluate it. And if the person who makes the decision can also initiate the evaluation of the decision, whether that's a minute later, a month later, a year later, then it's very powerful and humbling that you start by saying, well, this is what we did. How did it go? And if you are working in an environment like I am where there's critical time pressures or perhaps there's routine and mundane process, then you can even take decision making further by making checklists. And as a pilot, I love checklists, I live by checklists. And the beauty of a checklist is that it will make sure that in the heat of the moment, at the time when you most need that information, you aren't able to forget it. You have a checklist for that. And it means that when I find myself airborne with an engine on fire, it's actually no big deal. I can make it safe in quick time, follow my checklist. When this happens, do that. And then as a team in slower time, we can decide the better course of action using Grady. So the aspects in leadership that I've really learnt from my military experience have been communication, it's been decision making, and it's been the vital importance of diversity and inclusion. And I envisage a world where all children can have a dream, they can progress their dream, and everyone can actually reach their leadership potential. So please, as Dr. Souff said, why fit in when you were born to stick out? And let's all make sure that we raise our hands. Thank you.  We're gonna make sure the entire Royal Australian Air Force gets a copy of this section over here. But as we reset the stage a little bit, we can just ask one or two people what their concept of leadership is. So just in the line, what would you say leadership is, Jordan? I think leadership is really about caring and taking responsibility. Okay, Camilla, what does leadership mean to you in the line? Being responsible and setting a clarity. Okay, so a lot of human values there are ready. Samantha, let's get you back up onto the stage and we're gonna ask our other panelists to join us as well. Please welcome Arvind Satyam and also Ilona Sabha who are going to join us up here. And we're gonna look at what this really means. So Arvind, you are the manager director for Global Public Sector over at Cisco United States. What resonated for you in that? And perhaps what surprised you? Sure.  I'm very excited to see your journey. And as a kid that loved Top Gun as a movie growing up, I'm always excited to have a prop of this in the backdrop. So it's a lot of fun. One of the things that resonates to me is when we look at flying a plane, the instrumentation and being able to take the data at your fingertips to make critical decisions is important. But it's an analogy that applies to how we live our lives. It's an analogy as to how we actually make business decisions.  Similarly, would you fly a plane without a dashboard in the cockpit? So if you take that analogy, I think to me one of the most important things is knowing what data you need in order to drive the outcomes that you're looking for and then having that information in real time to enable you to make that decision. And so over the past 10 years, one of the areas I've focused in my work is working with mayors on helping them become a lot more dynamic in terms of decision making. So how do they deal with catastrophic incidents? They're dealing with a lot of changes in their lives. They're dealing with what's happening in cities, with what's happening with citizens. So you've got terrorist incidents. You've got cyber attacks. You're seeing climate change. So with that as the backdrop, how can you actually leverage data to make decisions in a more dynamic fashion? But we'll come back because I think some of the long-term decisions that we need to now contend and negotiate is worth discussing separately. But you touched on data points. And Samantha, you talk so much about the importance of information, how, what, when, who you say this to. And that also brings in communication. But I want to challenge this a little bit. And Ilona Savo, you're the executive director of the Igarapi Institute, which looks at everything from cybersecurity to citizen security to smart cities to justice and development and how that all comes together. So when we talk about the grassroots, is it really just about data? Is it just about people? After all, we heard about human values, emotional bonds when it comes to responsible and caring leadership. Well, first of all, it's just a real great pleasure. And I think it's so inspiring to have women in these unusual roles. And in a way, as a civic entrepreneur, a civil society person, I also took an unusual step on working with issues that were not, I'll say, bread and butter for civil society in Brazil. So I work with violence. I work with issues that are not also women issues. So on that front, I resonate a lot. And James, I think the data point, I think we cannot do anything without data these days. We have so much knowledge. We have so much, I would say, challenging complex problems to deal with. So my first approach in the think tank is data. But then you have to communicate to the broader audience. And today, in a polarized world, I would say that that's, I would say, my nightmare at the moment. How do you actually advance a balanced approach? Navigate the skies of polarization, of extremism, when we have very short time to take the right decisions to actually leave a better planet for our children for the next generation to come. So it's key, but I think we have challenges here to confront not only civil society, but a multi-stakeholder on how to use data in a responsible way to just manage the decisions that are not getting to the point at the moment. Sam, I just want to push you a little bit because I'm hearing the voices of civil society leadership, business leadership, military leadership. And there was a distinct aspect of your work, which is also humanitarian. So what about moral leadership? Where do you make that stand in that core so that the decisions that you make not only serve the purposes of your organization, which in this case is the Air Force, but really serves the interests and the needs of people? When do you make that jump? And have you been put in that position? Yeah, and it's a very, I guess it's a very loaded question, James, because in the military, ultimately some aspects it's to do harm to people. And some of the roles that people will find themselves in are to do that. So I guess you need to be very aligned with the values of your organization, the values of your mission. And certainly in my upbringing, it's been no and organizationally, if I have felt something isn't right, then we are encouraged and obligated to say so. So it's never a question of not having the courage to speak up.  You've been put through a number of processes and been exposed to some extraordinary situations which others, including ourselves here in this room, wouldn't have been. But going back further, you talked a little bit about your supportive family. What were some of the life lessons growing up, which imparted the values that you felt that you could leverage later on in your career that put you in an advantageous position? I think the main one, when I was learning to drive, and I have a sister, I don't have brothers, and I grew up in a small town in Australia, when I was learning to drive, before I could go for my driver's license, I could fly a plane by the way, but my dad stood there with a stopwatch and my sister and I had to be able to change our tyre, we had to be able to identify the oil and fill it up with the car with oil, and we had to change the fan belt with a pair of parity hose because no daughter of mine was gonna be stuck on the side of the road. So I guess I always was taught that it doesn't really matter what you do, just do it really well. And I think that is a philosophy for life. Okay, let's sit with that thought a little bit and head back to Arvind. Arvind, when we look at Samantha's story, this year she was promoted from squadron leader to wing commander, and obviously the military of all places must be hugely hierarchical. What's it like in business? Does it work the same way? And I also want to ask you, now that we have technology literally at our fingertips and within our own powers, that's enabled the individual to do extraordinary things beyond a role and a rank. Then what happens after that? Absolutely, I think one of the things that we're seeing from a Silicon Valley context, but more broadly is technologies enabling more of a decentralized structure. And so back in the day, whether it be a military institution or a traditional business institution, you had many layers and you had much more of a command and control approach. But today with the ability to capture data, you have a lot more empowerment of individuals in their particular roles and you're able to instrument policies to drive a decision. So I think the first thing is, you're not having as many layers as before. Two, a lot more empowerment to drive decisions. But three, it's also driven by using data to get towards a more accurate outcome. What do you think, Ilona, when you hear Arvin and Sam speaking about these issues, where does it chime? Where does it align or not with your work? Well, it totally does. But I think I'm taking a look at the society and how society is receiving all this data and how can we actually make more responsible leaders to act like that. So and I see challenges. I mean, I think both Samantha and Arvim and the principles, the training, we're doing the right thing, but it's not enough because in scale, we're not being able to do that. And I know most of our time and the military is very different in terms of the hierarchy, but we're trying to convince other people to do the right thing. So in a way, I think the leadership we need now is to do the right thing at the right time, regardless of it's gonna sound right to the people, but who is really willing to pay this price. So I'm in this kind of urgency call here for us to really try to make a way out of the sides. I think we have to bridge leaderships that can bridge across the divides. And just on the women's road to that, it's so immense because when you talk about the mental health, when you talk about giving hands, and when I work with police and I see they after like, we have a very violent police in Brazil and I look at them, they don't ask for help. Why are they violent? And as a woman, I can talk about this to them, but they feel very vulnerable. And as leaders, we can't show that vulnerability. So I think there are several issues you touch that would resonate so much to what I do, but in a totally different way. But there's an urgency here for bridging, for responsibility, but for communicating and for doing the right thing. And James, sorry. Please go ahead. And James, if I can just pick up on that, I think to me, the people aspect is the most important part of it. I think it ties to the theme of human-centric leadership, because it's about understanding people and across the board, up and down the chain, and making sure you communicate the values of your organization. People don't just want to work for you based on what you do, it's why you do what you do. And I think that part of it is important and it's imperative for leaders to have the entire organization behind the values. I want to talk about mental health because Sam talked about the psychological support that she and her colleagues were given in the immediate aftermath of Bali. We think of leaders being strong, you have to be robust, you have to be able to lead from the front. You're responsible for everybody else around and below you. It's the hierarchical structure that we spoke of. Who in this room, we can get a quick map, who would feel comfortable about saying, I would like to have some mental health support. I would like to have some kind of emotional support in the current roles in which you find yourselves in today. Hard, I'm learning. So he doesn't feel comfortable, he doesn't feel comfortable in that setting you're in, not because necessarily of you, but because maybe of the organization you're in or the sector or the person who's sitting next to you. Who doesn't feel comfortable? I mean, there can't be like a single hand going up here because only a few of your hands were not just now. Well, okay, I only saw one hand over here. Well, one over here, you would feel uncomfortable. Why would you feel uncomfortable about this in the year 2019? I think organized, so it's a cultural situation.  All the men rolled their eyes, they didn't want to go to it. So it's just not today. But I think situations like that, you feel the need to blend in instead of stand up and say, well, it does impact me, so I would like this. And what sector are you in? I'm in healthcare, actually, but in the business side. In the business side, but still even in healthcare, you would feel that way. I mean, Jonathan, Mari, would you feel comfortable about it or not? Thanks, James.  I do, I think it's changing. So I work in the insurance sector. We have an implication on a lot of the stuff, obviously, on the health insurance side. So I can say, seeing it from the data side, a lot more companies are doing a lot more. So I feel entirely comfortable to talk about these issues. Now, would I sign up and would I be the first leader moving in to take on healthcare counseling, et cetera? Maybe not, but I feel comfortable with the concept. Would you look at someone differently if they sought that help from you? I suppose it would be an odd answer because I think vulnerability is actually a great source of strength because only the powerful can afford to show vulnerability. Let's talk about Bali because you went into it in some detail and Bali was obviously, it wasn't a tragedy, it was a man-made tragedy. It didn't just happen like that. And you found yourself in a situation where you signed up, you essentially volunteered to do it, you didn't have to if you didn't want to. What do you take from that particular example, that very, very young age as well? Yeah, I guess I'd sign the dotted line to serve my country and Bali actually made me realize I had signed the dotted line to serve my country. So it actually forced me to decide was I just here to get enough hours to then go and fly for Qantas or was I committed to the military? And so that was a bit of a journey, those three hours. And then the debrief itself really taught me that I was recruited for who I was and my attributes and my skills. And then organizationally, we indoctrinate, we onboard, we kind of shrink everyone down in their initial training. And then I had this opportunity to sort of refined myself. And I wonder in our broader organizations when we go through that onboarding and the training and the indoctrination, do we allow people that the opportunity and the moments to then find themselves again so that they can bring themselves and their skills and attributes, which is what you first got recruited for or encouraged to be part of, bring that back into the fore. So for me, that was Bali with all of that and more. But I just remember sitting there thinking, I don't want to be like you. I don't, why am I trying to fit in so hard? I don't want to be like you, yeah. As you said, you could have opted for the private sector. You could have applied your skills to a commercial airline and like Qantas. I mean, it's amazing that the two of you have given your life to public service. And then there's Arvin, who went for the big salary after that. Thanks, James. He can still do good. He can still do good. Arvin, you know, the Robert Kennedy Center is, you should sign up actually. They're creating a course and they're encouraging leaders in public service. But on a serious front, on a serious front, you're working as head of the global public sector for major organization itself. It's then absenteeism. I mean, when I grew up, which is not that I'm 41 now, I couldn't think of anything greater. And I still don't think it's anything greater than to serve the needs of other people. What about public leadership, public leaders? And we're here in this incredible space with a lot of young global leaders here in the room, but we're also here at the World Economic Forum. And most people here are obviously committed to improving the state of the world, which is what it's all about. What types of public leadership are we missing today? Where's the gap between, say, for example, political leadership and moral leadership? Sure. So I'm part of the global public sector leadership team, so I just want to make sure I correct that. I think from a public leadership standpoint, you're starting to see different personas that are entering into the arena. So in the past, it would have been people that wanted to do good, be part of creating change. But I think, especially when you think about business leaders and technologists that are coming to it, right? One of the challenges we've faced as an organization is we notice that a lot of governments and public institutions want to leverage these tools. But frankly, if the institution does not have the capability to understand this, you're not going to be able to use this. And it starts with top-down. So I think in order to go through this change process, you need to have many different actors that are part of the team at the leadership level, but all the way up and down the chain. So that's one point. The second thing that I would say is, especially in the era that we're living in, of polarization, of anti-globalization, it's important for individuals like the YGL community and others to really step into this arena, because we do need change and we do need leaders from different arenas to help drive this forward. Ilona, when we talk about top-down, which has been mentioned a couple of times already, and Arvin has said so as well, does it work in the same way for civil society? And I don't just want to look at it in a vertical slump, but perhaps you can infuse us with ideas on what we can all do in a way civil society that is the body of people, for people. It's an incredible movement. I would put that all of us are part of civil society because I believe leaders can make a difference wherever they are, and that we have a business life and we have our civic life. So to start, we all need to engage. And it's not, I mean, I have my role as a think tank director, but I also have my civic role as a co-founder with other YGLs that are here in this room of a civic movement, a political movement in my country. So I think it's never enough. We have to do the best we can in our businesses to, like, also to advance the public good, but we have to put more there. Unless, you know, we're okay with the status quo, which I think we are not. So I think there's a role for everybody. And I think at the moment, we need to empower people because this idea that government will save us or even, you know, I think companies will play a much bigger role in the next stages of our, you know, planet. But I think all of us are in this to start. And when I listen to Samantha and when I think about decisions that were made, I also think we have to ask where we had value because when I started my work, I started very grassroots. I started working in favelas with children that were involved in the drug trade. I left a banking career before to do that, but I was, like, about to burn out because I couldn't work with those mothers close by. So I went to the policy side of this and I decided, okay, where can I make a difference in engaging the causes? I believe, reduce, violence, reduce inequality, you know, increase justice, but from where I will be healthy, where I can actually then build the coalitions and ask private sector, ask the military. I work with all sectors today to just, you know, pursue the cause, I believe. But I just say that the civil society, we should all feel part of that and choose your cause. It doesn't matter what is the cause, but choose one and start informing yourself, looking up to an organization that is doing something, build a coalition, but you know, unless really we don't wanna see our kids in a better place. And I'm just saying that because I come from a country that is in hard shape at the moment and I feel so many leaders are destructing, like, are destructive. They are not constructing something new. And I think this is a denial. We need neural models, we need Samantas out there for people just to say, we can do that, we need ovens. So how can we just rebrand, help, what are the inspiring leaders for today and what civil society can do to actually look for, you know, and allow these people to emerge? Because we're all being attacked by doing the right thing at the moment. Right. Do we have positive examples of leadership today? Well, Jacinda, for me, is top list. White gel as well, so I'm just like a little biased. But as a female head of state, I would say she for me is an example. And there was a huge, at the same day there was the massacre in the mosques in New Zealand. There was also a massacre in schools in Brazil. And if you see the responses of my leader, and Jacinda, I'll just tell you, just go and take a look what both did. It's beyond imagination what's also like a woman can play in this role with courage, with empathy, with compassion and being firm, being just. So I think, you know, we need more Jacinda and that's come like a, who will step into public life in a world that careers, reputation, defamation, polarization is up there. So we need to support new people. I would add Pete Buttigieg, who's also a YGL from this year. Pete Buttigieg, we're still learning how to say his last name. But he's the mayor of South Bend in Indiana and he's made an incredible impression in a very short period of time. He's gay, but he's one that's had lots of impact in terms, has commanded national attention in the Democratic Party. And I think when you think about being a role model for the youth, when you think about being a role model for diversity, when you think about being a role model in terms of change, I think we need these type of leaders to really change the status quo. Anybody in the audience with a question for any of us? Because if you don't put your hands up, I'll just ask one of you to ask a question. Abid, front row seat, always a mistake. A question for someone up here. He's not shy at all. I mean, he's very good at asking questions. Yesterday, you talked about India and Pakistan and you made the example that a couple of months ago, your country, Pakistan and your neighbor, India. And a lot of them are friends, sharing very similar cultures. You all came from the same place originally. Very, very nearly went to war. And obviously it was something that moved you and something was very, very emotional for you. How would you link that to what we're talking about so that navigating the skies doesn't stay up in the sky, but becomes a reality for all of us? Thank you, James. You're on the spot. Yeah, it does, for that, bringing the direction of the question also. Because I feel that in the case of Pakistan and India, exactly what we lack is leadership and compassionate leadership. And Pakistan and India both have had female heads of state. But I feel that because of the systems that they were from, they weren't allowed to have the impact that they could have. So what would you guys say to someone like Hina, for example, who's an aspiring politician, she's already a member of parliament, how should she do things differently in a male-dominated system like in our culture, in our country? Well, these resonates a lot with me in terms of gender because we try to emulate the male role, role model of leadership. And I think we need to be able to create the women's leading role. And I think we are on our way to that. But many of the women that were leaders of state were trying to emulate the same behavior. And I just quote President Santos, leading in war is very easy, but leading in peace and making peace is much, much harder. And that we have to learn. I mean, since we've got Hina Bhatt over here, why didn't we ask you, you're from Pakistan, you're taking lots of notes over here. What advice would you give us? I mean, you're actually in that position right now. You're wearing a name tag, although I wouldn't have noticed immediately. First of all, Samantha, I'm really proud of you. I think both of us were late, coming from the New World Hotel. So I noticed you immediately. So yeah, I'm really, really proud of you because as I saw that the breaking the stereotypes or the myth of, you know, having women not in these roles is excellent. But you were like very young and you knew your dreams. But there are a lot of girls who do not know their dreams. So I think, and they face a lot of problems, especially because of the culture and the society.  And the first time I walked in the assembly, I was told that this is a male dominated field and women should not be there. And like you said, the military pilot and the leader. So a certain image comes. Similarly with women in politics, a certain image comes. So breaking that label is a very, very challenging job.  And to tell our story, even when I met Sharmine and Ben Chenoy, she was doing a great job. And a lot of other women who are coming. So you guys are the role models for us. I think more of the women should come and share the stories of what they do. It's interesting here you say that, given that you've had Ben as your buttoe, you've had Indira Gandhi next door, Sheikh Hasina, not so far as way that you would still be made to feel that you didn't have a rightful place that you had already earned over there. Thanks for that, Jordan Kerr from EY. Yeah, thanks very much again, Sam, for your presentation today. And one thing that I really like to understand is these days governments and a number of companies lack a lot of trust. And I guess as a pilot, a number of people put their trust in you, not only to get the mission done, but also for their lives. And I'm wondering, is there anything that you think that the private sector can learn from the military or from the civil service on how we can help governments or help improve trust in not only the way that organizations operate, but also governments as a whole and society as a whole? Probably, Jordan. So I fly for the military. In order to have achieved my wings when I earned my wings, I did a 12 month intensive flying training course. And at the end there was a big parade and we all got awarded our wings. And they're pinned close to my heart and I see them and I know I earned them. At no point do I sort of decide internally that I don't belong, because even when I have those feelings, I look down and I see that I earned these. Yet I have friends who fly for airlines, men and women, who did a different program and there was no time on it and there could have been delays. And whilst they have got their wings, they didn't really celebrate the success. So I think certainly from my perspective, knowing that you've achieved something and that you own that right to be at that table, that's probably quite a powerful message that it sends for yourself so that you don't walk into a room and feel like you don't belong. Okay, one last word. We've got exactly two minutes left and we need to finish right on the dot. Arvin, you brought up the very, very important question of how to navigate long-term crises. Climate change is one of them. Poverty is another. Food, waste, we could go on and on and on. We live in a time that you say is divisive, very confusing as well. How do you find our place within that and how are we going to establish the system that will see us through? Sure, so I'll give an example. So we've been working closely with the city of Copenhagen, there's many cities that are focused on climate change, carbon emissions. And to me, a lot of this starts top-down. So Lord Mayor Jensen a couple of years ago said, we'll be the first carbon neutral city by 2025. As a result of it, the entire city's decision-making process has changed with this goal in mind. So when you're procuring technology or when you're making operational decisions, you have this goal in mind. And that to me is a really important part of it because you have a leader that's essentially laid out what that compass is and the value for that institution. And then two, then you are able to figure out what data you need and that decision-making framework that you laid out. Once you understand what goal you go for, then you figure out what data you need and what you're going to do about it, but also how you communicate that to citizens so they can change their behavior. I've been Satya from Cisco. It's a great pleasure listening to you and also to Lorna Sapo from the Iguarapa Institute coming all the way from America and also from Brazil. And I think it's been wonderful and elevating and enhancing to listen to the life lessons that you've brought with us today and for sharing with us all to Samantha Friedman. Thank you very much for joining us here for now. Thank you very much. Thank you, Dave. Thank you. Thank you. Thank you. Thank you. Thank you. Well done, Dave. Thank you so much.


Hi, my name is Gianna Hortez. My shop is prototype machining and design and I am your December student of the month. My favorite part about my shop is that it combines the theoretical side of engineering to the hands-on side of engineering where you can actually see a part come to life. After high school I plan to go to college for engineering where I hope to obtain my bachelor's degree in mechanical engineering and then hopefully in the future I'll obtain my master's. I am a member of LEAP. I'm the corresponding secretary of Student Council Interact, and then I'm also members of National Honor Society and World Language Honor Society. A fun fact about me is that I was actually a NASA inspector and contractor this past school year in correlation with my shop, which participates in national hunch each year. I'd like to thank my family friends and teachers for always helping me out on my educational endeavors.


Suffer less, but killing's fine Everyone's got a day Yeah, but it's written Come on everyone's got a day, it's better okay now Written us, sometime they got a day Like I could shoot someone in the head and they don't feel a thing, is that okay?  Are you um Okay, so I've got the sign here, there's no argument against being a vegan Right So what's your argument for not being vegan? Like why aren't you vegan? We can't survive without meat, like we need You need meat to survive? Yeah I've been vegan for seven years, how am I still alive? Seven years Yeah Long term, I don't know I don't know really Do you think you can survive without eating animal products? Personally, I'm not a fan of vegetables I don't like it, it's about personal taste as well I don't think it's about that I think it's about animal cruelty, animal suffering and like killing It depends, it depends what country I do agree with that Are you Muslim? Yeah So how do they kill them in their halal way? The readings And the slides they throw, let them bleed out So do you think that's ethical? It's a part of life in a part of circle Let's give you two choices, slash an animal's throat open Right Or not kill them and just eat plants What do you think is more ethical? Slash their throat open and eat them Yeah throat open is more ethical It's ethical What if you just left them alone, right? We didn't mass breed them and kill them by the bill Wouldn't they be overpopulated then? We need a way of cycle though Why do they exist anyway? How do they come into existence? I'll give you a clue These animals exist You don't eat pigs anyway, do you?   Stop breeding them They're not going to overpopulate are they? Yeah but then they're going to go extinct So which one is it? There is no They're going to overpopulate or they're going to go extinct In my opinion Wait a second If we don't eat rhinoceroses, is that why they're going extinct? Maybe If we start eating them, there'll be more of them That'll be ethical I mean people did eat them a time ago Then they learned the way he's not to eat Eat certain animals, certain not I'm a Muslim so I do believe in like There's something called Eid It's animal sacrifice But you don't have to sacrifice an animal to make a sacrifice to God Would you rather have an animal slaughtered Or What do you sacrifice your time? Your money? Sacrifice your time to help others Sacrifice your own kid Where our prophet was In a position where he was placed with his kid Like his son And would you rather sacrifice that Where he put his son down to be honest He was going to sacrifice his son for the gods But it got changed Into a sheep and then A sheep and I'm not quite sure With the nose But as far as I know it was that So what if I said okay it's Eid I'm going to sacrifice you I think there was a point I'll sacrifice you, would you think that's ethical? No but you wouldn't eat me though What do you mean? What if I did? Well that's a different topic we can go on No I want to know the difference But you know what I'm saying If I sacrificed you for Eid and ate you But that's not Eid though isn't it That's like killing someone It's a requirement to be a Muslim to kill animals So you can be a good Muslim Christian eat pigs But you can be a vegan Christian But you can be a vegan Christian And you can be a vegan Muslim Actually it's not about religion It's about your personal choice where you eat But you think this is personal choice? So you do have a freedom of speech right You can talk about anything We do have a freedom of what we want to eat But like when there's a victim involved Let's just say you can have freedom to do what we want It's a victim you know You don't think animals are victims? There is places like You know they abuse a lot of animals You don't think a cow can be abused?   They're not eating it What if I ate the dog? I'm not a Muslim so it's not Haram for me What if I ate the dog would you be okay with that? I can't really control you though Do you think it's ethical? You don't believe in morals? No I do but Do you think it's ethical for me to cut a dog's throat Give me a tricky question but I have to agree with you That's what I'm trying to say It's not a trick question it's just a simple question The simple answer is no It's not ethical Killing a eating a chicken Sorry bro Eating a chicken awesome I'm just saying If I replace these chickens with dogs And do you think that's ethical? Right so You're a vegan right? Plants do No wait before I go into the plants with you Which I will I'll happily do it But can you please answer If I replace these chickens with dogs Would you think that's ethical? Morally fine If it was done for a year then yeah No no just right now Morally okay This is me saving a chicken Do you think that's more ethical Do you think what I'm doing to this turkey is more ethical Than the halal killing There we go you're going back to the religion It's not about the religion Because I'm talking to you I want to make it personal to you so you understand I do understand I've watched these videos on YouTube I know where you're coming from I do disagree with the way they do certain things But it has to be a circle It has to be working in a certain way Right now though bro Where do you get your chicken sandwich from? Archies So you had a choice To either pay for a chicken to have their throat slashed open Live in a factory farm Halal animals are living in factory farms too The dairy products are forcibly impregnated cows And you know they're being executed In slaughterhouses You know the dairy industry has Well let's get to the plants though isn't it We can but you had a choice to either Eat plants or cause all that suffering To these animals They're suffering to the plants just cause they don't We don't hear them scream We don't see the blood coming out Don't you think they suffer from pain when you Absolutely not There's no scientist alive that believes plants Actually are conscious beings that feel pain No matter They're certain things that grow right You're still doing something to them It's alive though isn't it It's alive yeah You can't go through something without pain You have to go through something with pain Do you think there's a difference between me killing A human being and me killing a tomato No there's no difference the same thing Same thing So you think that we should be arrested for killing a tomato No cause we're eating that Do you think we should be arrested for killing a human We're in a world where we don't see killing plants As a certain like What's it called Out of law or something you know Yeah but I'm just saying like if I kill a tomato You're doing the right thing saving certain It's a good thing but I do agree with you But I don't agree with you fully Like you can't fully turn into Vegan you chose to be vegan right Well I chose to be against animal cruelty And animal abuse and needless killing Of animals But certain people don't do that What are you talking about you though bro I'm talking about everyone You don't care about animal cruelty in that I do But you pay for it We don't have to We choose to You're making a choice you're choosing to be cruel You're choosing to be cruel And away yeah if you have to say that You can also choose to find a vegan option You can still be fine in the eyes of Allah Yeah of course There's a lot of stories At least you 100% know it's all Halal Because you don't 100% know where this chicken come from You didn't follow it from the farm You're trusting them You didn't know how they were killed It doesn't convince me to change The way I do certain things But it doesn't give me Idea of what's going on in the world You can make Decisions like this That don't involve animals You know what I mean And that's a choice you can make I'm not expert with things I just came on I saw the sign earlier Do you honestly believe a carrot Is the same as a pig When you kill them I did hear it somewhere I'm not sure where I did What they do is they respond to stimuli In the environment but they don't have a brain There's no one in there But you come from the idea I'm trying to see You're still plugging the thing It doesn't matter because they're not sentient They're not conscious These are conscious beings They have a brain, they have eyes They have ears, they get scared But a carrot is not conscious How do you know? Science How do you believe in science?  Because they can tell with science There's no nerves, there's no brain, there's no consciousness That's what I'm trying to see How do you know this table isn't suffering Wait a second, how do you know? There's atoms in here There's atoms we're all made of atoms Maybe I should give this table rights It could be It's something called the burden of proof The burden of proof The table is hurting or not I'm making the claim so I've got to prove this table is hurting I need evidence don't you? You know what evidence is? Yeah of course I do You need evidence to make a claim If I just come into something I don't have any evidence Like you've got evidence right here They're suffering but there are so many people out there Helping our animals Charities, you know So many things You think you're helping animals when you eat a chicken sandwich? No but they're...  Everything's out of your hands Not everything You've been given freedom of choice by God You can choose to do something cruel right now If you wanted to Why do you choose to do something cruel?   There's only so much we can do Aware awareness Let people know, educate them End of the day it's a choice they're going to choose to do You can tell them, I can tell them They're going to choose to do I can be a vegan or I can deliberately go and buy a chicken sandwich And pay for animals to be tortured and killed So that's my choice And I had that choice 3 times a day when I ate So why not make the vegan choice That's what I don't understand, why not Why shall I when I'm choosing to do what I want to do But the animals don't get to do what they want to do as well So you have to think of yourself You have to think of others as well You can't always think about others Not always, but just like But that's me being vegan for 7 years Thinking about animals itself You know how easy it is to be vegan You can't think about others all the time But you've been vegan for 7 years Only when I ate Trying to protect or save animals I agree with that right That's a good thing that you're doing out there But at the same time You're thinking about animals You're not thinking about yourself You know I ate for lunch yesterday Subway, meatless maple sub You know how hard that was It was easy How does the It was easy Choice? It's almost like a meaningless choice So wherever the Friday Or whatever they did Was not cooked or fried Not oil that comes from Well I only care if I'm directly funding the industry So if I order a chicken sandwich I'm paying for the birds to be executed You might not know But you still might have something to do with animals There might be some cross contamination That doesn't fund the industry Like you fund it directly by a chicken sandwich It's about funding the industries that abuse animals So Now we're moving to funding but not Supply and demand do you know what I mean? Yeah I do but again Is it about animals or funding the Industry out there You said like You know like the subway I buy the plant based meatballs They have to replace those plant based meatballs with new ones If I buy the chicken They have to replace that chicken with new chicken So it comes from somewhere Where you got the subway from Didn't just touch Anything to do with meat And just touch your meatball That doesn't support the industry It doesn't matter That's a different topic industry You don't want anything to do You can't really say You've been vegan for 7 years Without Having nothing to do with animals If you were You wouldn't even have subway That's what veganism is to start with It's the philosophy against The exploitation and cruelty to animals How is it cruel? I'm not an expert I'm just walking about I know what the definition of vegan is We've got chars We do what we've got to do We do what we've got to do So if you want to choose to be Vegan for 7 years and I want to be Eating meat for 7 or 8 years Or my whole life I can do End of the day you can just Educate people and let them know What's going on in the world But we can't help everyone We can't think about everyone or the animals All the time we have to think about what we are I've just got hope in people I see the good in people I hope that people make the good choice The decent choice I'm trying to speak for the animals They can't speak for themselves They can't defend themselves from people I think we take advantage of them It's fine It's morally fine It's not certain ways I do agree with you It's bad again The way they do certain things is really harsh and cruel They don't have to make them suffer and kill them There are ways I don't know the exact ways but there are ways You can make them less suffer If that's the word Suffer less but killings fine Everyone's got to die It's written Everyone's got to die I can shoot someone in the head and they don't feel a thing Is that okay?  But it's accident It's life, you got to move on I'm not against transport But I'm against Executing animals for Sandwich Well I got driven here Had a bunch of equipment If you got an accident and you died Not right now while you were on your way here What would you call it An accident or what You could believe that it was fate Right? But I think shooting someone in the face Is your choice, you chose to do that It's the same idea with everything Not just shooting Getting shunked or anything Same idea You could have a knife in your hand and choose to stab someone innocent Or you could put the knife away And choose to go help them out With their shopping baskets Someone coming up to you right now with A weapon trying to kill you What would you do?   Why don't you stab them again? I would do Can you stop that? Can you stop it? Sorry? You can make a difference though You can make an awareness That's what everyone's trying to do I'm trying to You come from a vegan side perspective I come with the same idea Where people are killing each other, stabbing each other I've got so many friends who have been stabbed A lot of things going like that I do go and protest like that Do the same thing At the same time I'm coming from the same idea where you're trying to come from With animals, when human means So what we can do Is make awareness, we can let the people not educate them Like I'm trying to do here But you do it with your friends and you say Put the knife down sort of thing It's not about putting the knife down Do you ask me to make different choices? I still agree You can't just leave everything There has to be a pain Involving certain things Life is life It's not always going to be fair to you With these animals who are going to it Has this baby lamb ever heard anyone? I don't know I can just see I can't just believe everything that I see You're just recording something Suffering, suffering, suffering Why don't you record people taking care of it They do, they do And I've got some of that footage On the end here My uncle Goes every week and feeds street dogs Or just gives food out So that's what I'm trying to say It's not always But he still eats meat That's what I'm trying to say But I'll say what he eats But when he eats the meat I'd say that he's paying for the animal to be He's helping them with one hand while he's hurting them with the other That's what I would say about that You can't say both of y'all One's got to get hurt to get another one Reaching up there Tell me how hard it was for you to buy your chicken sandwich before Really hard to walk a lot Ah, come on But how much harder would it be to find A vegan option Maybe a little bit harder and you could save an animal's life To be honest When I went to Natchez and I looked in the menu I barely even saw any vegan option To be honest I've got a vibe here which would help Let's just say it was a little bit I appreciate your time anyway Take care mate You don't want to take this? No, not worth it with you Do you want to take this? That was a tough conversation I didn't know what to say at some points Very Very strong minded I'd say It seemed like a good kid though You know A good kid but very strong minded And couldn't see it from the Trying to ask him to see it from the victim's perspective Eh Are you a vegan? Yeah More vegetarian sometimes I do But I could just do it with ice cream But I try and avoid it because they're just There's vegan ice cream Oh my god, yeah there is It's been a student It's quite difficult with a vegan lifestyle Because it is a bit like


That was great, and I want to thank Sharon and the panelists once again. Our next speaker is Brad Bernstein from the Broad Institute, and Brad's going to be talking about systematic survey of human epigenomes. Well, needless to say, it's really a great pleasure to be here on this very special occasion. I have the privilege of representing a burgeoning field that was enabled by the Human Genome Project, if not created by the Human Genome Project. That's the field of epigenomics. So the field really is about the study of physical and structural organization of genomes with sort of the bold goal of ultimately connecting genotype to phenotype. As you will see, thanks to major technological advances and coordinated efforts that were really inspired by the Human Genome Project, a lot of progress has been made. So for my talk, separated into three sections, I'm going to give an introduction on the epigenome and its features. I'll talk about the mapping technologies that are now being applied very broadly. I'll talk about the NIH Epigenome Mapping Centers to tell you about some of the biology and how epigenome maps really inform on developmental, not only lineage, but developmental potential, but also with the goal of making the community aware of this resource, which whose value bridges across, I think, all of the institutes here in terms of disease. And then I'll turn to the ENCODE Project and really near and dear to the National Human Genome Research Institute, talk a little bit about how epigenomic mapping is now taking us beyond the genes and shedding light on the non-coding or the dark matter of the genome, and I think with important implications, as you'll see for human disease. So the fundamental challenge here is that we have a three billion base sequence of DNA, and this is two meters of DNA that needs to fit into a nucleus that's a tenth of the size of the head of a pin, right? So how does, how has biology dealt with this immense problem? Well, the DNA is, as we know, wrapped around the histone protein, spooled around these histone proteins to form nucleosomes, and these nucleosomes are then sort of arrayed into complex structures and fibers that then form into these higher order structures that make up chromosomes, right? But the structure is not static, right? This is a dynamic structure, and it varies greatly across the genome and with the genes and elements, right? So this is just a picture showing a Drosophila-Polytine chromosome, and what you can see here, the point is that the genes, if they're transcribed, the chromatin opens up and nucleosomes spread apart so that RNA polymerase and the transcriptional regulators can get access to the DNA itself, right? Whereas much of the rest is compacted. This can also be seen in this image of the nucleus where these silver grains show sites of transcription, which primarily occur internally in the nucleus, and these white structures reflect the heterochromatin, the peripheral heterochromatin that is compacted and sequestered away, right? So in this way, the genes and the control elements are made accessible to the polymerase and to the other regulatory factors that, they help those factors find these beacons of information in the genome. So one of the critical advances or critical elements that has enabled the field of epigenomics is that these structures are really predicated on chemical modifications. So these chemical tags exist not only directly on the DNA in the form of methylation of CPGs or cytosine bases. This is just shown here. It's often a repressive event that's associated with heterochromatin and transposed on silencing. And in addition, there is this, this is just shown, the nucleosome and the histone tails are subject to many different kinds of chemical tags or post-translational modifications, as we've heard about a little bit in Eric's talk today. So these modifications are intimately connected to the structure of the genome. Open structures have particular characteristic modification patterns, closed structures have yet others. And as I'll show you, the information content here is very high and can tell us a great deal about the DNA elements as we survey across them. So you know, a lot of the excitement in the field has stemmed from its connection to this concept of epigenetics, right? Epigenetics in some ways is a fancy way of thinking about development of how a single genome can begin early development and then through a pluripotent cell give rise to all these different lineages without essentially any change to the DNA sequence yet we know that these different cell types or lineages have, you know, markedly different phenotypes that are maintained throughout the lifetime of an organism. The different phenotypes are closely related to cell-type specific gene expression programs, right? Each of the different cell types expresses different genes and the gene expression patterns are in turn, as you might imagine, related to how the DNA is organized into the chromatin and at a certain extent some of these modifications such as DNA methylation and a select few of the histone modifications such as the modifications associated with polycomb regulation are epigenetic in themselves and some of these modifications actually help propagate and maintain the state of an individual cell and thus are epigenetic. And this is sort of the partial but not complete relationship between epigenetic and epigenome. Epigenome really studies the full structure in all these modifications and which can help us understand epigenetics. So I told you about development. What about human disease? Why is this so important? Well, it's, you know, increasingly being highlighted across many diseases. So cancer is a genetic but it's also an epigenetic disease. A baron DNA methylation is a hallmark of adult cancers. There are now increasing numbers of prevalent mutations being identified in a wide range of chromatin enzymes and other chromatin associated proteins are turning up in the large scale sequencing projects like such as the TCGA which we'll hear about next. You know, there are, there's increasing evidence for epigenetic dysregulation in neuropsychiatric disease, metabolic disease, developmental disorders, mutations in chromatin enzymes, aberrant epigenetic landscapes. And there's this sort of, I think at this point, admittedly ill-defined concept that we know there are long-term consequences of early environmental exposures and an open question remains, you know, how does this relate to epigenetics or epigenomics? And this is something that I think the field is also wishing to explore. More broadly, as I'll show you today, epigenomes enable a functional annotation that really can help us understand the way genotype gives rise to a phenotype in any tissue or disease that can identify the places in the genome where the activity is going on. And that's why I think it's very broadly applicable across different disease states. There's consequently this urgent need for, I think, reference human epigenomes. There are, of course, many of them for the different cell types and different disease tissues and for tools, importantly for tools to enable disease researchers to study and to understand the defects that might be present in their particular model system or disease. There are a number of groups of NHGRI, and ENCODE has put a lot of effort into this. There is the, I'll talk also about the epigenomics project, which has now spawned an international-level project as well. How, you know, again, going back to the genome project, and it's really, it's pushed technology to such a great extent that we've heard about the sequence technologies and how they've changed our ability to sequence genomes. They've also changed our ability to understand epigenomes, right? So these are the features, DNA methylation, accessibility of DNA, the histone modification patterns, high-ordered structures, and at every level, next-generation sequencing has really just changed what we can do. Whole genome by sulfite sequencing is now possible. You can sequence all the methylated DNA, pick those up. DNAs can be sequenced, hypersensitive sites, open genome, chromatin IP, chip-seq, as I'll show you, can be used to map histone modifications across the genome. And of course, I won't really talk about RNA-seq, but here's yet another technology. I don't want to say that, you know, we've solved the answers, right? There's a lot of challenges that remain. You know, I think key things in the field are people want to know how to do direct readout of methyl cytosines. Right now, everything we do is a little bit indirect. Single-cell analysis is critical. All our studies are ensemble analyses. We still need better ways to handle tissues and heterogeneity, a lot of challenges. We haven't really begun to have, you know, Eric alluded a little bit to how we're now studying higher-ordered organization of genomes, and we're just beginning. But I think what I'm going to really focus on today are histone modifications and some of the DNA methylation patterns. Because these are relatively mature technologies, and I think they provide an opportunity for researchers across many different fields. So first, some vignettes, a couple of vignettes from the epigenome mapping centers that the NIH has initiated and now has really extended to an international effort. One of the key milestones by Joe Ecker and Bing Ren and colleagues in the consortium was the whole methylome sequencing of ES cells that was published about almost two years ago now. Basically, bisulfite sequencing technology was used in which unmethylated Cs are converted to Ts. Deep sequence to 20x coverage, get a genome-wide map of methylation patterns in a given cell. So building upon this now, Joe Ecker, Jamie Thompson and colleagues have now taken a very broad look at many different ES cells and induced pluripotent stem cells, right? These are the reprogrammed cells and asked about the patterns of DNA methylation in these cells. They found a striking difference in the IPS cells. Many, many, these are just sites across the genome, and you can see the white and red and all these cells on the right in these IPS cells here really indicates there are many regions where there's a difference between the IPS cells and the ES cells, and in many cases this difference appears to reflect something remembered from the initial cell that was initially reprogrammed, right? Clearly a lot more work to be done, but it's an example of how this technology can help us to vet and quality control and analyze reagents for regenerative medicines such as IPS cells. Alex Meisner and Kevin Egan at the Broad Institute and Harvard Stem Cell Institute have undergone a similar analysis of DNA methylation patterns in ES cells and IPS cells. What they found was a very wide variation in DNA methylation patterns. Some sites in the genome tended to be very similar between cell types, but other sites in the genome such as some of these genes, S100, and some of these other genes had a very wide range of methylation patterns across these different cell types. Is this noise or is this functional? Well, what they were able to show is that actually the methylation patterns in an individual IPS cell or in an individual ES cell actually predicted the different lineages that the ES cell would be capable of differentiating into. So I'll just give you one static example of the CD14 locus which is important for macrophages. These are some of the Hughes ES cell lines. Here's Hughes 6 and you can see that there's partial methylation of the Hughes 6 promoter and you can actually, these cells, Hughes 6 can be differentiated into macrophages. The CD14 promoter now comes, the gene comes on. In contrast, they show that the Hughes 8 line which is completely methylated in the ES cell stage, CD14 cannot turn on CD14 and cannot make macrophages. So here's just one example where epigenomic maps can actually read out the potential of cells of clear value I think for regenerative medicine. So switching gears now a little bit to histone modifications. This is sort of, you know, another way to read out cellular state. Basically, as we heard this morning, we can use antibodies to a modified histone to pull out the chromatin that's marked by that particular modification. We can then use these new sequencing technologies to deep sequence the enriched DNA. Basically, take the reads, you count the reads and you integrate them into density profiles that basically tell you about the histone methylation patterns in these regions. Part of the beauty of the histone methylation is that there are many different marks that light up different kinds of entities. So for example, there's this green mark, lysine 4 trimethylation. This red is the lysine 27 methylation, a repressive mark. In ES cells, many developmental genes such as Pax 5 are marked by bivalent domains where you have sort of a mixture of these two marks. And increasing evidence suggests that this reflects sort of a poised state where the gene can be turned on depending on the fate of the cell in differentiation. And in fact, one can look at now down the lineage at hematopoietic stem cells. Pax 5 is still off in hematopoietic stem cells. You still see sort of a bivalent marking suggesting that it may still be poised in the hematopoietic progenitors. And as you can see in B cells, Pax 5 is a classic B cell marker, B cell lineage determinant. Here you have a switch. You keep this on mark, you lose the repressive mark. And this is a K36 methylation mark we heard about earlier today that is a mark that's telling you about a region of the genome that's transcribed. So here's the switch and basically kind of illustrates how one can use epigenomic maps to sort of follow gene expression in the fate of the cell. So the epigenomic mapping centers have looked very broadly at different classes of cells, pluripotent ES and IPS cells, different blood lineages, solid tissues, and then there's also cultured cells from the ENCODE project you'll hear about. We've mapped these cells using principal component analysis. You can take information from the methylation maps and project the cells into two-dimensional space based on these principal components. And I think you can see that regardless of the modifications we look at, we see sort of tight clustering of the pluripotent cells and each of these other types of lineages, blood or solid tissue, and culture cells seem to segregate into different parts of the map. So I show you this for a couple reasons. One is it's a resource that we can then project disease cells, regenerative medicine cells, and other lineages upon this and we can learn about how closely its epigenomic landscape maps onto what one would see for a normal tissue, right? Or whether it's looking a little more like culture has altered the epigenome. And the other reason is I could show you a little bit of some of the biology that's going on. And again, this is the K27 methylation mark associated with epigenetic repression. ES cells are clearly in this own space up here and there's this axis here in the PC1. What does this axis reflect? So in the next slide we'll look a little bit at this. And I think what I'm trying to show here is this is a large locus. And what you can see in ES cells is that the background for this repressive modification is very low and there's some peakingness across the genome. But as you differentiate into some of these terminally differentiated cell types here, you see a spreading out of this repressive modification. And this is something we see again and again in almost all of the tissues we've looked at. It's a thing that distinguishes pluricotin cells from committed cells. There are large portions of the genome sort of sequestered into repressive epigenetic or repressive chromatin. We think this reflects sort of a compaction of chromatin shown here. We can recreate it in cell culture by taking ES cells and differentiating them into EBs, neural progenitors into neurons and this leading to the sort of spreading or compaction of the genome. So I think this sort of, you know, together with the DNA methylation data shows how the epigenome mapping center data is highlighting a prominent role for epigenetic restriction both at specific loci but also across broad regions in lineage fidelity. There's a rich resource here too for developmental regenerative medicine and disease research. So for the last section of my talk now I want to sort of explore a little bit more deeply. What's going on in these very large portions of the genome here where you don't have any genes? Why has the epigenomic machinery gone to such a length to sequester these large portions of the genome away from activity? What's going on there even when they're non-genic regions? What's going on in this dark matter? And so I'm going to turn to another project.  Here we are using signature histone modification patterns, so sort of combinations of histone modifications to very powerfully identify non-coding DNA elements such as enhancers or insulators or silencers, right, these things sitting out in the non-coding genome. What we found is that combinations of modifications are a very powerful way of picking up these different types of regulatory elements across the genome. We've collected very large data sets in the context of ENCODE. A matrix or a compendium of all these different cell types across all these different modifications map genome-wide in each of these cell types for well over 100 maps. We've heard a little bit about the importance of computational biology, software engineering this morning, and so I do want to use this opportunity to just really emphasize that we were so fortunate here to have a team of exceptional computational biologists led by Manolis Kellis at MIT Computer Science Department really mapping out an effective strategy for analyzing this very large data set as you'll now see. So the strategy, the goal was to annotate the genome very robustly by chromatin state. The strategy is to take an unbiased look, use one of these hidden Markov models, and learn about what are the recurrent modification patterns. So which modifications like to show up together? Which show up in different patterns? What are the different kind of combinatorial patterns that exist across the genome? We call these different patterns states. Once we learn these patterns, we then can annotate the genome by these states and we can pick up enhancers and all these other regulatory elements, right? So this is a little complicated, but this is sort of the different states. We found about 15 chromatin states. They each have different combinations of these methyl marks. I'm not going to go into detail here too much, but I want you to understand that, you know, these top three states, these are promoter states. They coincide with annotated TSSs. They are, you know, accessible and there's TS bound to them, right? Some of them are active promoters. Some of them are sort of poised promoters. We have a number of states here in orange and yellow that are really, I think, important for the story here. These look a lot like enhancer states. Some of them are known enhancers. They bind different TS, right? And they're accessible and they're very cell-type specific. So an example of enhancer state, we have insulator states. We have regions of transcription. So we're basically marking up the genome now based on chromatin to learn about the functions of all the individual regions and bases. So, you know, this kind of approach allows us to compress a very large amount of information, almost 200 different chip-seq experiments, 2.4 billion reads in about 100 billion bases into a single genome-wide annotation for each of the cell types, right? So we can then show you these are what the annotations look like. They're colored according to those states that I just showed you. Here's ES cells, erythrocytic cells, immune cells, hepatic cells, right? These are the patterns. We can see coordinated changes. For example, this is the witless gene in ES cells. It's got this little pink here, poised. It's off, but poised. In these cells here, it's active, it's transcribed, and there's a lot of these orange enhancers across the region, right? So we can study coordinated changes in chromatin states. I should show you that we've spent a lot of time validating that when we call something an enhancer, we light it up orange and we then go and do an enhancer assay. It, in fact, does enhance luciferase reporter activity. And our calls are cell-type specific. If you take an enhancer from an immune cell and you test it in a liver cell, it doesn't do anything. It has to be an enhancer annotated in the liver, works in the liver. So in the last couple of minutes, I want to talk to you about how we're trying to take this information and integrate it into a regulatory network that goes beyond just incorporating the genes and their interactions, but now brings in these distal elements, these enhancer elements, and links them into a genome regulatory network. So first thing we need to do is to take elements such as promoters and cluster them based on their patterns of activity across the different cell types. We did this for promoters, and what we can find is that some promoters that are specifically active in lymphoblastoid cells, well, they tend to regulate immune genes. Promoters active in hepatic cells tend to regulate cholesterol transporter lipid genes. But we can do the same thing for enhancers. We can cluster enhancers, and again, enhancers in immune cells tend to be near, not right at, distal, but near to genes that have immune functions. So we're doing something right here. Here are the ones in the liver cells involved in lipid metabolic processes. What can we do next? Well, we can now take coordinated patterns of enhancer activity, and we can correlate those patterns to gene expression patterns of nearby genes, and we can begin making probabilistic linkages between enhancers and genes. So now we're linking the enhancers to predicted target genes based on patterns. I don't have a lot of time to tell you all the details here, but basically we're using correlated patterns to link genes, and there's evidence that we're doing something right here because there's a rich field of quantitative trait loci studies. We haven't heard a lot about this today, but it's a genetic approach for linking enhancers or regulatory elements to distal genes. The linkages that we've drawn based on patterns of chromatin activity across many cell types to genes actually correspond nicely with a high significant enrichment to those linkages drawn from genetic studies. So there's something that we're doing right here. We're beginning to draw a model of the enhancers, their gene targets. What about the upstream regulators? We can also link enhancers to upstream regulators, upstream TFs by identifying enriched motifs, looking at the expression patterns of the cognate transcription factors, identifying signatures. Again, not a lot of time to go into all the details here, but what we can see is that an ESL-specific enhancer cluster, well, it's highly enriched for oct4 motifs, and it's on when oct4 is on, right? Liver enhancers tend to be enriched for H&F sites, and in fact there's evidence that H&F's regulating these. We can then go to do, again, our enhancer assays, we can take those enhancers, we can mutate the H&F sites that we predict are activating these enhancers, and sure enough, the activity is lost or goes down significantly in these examples, okay? So to summarize here, we've got now a model, a regulatory model, where we've identified enhancers and we've linked them to TFs and to downstream genes. Probabilistic is just a start. We're only linking about 10% of enhancers that we've identified. There's much more work to be done, but here's where it gets interesting. So we've now intersected these enhancers with the SNPs from the GWAS studies. So these are the SNPs associated with human disease. So most of these SNPs are non-coding. So what are they doing? Well, it turns out that disease SNPs are enriched about two-fold in the enhancer chromatin states. If you look at control SNPs, they don't show any preference for any of our different chromatin states, so, moreover, the correspondence between SNPs associated with a particular disease and the enhancers is cell-type specific. So erythrocyte phenotype SNPs are associated with this erythrocytic cell line. The SNPs fall in enhancers that are specifically active in the cell line. SNPs associated with lipids sit in enhancers active in hepatic cells. SNPs associated with immune diseases sit in enhancers activated in immune cells. Here's just some connectivities that we're drawing here. To give you just a little bit of examples of looking at the individual SNPs for the blood lipid disease study, you can see clearly there's a nice little stripe of enhancer activity going down in orange and yellow, specific to hep G2, liver hepatic cells, right? Drawing the connectivity, these things are falling in enhancers that are specific to the liver cells. Same for erythrocytic phenotypes. Same for SLE. We can pause it based on our model, some of the target genes that might then be regulated by these enhancers, possibly affected by these SNPs. And getting a little speculative, but I really think this is kind of the future of what we're going to see here, we can now, I think, assist in the interpretation of genome-wide association studies in the following way. First of all, in some cases, the lead SNP in a study is sitting in sort of an unannotated region, but an associated variant is sitting in an enhancer with just the right cell-type specificity. This may be a means to try to triage variants. This may be a likely causal variant as it's sitting in enhancer, a speculation, but I think it's something that is going to, should and will be followed up upon. We can also make predictions about regulatory interactions with TS. So what we find is that some of the SNPs affect the binding sites for some of the predicted regulators. So here's an example for an erythrocyte phenotype GWAS where the SNP is affecting a site for GFI-1B, which is one of the predicted, actually repressors of enhancers in erythroid cells. And finally, there's an example from SLE where there's an S site that is affected in a immune-specific enhancer element. And in fact, S is in SIS, already been associated with lupus, which is a variant in the edlocus itself. So my last slide. I tried to convey to you how valuable epigenomic maps are for finding the non-coding elements in the human genome and even for determining their cell-type specific activities. I've shown you how chromatin dynamics can help us link enhancers to regulators as well as to target genes. I've shown you some evidence of these annotations and regulatory predictions can be useful for interpreting GWAS studies. And I would like to just finish by arguing that integration of ENCO data, there's a lot more data here for T transcription factors and RNAs, hundreds and hundreds of data sets. As well as epigenomics data, the in vivo tissues, the mapping of the in vivo tissues that are really the site of these disease processes can provide an incredibly rich resource for interpreting many different types of human disease. And I've acknowledged people as I went along. So thank you very much. We have time for a question. That was just a fantastic talk. Hi, I'm Steve Lincoln from Complete Genomics, and obviously one of the problems that we wrestle with is the question of how to sort of make the bridge from exome sequencing to genome sequencing. When will it be that perhaps using the techniques that you described here, that one wouldn't just be able to apply the annotations to GWAS studies as you described, but actually have an equivalent of Cypher polyphen, if not better, that can help annotate variance in genome sequences outside of coding regions? Yeah, well I think what's clearly happening is that the field is moving so quickly. The sequencing technologies are moving so quickly thanks to places like Complete Genomics that very quickly, whole genomes will simply be sequenced, and that will be the most straightforward approach. So I think then this kind of information on epigenomes, possible functions of the non-coding regions and the non-coding elements can become even more important as we get more data down the line. If you use the same cell line to make IPS or mRNA stem cells, which one will be more lineage restricted? Say making brain cells or heart cells. The issue here is you can make IPS cells, but you can't make ES cells. So I think the question then becomes which is the best cell to start with to make an IPS cell? And I think I'm a skeptic in science. I think we need a lot more data. I think we need to take a much more in-depth look at the different ES cells and the different IPS cells as my colleague Alex Meissner has shown. There's a lot of variability across different ES and across different IPS. And I think we need to get a better handle on the nature of this variability before coming up with a clear picture on what the best approach is. More data.


An isthmus is a narrow piece of land connecting to larger arias across an expanse of water by which they are otherwise separated. The tomb below is an isthmus that consists of a spit or bar, and a straight is the sea counterpart of an isthmus. Kynos are often built across isthmuses, where they may be a particularly advantageous shortcut for marine transport. For example, the Panama-Kynal crosses the isthmus of Panama, connecting the North Atlantic and Pacific Oceans. The Suez-Kynal connects the Mediterranean Sea and the Red Sea, cutting across the western side of the isthmus of Suez, formed by the Sinaiton insula, and the Cranant-Kynal crosses the isthmus between Blok Cranant and Lok Gilp, which connects the Kintyre Peninsula with the rest of Scotland. Another example is the Wethland-Kynal in the Nyagretan insula technically an isthmus. It connects Lake Ontario to Lake Erie. The city of Auckland and the North Island of New Zealand is situated on an isthmus.


So, it's got a little bit further, show everyone, let people see that I'm not alone here. You can show us all those tracks, just those tracks there. So, come close, just come close so that people can hear what I'm saying. Okay, so very good, you can see my handsome face there, very good. So, I'm not going to say exactly where I am, but the issue is I've got these gentlemen here. These are drivers coming from Zambia, they are local citizens, they are drivers. We also have some drivers coming from Zimbabwe and we have drivers coming from Malawi. These people work for a company which is owned by a Chinese called Kevin Yang, or what is it, Peng Yang. I don't know which one, these guys, you know, they like to play with names. Peng Yang, Kelvin Yang, I don't know. But anyway, the issue is that this Peng Yang has registered this brick first here in Zambia and in South Africa. Now, as usual, the fashion of Chinese, they like, you know, to do things underhand and evade tax in most cases. So what he has done, he has registered a company here in Zambia and he has employed drivers. Then in South Africa, he has registered the same company and he owns tracks. So you can imagine the situation that we have is that in Zambia, that is where Malawi, Zimbabwe, that is where he has the drivers. In South Africa, he has a company which owns the tracks, but he's the same guy, it's the same Kelvin Yang. Now, what is the issue? The issue is that these people here have been here for about 42 days. They have just been here. Why have they been here? They have been here because, as you remember, the issue of genophobia in South Africa. South Africans don't want foreign drivers to be driving the South African tracks. So you can imagine this guy has got workers coming from Zimbabwe, coming from Malawi, coming from Zambia, driving South African tracks. When you go to South Africa, you are coming from another country, you are not South African, driving a South African track, you are in trouble. Some of them have been killed, I think we have seen on social media, whereby tracks have been banned and people are shorter. So the situation is that these people can't drive, they can't go into South Africa with these tracks, they can't because of the risk that is there. So they came to an agreement, they packed these tracks, they can't go to South Africa, so they packed them here. Some of the tracks, is it in Congo, isn't it? Some of them are in Chingolai. Total, we are talking about how many drivers, 350 drivers. We are talking about 350 drivers who have been employed, but they can't go into South Africa. The tracks, they have kept the tracks here so that they can resolve this issue. The owner of the tracks went to Forced Quarters because he wants his tracks, but these people want their money. Now this Chinese is interested in the tracks, he wants his tracks and yet he has not paid these people. These people have not been paid and they are being owed money about how much in total? How many millions are we talking about? 47 million in total because they are about 350 and in total we are talking about 35 million somewhere there. Now, he wants the tracks but he hasn't paid them and then he comes here, he goes to police so that these people can release the tracks. I want to commend the police at Forced Quarters. The commissioners there, these people are very happy with the way you handled the situation. They are very happy, you handled it professionally. I think this is where I must commend the new Don. At least I'm not doing politics, it's not me, it's themselves. They have told me that the police at Forced Quarters, they were very helpful and they are appreciative of what you did. An agreement was signed, this is the agreement which was signed between this director and these people. The agreement was very clear, it's very clear here that this man must pay them their money. Once he pays them, then the tracks can go and to calculate, to compute how much they should be paid, they were sent to labor office. But this Chinese, instead of waiting for these people to go there, he went there quickly thinking that he can corrupt the people at the labor office. Thank God to Mrs. Moyo, she acted very professionally, they are appreciative. They have told me how this man wanted to have a private meeting with you and you refused, Mrs. Moyo isn't it? Yes. Yes, you refused, that is very good, I think this is how it should be. People must have confidence in the government institutions and I'm very happy that you handled them very well. Unfortunately, the matter was not settled at labor office because this person, the director, the company has not brought the details of their work conditions and the live days and how long they have saved for this company. So because of that, they couldn't agree how much really they are going to be paid. But for them, the drivers, they know.  Unfortunately, from the company side, from the company side, they haven't brought the issue.  Whilst they are trying to resolve issues at labor office, this Chinese ran to court and got an ex-party. He got an ex-party. Instead of agreeing at the labor office and pay these people, he rushes to court and got an ex-party injunction. An injunction so that these tracks can be released. I am actually happy also that it seems even the judiciary have handled this issue very well because they started with an ex-party. Now it is an inter-party. And unfortunately, the boy is in the court of this Chinese. He is the one who has to provide to answer to this ex-party. Legal aid is helping these drivers, which is very good. Now, what is the point here? The point I am trying to address here is that these people, these are vulnerable, much as they are drivers, but they are vulnerable. They are vulnerable in the sense that they are fighting with their employer, the person that has employed them. Instead of giving them what is due to them, he is busy trying to cut corners. He is busy moving from this to that that he wants to run away from paying them their money. This Chinese doesn't seem to want to pay these people. Instead, he is going from this place to that place, instead of following what he was advised at the forced headquarters to agree to compute how much he must pay these people and pay them. Then he can get his tracks. But you can imagine the arrogance of some of these Chinese. He says, I would rather pay a judge than pay you. And this is why these people have called me, because they are scared. They are scared that this man might corrupt the judge. I am very sure I know Judge Joshua Bander. I think this man is wrong. I know Judge Joshua Bander. I don't think he is the man that will sacrifice these people who have got families who are here struggling because of a few coins. I don't think he can do that. I don't think he can do that. And I want to take this opportunity to send a message to some of these Chinese who think that they can buy our judges. You are wrong. Not in Zambia. Not in Zambia. In Zambia, we don't buy judges. Our judges have got credibility. Our judiciary is solid. And I'm sure this case, this case, let me note it, because I don't know the concept number. Anyway, this case will be judged accordingly. The fear that they have, the fear that you have, you people that know the judge might be corrupted, I want to assure you. The judge cannot be corrupt in Zambia. You my brother, the judge in Zambia cannot be corrupted. Nothing. So this guy, he can be bragging to say, no, I would rather pay a judge who is dead home. You have got a right cause. It's your money. You worked for it. I must pay you. And they are scared that if they release the tracks, they will lose the money. And indeed, this should not happen. These people cannot release the tracks because these tracks are South African. If this guy gets the tracks, he takes them to South Africa. He's a Chinese. Do you think they will get the money? They can never get the money. They can never get the money. Therefore, I think the new dawn, so far, I think things have been very good, but I think you need to help these people. That's why I'm standing here as a public lawyer to encourage you to help these people. Make sure they get their money. Make sure these tracks don't go anywhere. Because if they go, the guys Chinese, tracks are registered in South Africa. They will lose out. And it's a lot of money we are talking about. Some of them, on average, each of them is being owed about 300,000 Kuatia. That's a lot of money. That's a lot of money. They can't just go. So please let everyone, let everyone who will come across this case, look at the plight of these people. These people have got families. These people have been suffering. I've been working for these people, for these Chinese. They should not be neglected. They should be helped. I'll talk about it later on. But for now, let me just show you the tracks and what they are carrying. After they are carrying things. Let me just show you. These are the tracks. They are loaded with things there, you see? How far? There is, you see? South African tracks. You see there, it goes. And these Chinese, he doesn't think properly because he's delaying. These tracks are loaded. Look, they are all South African registered tracks. If they leave, these people will lose money. There is the company. This is the company. Registered in Zambia and South Africa. They go up to there. There are a lot of them. And they have got a just cause to keep these tracks because they have not been paid their money. Can anyone, anyone who come across this case help out? Look what they are carrying here. These Chinese, I wonder why they behave like this. Anyway, this is the issue. Okay, so, I think... This is a big story. This is a big story. This is a big story. This is a big story. Let people know about this. This is a big story. This is a big story. This is a big story. So that they should learn. I think I've made my point. I'll talk about it later on. For now, let me go back and see my wife. Bye.