[User] Please transcribe this text

[Assistant] What folks are getting smart about is taking that water and using it, retreating it, and then using it for other purposes. We have a Hyatt Resort that I love to talk about because it takes water, treats it with our systems, saves tremendous energy as well as water because they don't have to pump that water


[User] Please transcribe this text

[Assistant] From one place to another, they already have it. They just use our systems to treat it. And then they water the golf course and all the agriculture.


[User] Please transcribe this text

[Assistant] on the property and it's when you do the economics on that it's amazing because it's not just the chemical you're saving you don't have to


[User] Please transcribe this text

[Assistant] Pump the water, which is really one of the big energy consumption aspects of water.


[User] Please transcribe this text

[Assistant] So yeaah, very, and increasingly that's part of our strategy going forward, quite frankly. You're gonna see us on, uh,


[User] Please transcribe this text

[Assistant] Uh, water reuse systems even capturing rainwater harvesting and making it safe. A big area and opportunity. Does that answer your question? Okay, thanks. In the back?


[User] Please transcribe this text

[Assistant] Yeah, the question is, what is the limiting factor to getting this deployed, uh, worldwide and even more aggressively? Uhm, you could be on my board of directors. Uh, I get that question all the time.


[User] Please transcribe this text

[Assistant] To deal with now is it's about finding channel partnerships. I'll give you an example. We had


[User] Please transcribe this text

[Assistant] Uhm, really good success in the US and in Mexico in beverage, which I talked about earlier.


[User] Please transcribe this text

[Assistant] A couple of times, and then that same corporate player said, we love this.


[User] Please transcribe this text

[Assistant] Now we want to go take this to Europe and East Europe and other places, uh, even in the Middle East. And we said, whoa, we're not prepared to go do that just yet.


[User] Please transcribe this text

[Assistant] You can actually install and maintain, so it's not just the sales component.


[User] Please transcribe this text

[Assistant] Uhm, where somebody sees that there's a real opportunity and there's customers who want the product. Second, yeaah, following question?


[User] Please transcribe this text

[Assistant] To be specific about it, because this is work, uhm, that's still in process.


[User] Please transcribe this text

[Assistant] But, uh, yeaah, for us we know that we cannot get to all these markets simultaneously and that one of the best ways to do it might be to license, uh, as well as to, to provide distribution access.


[User] Please transcribe this text

[Assistant] Uhm, Siemens is a company we're very close to, uh, several of our key executives and one of our board members were part of the Siemens network at one stage. But we, you know, we talk with all of those large companies and that is a key part. And that's one of the issues of scaling up a clean tech company, right? It also gets to that earlier comment that I said,


[User] Please transcribe this text

[Assistant] You know, people like to buy from people they know and, and clean tech industry, uhm, industries in general.


[User] Please transcribe this text

[Assistant] Because of that momentum factor I talked about, it's even more important to think about who you're selling with or through.


[User] Please transcribe this text

[Assistant] Because their brand name actually means a lot in some cases. Not just because


[User] Please transcribe this text

[Assistant] I'm gonna repeat your question and I may modify it a little bit, so give me liberty and if I'm not answering just let me know. Uhm, I think the question was, it seems like, and I think if this is your assertion this is correct, that our technology isn't as capital intensive to test in terms of the development of the technology.


[User] Please transcribe this text

[Assistant] It actually has a lot of rigorous testing though in the sense probably more than is apparent because it goes into


[User] Please transcribe this text

[Assistant] There's a tremendous amount of regulatory oversight and hurdles that you have to go through. So it is a very rigorously tested device.


[User] Please transcribe this text

[Assistant] Probably much more than solar and hydro and other energy related clean tech devices that I can think of in terms of


[User] Please transcribe this text

[Assistant] Is it certified, if you will, by the relative agencies? Uhm, the other part of your question, though, I think is spot on, which is


[User] Please transcribe this text

[Assistant] To develop the technology wasn't as capital intensive as say developing a new solar fab, where you not only have the technology issues to deal with,


[User] Please transcribe this text

[Assistant] You also have the capital intensity associated with ramping up production and I think that's one of the things that


[User] Please transcribe this text

[Assistant] The investment community is coming face to face with in clean tech very quickly is if you look at the way the venture capital community is set up for the most part and there are exceptions, it's really set up to take smaller


[User] Please transcribe this text

[Assistant] Bites at the apple. Five million, you know. Let's see this with a couple hundred thousand or a million.


[User] Please transcribe this text

[Assistant] Get to proof of concept, then put a couple million in, then we'll get the revenue, then we'll put a couple more million in. And, you know, you have 10 million in.


[User] Please transcribe this text

[Assistant] Trajectory, maybe you're, you know, worth two or three or four or five times that. You know, good outcome.


[User] Please transcribe this text

[Assistant] And you look at a solar company which might take 200 million on an extreme case.


[User] Please transcribe this text

[Assistant] To get ramped up and then only to find out you're not cost competitive etc. That's a really big investment chunk. And I think that has already played itself out to some degree.


[User] Please transcribe this text

[Assistant] And the investment community is getting more thoughtful about how to either share that cost with either large companies or governments or others.


[User] Please transcribe this text

[Assistant] If we provide this payback period of a year or two, or we save huge costs over the life of the product


[User] Please transcribe this text

[Assistant] You didn't say it, but I'm interpreting your question to me. Are we maybe leaving money on the table around pricing? And the answer to that is sometimes


[User] Please transcribe this text

[Assistant] Flat out, that's not the case and we'll, uhm, we'll structure the deal.


[User] Please transcribe this text

[Assistant] In a particular market where we know there's a really strong need and we can price accordingly.


[User] Please transcribe this text

[Assistant] And the longer or more entrenched the industry you're trying to displace, the bigger that price advantage.


[User] Please transcribe this text

[Assistant] Uh, and I was the CFO and he was the CEO and he said, look, if you want somebody to change their behavior, you gotta be twice as good at half the cost.


[User] Please transcribe this text

[Assistant] You have to be twice as good at half the cost, which kind of gives you a rough 4x better mindset. I'm not sure if you can distill everything down that way, but


[User] Please transcribe this text

[Assistant] Uhm, I truly believe that if you want to get more than the early adopters, more than those first few folks, and there are some, you know, some people who actually pay more.


[User] Please transcribe this text

[Assistant] If they realize there's a benefit. And some of our early customers were like that. They didn't get any economic payback, but they knew they had a huge safety benefit or they had a...


[User] Please transcribe this text

[Assistant] Concern about the environment or about their worker safety or whatever it might be and they still paid that premium. But that's not how you get the mass markets.


[User] Please transcribe this text

[Assistant] Let me just, uh, I think a couple more questions if I'm trying to keep two more, two more questions so I'll get to you in one second. So, yes, in the white.


[User] Please transcribe this text

[Assistant] Uhm, was I tinkering in my garage? Kinda like, uh, you know, Steve and Steve with Apple. Uhm, or a lot of these stories we read about. Uhm, the simple answer is no. Uhm, I'm actually not even the founder of the company.


[User] Please transcribe this text

[Assistant] And the company itself started many years before I joined it. It was really


[User] Please transcribe this text

[Assistant] A bunch of ex Los Alamos lab scientists who are working


[User] Please transcribe this text

[Assistant] Uh, and uhm, I came across it and it was very much focused at military and government applications. And so one of the things that I kind of think about as a parallel, I didn't say this earlier, but uhm,


[User] Please transcribe this text

[Assistant] In water treatment, we take the whole equation and we push it out to the end user. And we give them the power to create what they need, when they need it. But to your origin question,


[User] Please transcribe this text

[Assistant] We're kind of like lithium batteries. If you look at a lot of technologies, they started with real military applications and then eventually found their way into the


[User] Please transcribe this text

[Assistant] And we're kind of following that path. The technology did incubate for a number of years.


[User] Please transcribe this text

[Assistant] Uhm, I came across the company Intersected at a time where it was really looking to go a commercial path, uh, and, and I got very excited about it. So last question. Two questions.


[User] Please transcribe this text

[Assistant] I think the answer, my short answer is no, which might be surprising, but it's not that desalination doesn't have a play, but you have to remember and start from the big picture. The world has plenty of water.


[User] Please transcribe this text

[Assistant] But about, uh, sorry, 97% of it is tied up in the oceans. About another 2% is tied up in glaciers and ice caps.


[User] Please transcribe this text

[Assistant] And so of the total available water, only 1% is kind of available for us to use. So a really


[User] Please transcribe this text

[Assistant] Well there's two problems with that. One is it's very energy intensive, even today with some of the technology, so you have to put even more energy in to get that water.


[User] Please transcribe this text

[Assistant] Uhm, and then if you want to take it any place besides the coast, you have another issue, but for a moment, let's just say there's a lot of problems you can solve on coastal cities with desalination. Uhm, you also have to do something with that brine, and that is an environmental issue, and I think


[User] Please transcribe this text

[Assistant] Uhm, I am pro desalination and we have some of our systems that sit behind desalination plants to do the final disinfection. But today's desalination technologies, as they are, are certainly not enough to solve the problem. And we have to think about the consumption side and the reuse side. Because it's actually a lot cheaper to take water that you use once and then retreat it for use than it is to take salt water and make it ready for use. It's just much more economical.


[User] Please transcribe this text

[Assistant] DeSale has a play, and I think there's some really exciting DeSale companies, uh, and folks who can do it with less money, which is less energy.


[User] Please transcribe this text

[Assistant] That's part of the equation, but you also have to solve what do you do with the brine that you get from that and pumping it back into the ocean, uhm, has a whole set of issues and implications as well.


[User] Please transcribe this text

[Assistant] You know, more than the reporters I was talking with last night, so that's good. Uhm, the, uh, I mean it's very bad.


[User] Please transcribe this text

[Assistant] There's uhm, a lot of technologies that do water treatment from filtration and


[User] Please transcribe this text

[Assistant] Desalination is kind of an ultrafiltration or reverse osmosis process often. Um, UV and ozonation and others. Ours is attacking the chemical side of the equation and replacing it with a better solution. Um, there are some systems where we are behind UV and help to keep UV free from, uh, or operating better.


[User] Please transcribe this text

[Assistant] Uh, or sometimes we actually, because UV can do some really nice things without chemical, you still haven't solved the whole equation because you haven't prevented the recontamination of that water. And so, ironically, in the US at least, UV is a really strong play in waste water. It really doesn't have a strong hold in drinking water, uhm, because it doesn't prevent the recontamination. But UV is a great technology, and again, like DSAL, if any of you are going to go create a really, uhm, low-power, uhm, UV,


[User] Please transcribe this text

[Assistant] I'd love to talk to you, because we could probably put it to good use. And we are partnering with a lot of UV companies, uhm, and we partner a lot with


[User] Please transcribe this text

[Assistant] Uh, membrane companies, uhm, actually no ozonation companies right now, but we did look at buying one once, but another.


[User] Please transcribe this text

[Assistant] But soon after the first fleet arrived in Sydney Cove in January 1788, a major gap appeared in the supply chain for building. In a word, lime.


[User] Please transcribe this text

[Assistant] You need lime to make mortar, and that generally comes from limestone. But Sydney didn't have any limestone.


[User] Please transcribe this text

[Assistant] A solution was needed and fast if the city was to grow. But where to find it?


[User] Please transcribe this text

[Assistant] Looking for answers, I'm travelling to Goat Island, the largest island in Sydney Harbour, to meet Jackie Goddard, a heritage expert at Sydney's Lime Forum. So what have we actually got here?


[User] Please transcribe this text

[Assistant] Traditional aboriginal feeding grounds provided a ready supply.


[User] Please transcribe this text

[Assistant] Heaps of discarded shells, or middens, piled up over thousands of years. Oysters were a staple for indigenous Australians here.


[User] Please transcribe this text

[Assistant] Most people have never seen a midden now. But when Philip and his cohort arrived, the Sydney foreshore would have been dotted with them. From Lane Cove in the west, to here, at Cockle Bay. That's the name.


[User] Please transcribe this text

[Assistant] I'm following up Jackie's mention of Hyde Park Barracks, which are located at the end of Macquarie Street, Sydney's grand old sandstone canyon.


[User] Please transcribe this text

[Assistant] Back to Goat Island and our experiment on how the humble oyster shell is turned into mortar.


[User] Please transcribe this text

[Assistant] City built on blood, sweat, tears of convicts. And, oyster shells. Fantastic!


[User] Please transcribe this text

[Assistant] Thank you Tom, and thank you all for coming out on a


[User] Please transcribe this text

[Assistant] Beautiful May afternoon in Palo Alto for y'all to come in and


[User] Please transcribe this text

[Assistant] May afternoon in Palo Alto I think is humbling because I was wandering around campus before this and


[User] Please transcribe this text

[Assistant] It's exciting to be able to speak with you all this afternoon when I was asked to give this talk by Tom Byers.


[User] Please transcribe this text

[Assistant] He said, think about the advice that you'd like to give to the next generation of leaders and entrepreneurs and, and for me that was sort of an irresistible offer. Uhm, I'll talk a little bit about, you know, my own personal story and


[User] Please transcribe this text

[Assistant] And some of what I did going into government and some of what I'm now doing in public service. But I want to spend a bulk of time just sharing, sharing four lessons with you. Uhm, first, manage time like you manage your money. Two, hire true believers. Three, stay connected. And four, stay out of the gray twilight.


[User] Please transcribe this text

[Assistant] I'll come back to those four later. But first I wanted to give a little bit of background about, you know, my history as a


[User] Please transcribe this text

[Assistant] As an entrepreneur outside of government and now inside government, as Tom Byers mentioned, uh, when I first got out of school, in the age of many of you, I


[User] Please transcribe this text

[Assistant] Became a middle school teacher in West Baltimore through a program called Teach for America.


[User] Please transcribe this text

[Assistant] And at this point, this was the early 90s and this was the pre-internet explorer, pre-broadband, pre-mass use of the internet. And one of the things that I saw when I was teaching these middle schoolers


[User] Please transcribe this text

[Assistant] My incredibly overcrowded classroom, I mean this is a, this is a beautiful amphitheater that probably holds


[User] Please transcribe this text

[Assistant] You know, 100-150 people, if there were this much space at


[User] Please transcribe this text

[Assistant] Uh, middle school students who were, who were just jumping beans in terms of their


[User] Please transcribe this text

[Assistant] It connected and engaged educationally and the one place where I saw those young people really be able to learn


[User] Please transcribe this text

[Assistant] The way that they were supposed to learn, as opposed to being stacked into a classroom and learning out of 30 year old textbooks, was when they used technology.


[User] Please transcribe this text

[Assistant] During the week where we would march down to the computer lab, uhm, for an hour a week


[User] Please transcribe this text

[Assistant] And one of the things that I saw with these young people in the computer lab and using technology to use self-paced learning was that there was something incredibly intuitive.


[User] Please transcribe this text

[Assistant] About the use of technology among that generation of young people.


[User] Please transcribe this text

[Assistant] You know, you probably would have been about the age of my, of my sixth graders then.


[User] Please transcribe this text

[Assistant] And I thought, you know, as this was taking place again during the early 90s in a period of the massive deindustrialization of the economy, the loss of America's manufacturing base, a time at which people could no longer count on


[User] Please transcribe this text

[Assistant] That the American economy was basically splitting into two.


[User] Please transcribe this text

[Assistant] On the one hand, increasingly technology rich, knowledge based jobs. On the other hand, instead of those good old jobs at the port, the mill, and the factory, people were having to go into service industry jobs.


[User] Please transcribe this text

[Assistant] And more often than not, mom and dad having to take those service industry jobs take not one but two of them and four jobs then between


[User] Please transcribe this text

[Assistant] And so, you know, what I and somebody saw at that time with the changing nature of the economy and sort of the rise of technology, uhm, was that, hey, this was an opportunity.


[User] Please transcribe this text

[Assistant] For people from historically low income and working class communities to enter the economic mainstream.


[User] Please transcribe this text

[Assistant] If it's the case that it doesn't matter how much money is in your wallet, or how much melanin is in your skin,


[User] Please transcribe this text

[Assistant] That the use of technology is incredibly intuitive regardless if you're a young person, then that's an asset that you could build on to help people enter the economic main street and compete and succeed


[User] Please transcribe this text

[Assistant] In our technology-rich knowledge-based economy. So after my history,


[User] Please transcribe this text

[Assistant] As, uh, after my time as an inner city school teacher,


[User] Please transcribe this text

[Assistant] I and three friends started a non-profit in a basement, uh, called One Economy. And, you know, if I knew then what I knew now, I wouldn't have bothered starting it. And if I had, I would have been incredibly unsuccessful.


[User] Please transcribe this text

[Assistant] So there was something about being a twenty-something year old, naive, hopeful individual that allowed me and my colleagues to become successful. And I'll get to the why of that a little bit later. And we built that, that non-profit


[User] Please transcribe this text

[Assistant] With the mission to maximize the potential of technology to help people of low incomes.


[User] Please transcribe this text

[Assistant] Enter the economic mainstream and, and we grew up from being four people in a basement to the world's largest digital divide organization, eventually helping more than 20 million people in more than 10 countries on four continents use technology to get the skills that they needed to live better lives. And, you know, I did that for, for a period of, you know, eight, nine, 10 years and


[User] Please transcribe this text

[Assistant] Personal and professional roots were in the south side of Chicago. And I saw in, in this man, Barack Obama, that he got it. He truly got how technology could be a difference maker.


[User] Please transcribe this text

[Assistant] You know, I was very fortunate, as Tom mentioned, to work, you know, amidst a great many people.


[User] Please transcribe this text

[Assistant] To help build a technology and innovation agenda for then Senator Obama's presidential campaign, which then propelled me into government service and what I'm doing now.


[User] Please transcribe this text

[Assistant] One of the real gifts of public service for me


[User] Please transcribe this text

[Assistant] Is getting to work for Secretary of State Hillary Clinton.


[User] Please transcribe this text

[Assistant] Uhm, she is a truly muscular secretary of state. Uhm, she's very, very good at her job.


[User] Please transcribe this text

[Assistant] And one of the things that she did upon becoming Secretary of State


[User] Please transcribe this text

[Assistant] was create an innovation agenda for America's foreign policy. If you think about foreign policy a lot of the time you might think about


[User] Please transcribe this text

[Assistant] The formal interactions between sovereign states with a flag flying in the background. But what she said is that not all of our diplomacy needs to be conducted government to government. But by using the tools of the 21st century, we can now engage government to people, people to people, and people to government. How can we connect and engage with the wider world in ways that we previously hadn't?


[User] Please transcribe this text

[Assistant] And if you think for a moment about some of our recent, uhm,


[User] Please transcribe this text

[Assistant] Uhm, I kept hearing the United States' foreign policy described as overpowering. The United States trying to overpower its interlocutors around the world.


[User] Please transcribe this text

[Assistant] And one of the things about Secretary of State Clinton is that she is now very much focused on empowerment. Empowering versus overpowering.


[User] Please transcribe this text

[Assistant] Twenty miles north and south of here in Silicon Valley, everybody knows and understands the role that technology can play in empowerment.


[User] Please transcribe this text

[Assistant] Technology is something that can be empowering and can get people engaged in diplomacy and development in ways that weren't, you know, the case historically. One example, uhm,


[User] Please transcribe this text

[Assistant] There was, in the hours after the earthquake in Haiti, uhm, there are these, these fantastic, uh, women who work in the innovation space at the State Department.


[User] Please transcribe this text

[Assistant] And they got the idea in the hours that followed the earthquake that you know, hey, tomorrow morning when people wake up and are having their morning coffee and they've heard about what happened in Haiti,


[User] Please transcribe this text

[Assistant] We should be able to do something so that those people hearing about this for the first time over that morning cup of coffee can do something right then. And so what they did is they worked with the private sector


[User] Please transcribe this text

[Assistant] Uhm, at the secretary's direction to immediately stand up a program so that people who texted the word Haiti to a short code 90999


[User] Please transcribe this text

[Assistant] Could donate ten dollars for earthquake relief.


[User] Please transcribe this text

[Assistant] And at the time, we, we thought, you know, hey, maybe we'll raise a couple hundred thousand dollars if everything breaks right. You know, wow, we might be able to.


[User] Please transcribe this text

[Assistant] Raise a million dollars and that would be of a truly historic nature.


[User] Please transcribe this text

[Assistant] Over the Twittersphere, in social media space, in other social media spaces, and once it became viral,


[User] Please transcribe this text

[Assistant] In, in the days immediately after the campaign in social media spaces, it was then adopted by the mainstream media.


[User] Please transcribe this text

[Assistant] Chose to use their cell phones to make a ten dollar donation.


[User] Please transcribe this text

[Assistant] And more than 30 million dollars were, was raised for, uh, earthquake relief in Haiti.


[User] Please transcribe this text

[Assistant] That Secretary Clinton is lea- is- is leading


[User] Please transcribe this text

[Assistant] Uhm, is an example south of our border here in Mexico. As I'm sure many of you are all too familiar with, the drug cartel fueled violence


[User] Please transcribe this text

[Assistant] Far too many people are dying, especially at border towns like Ciudad Juarez.


[User] Please transcribe this text

[Assistant] And one of the things that the Secretary of State and our Ambassador to Mexico, Carlos Pascual, said is, you know what, we need to take a new and innovative approach to this. Let's get some people from Silicon Valley.


[User] Please transcribe this text

[Assistant] And so we, so I and others were deployed down to Mexico.


[User] Please transcribe this text

[Assistant] To meet with the president's cabinet, to meet with people like Carlos Slim, to meet with leaders from civil society, and our goal was to come back with one idea, uh, that could help reduce crime in Mexico.


[User] Please transcribe this text

[Assistant] And so we came up with a program that is likely going to launch sometime in the fall, uhm, based on what we learned down there, which was that the Mexican citizens themselves will no longer report crime, by and large.


[User] Please transcribe this text

[Assistant] Because they're afraid that if they walk up the literal or proverbial steps of the station house to, to, uhm, report crime, they're gonna get found out and will therefore be in danger.


[User] Please transcribe this text

[Assistant] One of the things we learned while we were down there is everybody, even in the lowest income barrios in places like Ciudad Juarez, they all have cell phones and they all text message like crazy.


[User] Please transcribe this text

[Assistant] So we've set up a program where people are going to be able to anonymously text message, and I could explain how that works, but that's not the best use of this time, just take


[User] Please transcribe this text

[Assistant] Take for granted, I'm telling the truth, people will be able to anonymously text message, uh, a crime report.


[User] Please transcribe this text

[Assistant] So what we're trying to do with this program is to restore anonymity, transparency, and accountability back into crime fighting in Mexico.


[User] Please transcribe this text

[Assistant] And we don't yet know if that'll work, just like when we launched the text hating program. We didn't know what the results for that will be, but we're very hopeful.


[User] Please transcribe this text

[Assistant] So these are just two very quick examples of some of the kinds of things that we're trying to do.


[User] Please transcribe this text

[Assistant] Uhm, in a very innovative and very non-traditional way, uhm, in sort of the fusty old world of, of diplomacy. But I wanted to sort of turn to, uhm, the lessons that I've learned, having been an entrepreneur, having built


[User] Please transcribe this text

[Assistant] Manage time like you manage money. Hire true believers. Stay connected and stay out of the great twilight.


[User] Please transcribe this text

[Assistant] Briefly on each of those, number one, manage time like you manage money. So think about the amount of effort that entrepreneurs spend thinking about the allocation of capital and the effort that they put into managing their money.


[User] Please transcribe this text

[Assistant] That and building their product are the two most important things that they do, right?


[User] Please transcribe this text

[Assistant] Well one lesson that I would learn, that I've learned, that I think any entrepreneur


[User] Please transcribe this text

[Assistant] Must learn if she or he is going to be successful.


[User] Please transcribe this text

[Assistant] You know, and this is something that took me a long time to get right. You know, from age 22 to about 30, it was something that I struggled with. And I used to go through this exercise, you know, beginning when I was about 30, where I would


[User] Please transcribe this text

[Assistant] And I would literally go day by day and appointment by appointment and see what I was doing. And it made me want to like crawl into the fetal position.


[User] Please transcribe this text

[Assistant] To see all of these things that I thought were worthwhile and important and worth doing at the time.


[User] Please transcribe this text

[Assistant] And to realize after the fact that my gosh, I spent a lot of time.


[User] Please transcribe this text

[Assistant] Working on things that ended up just being losses.


[User] Please transcribe this text

[Assistant] What I would argue to you is that as much time as you put, as much effort as you put into figuring out how you're gonna manage your capital becomes similarly focused, similarly ruthless about how you manage your time. Because just as, as dollars drain out of your checking account, so too does time pass and time


[User] Please transcribe this text

[Assistant] And there's certainly a lot of smart people in Silicon Valley.


[User] Please transcribe this text

[Assistant] And one of the things that I've come to believe is that as people are building their teams, entirely too much emphasis.


[User] Please transcribe this text

[Assistant] Is placed on sort of the conventional notion of what appropriate qualifications are. You know, oh, this person has a master's from this school.


[User] Please transcribe this text

[Assistant] Oh, this person has ten years experience as opposed to this person's five years experience. You know,


[User] Please transcribe this text

[Assistant] I think that that is a wildly overrated measurement for how to build your team. Uhm, you know, certainly as you become, as companies go from being big to being really big,


[User] Please transcribe this text

[Assistant] I would argue that that's an appropriate time to really get very deep into the skill sets that you're trying to build.


[User] Please transcribe this text

[Assistant] But if you're an early stage company, if, you know, looking out among


[User] Please transcribe this text

[Assistant] This audience and seeing a lot of aspiring entrepreneurs, what I would counsel you to do


[User] Please transcribe this text

[Assistant] is focus on hiring people who would run through a brick wall uhm, who are true believers


[User] Please transcribe this text

[Assistant] In the mission of your organization and the product or service because even if somebody isn't as smart


[User] Please transcribe this text

[Assistant] As another qual-, as another applicant, even if somebody isn't necessarily as well qualified as another applicant, in my own experience, it's people who have the will and hunger to succeed that more likely than not are going to be the ones who end up


[User] Please transcribe this text

[Assistant] And what's interesting is that five years after the fact, everybody presumes that they're the smartest, most talented, most experienced people.


[User] Please transcribe this text

[Assistant] But especially when you're building a business, the thing that I would most measure is not necessarily the amount of experience or even the IQ of the person who you are evaluating, but the level of passion that they're gonna bring. Number three, stay connected. What do I mean by that?


[User] Please transcribe this text

[Assistant] So I'm at this really weird point in my career where a lot of my peers are suddenly very important and very powerful.


[User] Please transcribe this text

[Assistant] Them and others as people ascend in their career.


[User] Please transcribe this text

[Assistant] The degree to which people stop engaging with young innovators and younger people. You know, I think that there's a lot of earnestness.


[User] Please transcribe this text

[Assistant] Uhm, among young entrepreneurs, among people who are newly successful to say,


[User] Please transcribe this text

[Assistant] Oh, I want to stay connected. I want to mentor young people.


[User] Please transcribe this text

[Assistant] You know, pay attention to the innovations that are taking place in the proverbial garages. And what often times happens is that only lives rhetorically. I would argue among most successful people.


[User] Please transcribe this text

[Assistant] And what's, what I think is gonna be interesting for many of you is once you're successful, do you focus all of your attention, uhm, on managing up


[User] Please transcribe this text

[Assistant] Getting to know more similarly successful and impressive people and staying amidst them or can you, will you stay grounded?


[User] Please transcribe this text

[Assistant] And make a priority out of spending time with young people and young innovators.


[User] Please transcribe this text

[Assistant] You know, in Silicon Valley, there are many one-hit wonders. There are many people who have enjoyed success one time. I would argue that people who have founded and built two great companies


[User] Please transcribe this text

[Assistant] What often times distinguishes the entrepreneur who has built two great companies versus one great company is that that person who's built two great companies


[User] Please transcribe this text

[Assistant] Mindfully or less mindfully isolate themselves from young people and from young innovators.


[User] Please transcribe this text

[Assistant] So, there's a sentence, there's a line by Theodore Roosevelt that I'll repeat that's the third most important sentence I've ever read in my life. The first two were written by my wife. Number one was, I love you. Number two was, I'm pregnant. So my piece of advice to you goes to number three. And Theodore Roosevelt in 1899 said,


[User] Please transcribe this text

[Assistant] Far better to dare mighty things, to win glorious triumphs even though checkered by defeat than to rank with those poor spirits who neither enjoy much nor suffer much because they live in the grey twilight that knows not victory nor defeat.


[User] Please transcribe this text

[Assistant] I would argue that there's a lot of great twilight out there. There's a lot of comfort to be had by people getting good jobs.


[User] Please transcribe this text

[Assistant] Uhm, and to dare mighty deeds and to win glorious triumphs but then to have similarly big failures. And what I've learned is that failure isn't the end of the world. And in fact, it makes you a lot stronger. And I think that success in this world has to do with a spirit of audacity. You've got to be audacious and not care so much


[User] Please transcribe this text

[Assistant] If you win or lose, or to fling yourself into things, mind, body and soul, and more likely than not


[User] Please transcribe this text

[Assistant] Even if you lose, you're gonna have fun and you're gonna learn from it.


[User] Please transcribe this text

[Assistant] And the people who I've gotten to know who are now


[User] Please transcribe this text

[Assistant] You know, several steps past you in your lives, people in their...


[User] Please transcribe this text

[Assistant] They regretted not taking some of those big chances.


[User] Please transcribe this text

[Assistant] So the last piece of advice that I'll give to you just as many of you began


[User] Please transcribe this text

[Assistant] Your career is to stay out of the grey twilight.


[User] Please transcribe this text

[Assistant] And with that, I'm happy to take, uh, some questions for the next 20 minutes or so.


[User] Please transcribe this text

[Assistant] Uhm, so let me answer that. So in terms of our interactions with China on, on cyber policy,


[User] Please transcribe this text

[Assistant] has gotten, has been very plain spoken. Uhm, there's an issue called internet freedom, which we define to mean the right to access, the freedom to access the internet, the websites of one's choosing, and each other. And internet freedom, you take for granted in a place like Palo Alto,


[User] Please transcribe this text

[Assistant] That the web is built on this end user to end user principle that anybody can connect to whomever they want without intermediation in the middle of that. That's what allows people to communicate and collaborate in real time. It's what allows capital to flow with the click of a mouse.


[User] Please transcribe this text

[Assistant] But it's increasingly the case that that isn't true around the world.


[User] Please transcribe this text

[Assistant] And as I've said in the past, 2009 was the worst year in history in terms of internet freedom. And while countries like Iran and China


[User] Please transcribe this text

[Assistant] One of the things that I think is very important to understand and be aware of is that there are actually now dozens of countries


[User] Please transcribe this text

[Assistant] On something other than the end user to end user principle that


[User] Please transcribe this text

[Assistant] Uh, where she spoke bluntly to some of the differences.


[User] Please transcribe this text

[Assistant] Uhm, that we have with the Chinese on this. I will say that I think that demographics are destiny. There are about 400 million Chinese online right now, 200 million of whom are under the age of 25.


[User] Please transcribe this text

[Assistant] Chinese under 25 who are currently online, that number is going to grow far larger and I bet


[User] Please transcribe this text

[Assistant] You know, comment about any comments that, uhm, you know, other government officials have made. I'll let, you know, Mr. Schmidt speak for himself. Uhm, yes, Tina.


[User] Please transcribe this text

[Assistant] Uhm, certainly there were initiatives at my non-profit, uhm, that we thought were gonna be a big deal that just thudded. You know, it's really interesting the degree to which things that you think are gonna be successful fizzle.


[User] Please transcribe this text

[Assistant] And some of the things that you think are promising turn out to be big. So just like the example that I used with the text Haiti example, uhm,


[User] Please transcribe this text

[Assistant] You know, there's an example of something that I think we had modest hopes for what it could do, but it turned out to have this big impact.


[User] Please transcribe this text

[Assistant] And what it's now doing far more significantly than just the 35 million dollars that the Red Cross now has to do earthquake relief is little non-profits all around the country.


[User] Please transcribe this text

[Assistant] Uhm, in $10 increments over cell phones, but maybe we can raise $35,000. You know, so it's, it's interesting if you think


[User] Please transcribe this text

[Assistant] You know, I guess you all are too young to be at this point yet, but...


[User] Please transcribe this text

[Assistant] You know, for myself and many others, we're used to getting, you know, things by snail mail, you know, from charities, you know, with sort of the heartfelt letter and, uh, and, uh,


[User] Please transcribe this text

[Assistant] And a return address where they ask for 25 bucks.


[User] Please transcribe this text

[Assistant] And think about how they can do, uh, mobile giving programs. Yes in the back.


[User] Please transcribe this text

[Assistant] Uhm, I think that there are a couple big inhibitors to innovation in government. Uh, one is, uh, statute and regulation. So what that means are, you know, basically the rules that we have to follow. Uhm, when I was at my non-profit, if I wanted to hire a particular web design firm, because I thought they were the best web design firm, you know, I could hire them. Now, if we want to hire a web designer,


[User] Please transcribe this text

[Assistant] We have to go through an elaborately formal process which more often than not means that we can hire somebody in six months.


[User] Please transcribe this text

[Assistant] The system is set up to not always be able to move fast.


[User] Please transcribe this text

[Assistant] Not be able to be flexible and I would argue it actually prejudices against smaller companies and more innovative companies. That's one. Uh, challenge number two is you've gotta have support at the top of these organizations to sort of force innovation and change through a bureaucracy. So in my case I've been very lucky.


[User] Please transcribe this text

[Assistant] You know, my association with the Obama campaign, you know, in that case, we had a candidate and we had campaign leadership that was very supportive.


[User] Please transcribe this text

[Assistant] You know, thinking about, they were, they were very supportive from the top about what, how technology could revolutionize campaigning. Now at the State Department,


[User] Please transcribe this text

[Assistant] You know, the secretary of state is really the godmother of 21st century statecraft and she, above anybody else, has been aggressive and smart and supportive of how innovation can be integrated into our statecraft. If you take her out of the equation, like if she's not secretary of state,


[User] Please transcribe this text

[Assistant] You know, I and my colleagues would have enjoyed


[User] Please transcribe this text

[Assistant] You know, 10% of the success that we did over the past


[User] Please transcribe this text

[Assistant] Over the past year, so you've got to have that leadership from the top driving this. And that's not universally the case.


[User] Please transcribe this text

[Assistant] Yeaah, so, it's interesting, uhm, you know, technology, innovation obviously is, is something that's about much more than technology.


[User] Please transcribe this text

[Assistant] Uhm, one of the things that we're trying to do, uh,


[User] Please transcribe this text

[Assistant] In the innovation space that isn't technology specific is aid coordination.


[User] Please transcribe this text

[Assistant] Now that is not at all a sexy topic, but it's actually incredibly important.


[User] Please transcribe this text

[Assistant] The Democratic Republic of Congo, uhm, about six months ago.


[User] Please transcribe this text

[Assistant] And, it was a fascinating experience. You know, the Democratic Republic of Congo is one of the poorest places on earth. It has a per capita GDP of $184.


[User] Please transcribe this text

[Assistant] So literally 50 cents of economic output per person per year. And it has this horrible history of colonialism and of outside interference inside the, inside the country.


[User] Please transcribe this text

[Assistant] You know, from the United States government, from the British government, from the Belgian government, from the EU, and then from big foundations, and then from wealthy individuals. And none of it was connected in a way that made any sense whatsoever. And so one of the innovations that we're trying to bring, uhm, into our development policies, by way of illustration,


[User] Please transcribe this text

[Assistant] Is thinking about how to do aid coordination in a new and different way. And again, that's not terribly sexy, but if you're looking


[User] Please transcribe this text

[Assistant] Uhm, transnationally. So, the United States and the Chinese, for example, have very different, uh, development policies in Africa.


[User] Please transcribe this text

[Assistant] So China oftentimes is very focused on, uhm, big infrastructure projects. And the United States historically has been focused on the provision of service.


[User] Please transcribe this text

[Assistant] So the Chinese are building roads and we're helping support hospitals and healthcare networks. And so just one very, it seems obvious, but it's not anything that we've done, is say to the Chinese, hey, let's make sure


[User] Please transcribe this text

[Assistant] That we build our hospitals where you're building your roads. Seems incredibly obvious, but decades have passed without coordination. So there's one example. Other questions? Yes.


[User] Please transcribe this text

[Assistant] And I'm gonna s- eh, this is gonna sound like a cop out, but it has the virtue of being true. Both. So, let me, let me give some history to this. I, I would argue that,


[User] Please transcribe this text

[Assistant] What's happened since Secretary of State Clinton became Secretary of State?


[User] Please transcribe this text

[Assistant] has been revolutionary in nature and spectacular in terms of a very fast impact. However, the roots for this, I would argue, actually go back to the beginning of 2008. There's an interesting story, uhm, you know, 21st century statecraft as we think about it, really has its origins


[User] Please transcribe this text

[Assistant] In February of 2008, where a Stanford graduate, guy named Jared Cohen,


[User] Please transcribe this text

[Assistant] Most of you, since you're still in school, I don't know if you're getting Stanford Magazine yet, but if you are, there's an article about my colleague Jared in there.


[User] Please transcribe this text

[Assistant] One of the things, one of the things that happened in February of 2008 was there was this movement, uh, A Million Voices Against FARC, the FARC terrorist organization in Columbia. And there were,


[User] Please transcribe this text

[Assistant] Demonstrations by 12 million people in 190 different cities around the world.


[User] Please transcribe this text

[Assistant] And following those demonstrations, the FARC saw more demobilizations in a couple weeks than it happened in the previous decade in terms of, uh, military action. And so the State Department was like, how did this happen? Who's the leader? Who's behind all this?


[User] Please transcribe this text

[Assistant] And so what they learned was that it was largely leaderless. That it was started by an unemployed, uh, engineer.


[User] Please transcribe this text

[Assistant] At that point, the intersection between social media, uh, and foreign policy. And so, what then happened over the course of 2008 was a growing recognition within the State Department in the beginning of an understanding


[User] Please transcribe this text

[Assistant] Then, boom, it sort of exploded, and she began to allocate resources to it.


[User] Please transcribe this text

[Assistant] And, you know, things like a million voices against FARC, which is relatively recent, just a little over two years ago. Now that thing, now that dynamic, uh, is commonplace. Yeah. Yes.


[User] Please transcribe this text

[Assistant] One, uhm, President Obama actually just convened a summit in April, uh, focused on entrepreneurship, uh, in Muslim communities.


[User] Please transcribe this text

[Assistant] I think that's a good model. So if you, if you think about


[User] Please transcribe this text

[Assistant] One of the things that we realized that we could do that would have the greatest impact is foster entrepreneurship. And so as a very practical matter, you know, what do we have to offer? We have money, we have tools, and we have people.


[User] Please transcribe this text

[Assistant] Uhm, and so the key for us is to, to put all three to work. So in terms of money,


[User] Please transcribe this text

[Assistant] A lot of what we're doing is focusing our development agenda.


[User] Please transcribe this text

[Assistant] Experimental ways, taking some kinds of chances that historically haven't been the case.


[User] Please transcribe this text

[Assistant] Uhm, you know, there's this thing called the Overseas Private Investment Corporation, OPIC, and for this initiative,


[User] Please transcribe this text

[Assistant] Uhm, that's focused on Muslim communities and Muslim entrepreneurship.


[User] Please transcribe this text

[Assistant] They're dedicating, I think it's literally a couple hundred million dollars, uhm, in debt and equity financing, uhm, into places where historically


[User] Please transcribe this text

[Assistant] And into entrepreneurs where historically the United States government just wouldn't have put money in there. So that's one thing. Another thing is


[User] Please transcribe this text

[Assistant] A focus on what are those things that can be done to support innovation and entrepreneurship given


[User] Please transcribe this text

[Assistant] Sort of the new layer of personal infrastructure that exists in the developing world.


[User] Please transcribe this text

[Assistant] Uh, when I, on my first day of work in April of 2009,


[User] Please transcribe this text

[Assistant] There are 4.7, 4.8 billion mobile handsets on the planet.


[User] Please transcribe this text

[Assistant] So literally in just one year there's been a more than 10% increase.


[User] Please transcribe this text

[Assistant] And with that increase of more than a half a billion handsets, 75% of those, 75% of those are in the developing world.


[User] Please transcribe this text

[Assistant] So the challenge that we're putting to ourselves right now is, okay, if we're now past the tipping point, it's sort of like we're, we are tipping in the tipping point right now.


[User] Please transcribe this text

[Assistant] Where people in the Congo and people in Malawi, people in Bangladesh, people the world around, even people of low incomes have


[User] Please transcribe this text

[Assistant] So what there is right now is there's a big strategy being developed through what we call


[User] Please transcribe this text

[Assistant] Sort of bureaucratic speak, the Quadrennial Diplomatic and Development Review.


[User] Please transcribe this text

[Assistant] What that means is figuring out where our money and efforts are gonna go for the next four years. And this is a big chunk of it. Is to say, you know, what are things that we can do that are empowering, that are based on this personal infrastructure that most people now have, you know, you know, riding on their, on their belts. Uhm, couple last questions. Uh, Chris Peacock.


[User] Please transcribe this text

[Assistant] You know, I could look out and say I'm giving it to about 100 people, but I'm told that the podcast will reach about 10,000.


[User] Please transcribe this text

[Assistant] So part of it, it sounds trite, but part of it is trying to figure out how we can use digital communications to reach people.


[User] Please transcribe this text

[Assistant] And foreign policy generally is still a hierarchical place. And so, what the Secretary of State says and does matters a lot. You know, people are still used to hearing things from the top.


[User] Please transcribe this text

[Assistant] And then integrating that into their life because they've heard it from the top.


[User] Please transcribe this text

[Assistant] Uhm, and so another way we do it is, is this is something that the secretary's made up a priority of.


[User] Please transcribe this text

[Assistant] And she talks about it. So when she goes to places, she talks about the value and virtue of innovation.


[User] Please transcribe this text

[Assistant] And what she is personally doing, what the State Department is doing to support it. Uhm, so that's important.


[User] Please transcribe this text

[Assistant] And in terms of how that thing can be transferred, because this shouldn't all be just about what's in


[User] Please transcribe this text

[Assistant] You know, it now seems to many people like a long time ago, but when we all came into government, the financial crisis,


[User] Please transcribe this text

[Assistant] Was something that, it didn't matter that we were working in foreign policy, it was still something that was completely upending, uhm, all of our point of view.


[User] Please transcribe this text

[Assistant] One of the things that the president recognized and which we're trying to now be supportive of in our foreign policy is that


[User] Please transcribe this text

[Assistant] If there's gonna be, if we are going to regain the kind of global prosperity that we want and need, it's not going to be because of, uhm, asset building in real estate. It's not going to be because of some fancy new financial instruments. It's going to be because of innovation. It's going to be because people have built new things,


[User] Please transcribe this text

[Assistant] That help people live better, healthier, wealthier lives than they did before. So innovation, forgetting about our foreign policy for a moment, for a moment.


[User] Please transcribe this text

[Assistant] Innovation is really at the core of our economic future.


[User] Please transcribe this text

[Assistant] And so that's something that the President has prioritized and the Secretary of State has duly noted. So that's, that's another big push here and, and even though the economy's improving right now, to not forget about that.


[User] Please transcribe this text

[Assistant] Uhm, as we try to do, as we try to steward smart economic policies. Yes?


[User] Please transcribe this text

[Assistant] And so if you actually look at the study, you know, if you actually look at studies,


[User] Please transcribe this text

[Assistant] You know, the specific kinds of environments that Teach for America teachers are going into. What you now see


[User] Please transcribe this text

[Assistant] Is that the retention levels are often times equal to or better than


[User] Please transcribe this text

[Assistant] The innovation, often times that is, this sort of the non-traditional, uhm, point of origin of Teach for America. The second way that I would answer is by saying,


[User] Please transcribe this text

[Assistant] Even among those teachers who do leave the classroom, a lot of what they do, again looking at the data,


[User] Please transcribe this text

[Assistant] Uhm, a lot of what they do, even if they aren't in the classroom anymore, it's still doing things that, uhm, are very focused on education in underprivileged environments. So, you know, I for example,


[User] Please transcribe this text

[Assistant] I left the classroom and what I chose to do was start a nonprofit, the purpose of which was to help kids


[User] Please transcribe this text

[Assistant] Even those Teach for America teachers who are leaving the classroom, uhm,


[User] Please transcribe this text

[Assistant] You know, historically maybe these people would have gone to Goldman Sachs or to McKinsey or to any of a variety of other things and there's nothing wrong with any of that.


[User] Please transcribe this text

[Assistant] But a huge percentage of those people are becoming assistant principals. They're becoming principals. They're going to think tanks. They are...


[User] Please transcribe this text

[Assistant] Becoming, they're becoming lawyers, but they're becoming public interest lawyers, or...


[User] Please transcribe this text

[Assistant] Like me, they start a non-profit and then go into public service. I think I've got time for one more question. Yes.


[User] Please transcribe this text

[Assistant] So when you say in the state, do you mean at the State Department specifically?


[User] Please transcribe this text

[Assistant] Yeaah, you know, so, so the State Department is not the historic locust.


[User] Please transcribe this text

[Assistant] For education policy within the American government. Uhm, but what, you know, I will, I will point out two things. Uhm, number one,


[User] Please transcribe this text

[Assistant] Uhm, under the leadership of Secretary of Education Arne Duncan is pretty remarkable.


[User] Please transcribe this text

[Assistant] And you know, I read something recently where it described what President Obama and Secretary of Education Duncan are doing is very similar to


[User] Please transcribe this text

[Assistant] Uh, very similar to what Richard Nixon did, sort of opening the gates into China.


[User] Please transcribe this text

[Assistant] An urban superintendent like Arne Duncan and somebody who has, has


[User] Please transcribe this text

[Assistant] Obvious a commitment to urban education is Barack Obama to say, you know what, this is a problem that involves more than just adding dollars to it. You know, let's take away the firewall that exists between students, uh, educational performance and teacher evaluation. You know, that might seem obvious to a smart young person like yourself, but that historically has been a firewall that you absolutely couldn't cross.


[User] Please transcribe this text

[Assistant] In terms of the State Department, and in terms of the United States' role promulgating policies like that abroad,


[User] Please transcribe this text

[Assistant] You know, I think this is a case where a little bit of humility is called for.


[User] Please transcribe this text

[Assistant] Nobody's a prouder American than I am and, you know, I'll beat my chest.


[User] Please transcribe this text

[Assistant] About all of those things that I think we do best and that I think we can do to empower citizens of the world around.


[User] Please transcribe this text

[Assistant] You know what, I think we can learn a thing or two about math education ourselves from people in Singapore. You know, I think we can learn a lot about public education


[User] Please transcribe this text

[Assistant] From public education systems from outside of the United States.


[User] Please transcribe this text

[Assistant] So while I and while we as Americans, I think we have


[User] Please transcribe this text

[Assistant] A unique and important role given our global leadership to assert ourselves in a variety of ways


[User] Please transcribe this text

[Assistant] And while I think that President Obama and Secretary of Education Duncan are doing spectacular things,


[User] Please transcribe this text

[Assistant] Before we get on our high horse and start evangelizing for the way that America does public education.


[User] Please transcribe this text

[Assistant] You know, I'm personally of the point of view that


[User] Please transcribe this text

[Assistant] We're still in a good point where we could do a little bit more listening than talking. So with that, thank you all.


[User] Please transcribe this text

[Assistant] Uhm, I apologize for the delay, but now we have slides, so that's exciting.


[User] Please transcribe this text

[Assistant] So, just a couple of general announcements before I get started.


[User] Please transcribe this text

[Assistant] Remember that you have your, uh, first inquisitive assignment. Do today by five.


[User] Please transcribe this text

[Assistant] Uhm, so please go ahead and work on that and let me know if you have questions.


[User] Please transcribe this text

[Assistant] Uhm, we will be having lab tomorrow, uhm, in fact here.


[User] Please transcribe this text

[Assistant] And tomorrow is the lab where we're going to be working with, uhm, the mice to both identify some of the organs we've been talking about in the immune system and also, uhm,


[User] Please transcribe this text

[Assistant] To harvest some of those so that we can actually use them for ourselves for the rest of the semester.


[User] Please transcribe this text

[Assistant] Uhm, and this is the one where I noted that you probably want to pair up in a situation where if you are less excited about doing this, that maybe you pair with someone who is more excited about doing this and are perhaps a bit more of the, uhm, assistant.


[User] Please transcribe this text

[Assistant] And, uhm, you do not need to be with your, like, longer term lab partner, uhm, in working on that.


[User] Please transcribe this text

[Assistant] Uhm, so that is our plan for tomorrow. Uhm, if you go on the Moodle site right now, you can also, you'll also find that there are


[User] Please transcribe this text

[Assistant] Uhm, practice problems about, uhm, exam one material in general as well as, uhm, specifically an innate immunity set of practice problems, uhm, that I had used in past years as a problem set, but I just put it up as practice stuff for you this year.


[User] Please transcribe this text

[Assistant] Uhm, as well as all the old exam ones and keys. So all of those things are available on the Moodle site for practice. Uhm, I will let you know when I am up to date with putting videos onto YouTube.


[User] Please transcribe this text

[Assistant] So today we are going to continue talking about innate immune responses.


[User] Please transcribe this text

[Assistant] Uh, we have a couple of points that I left about


[User] Please transcribe this text

[Assistant] Compliment that I didn't finish last time, so I want to make a couple of points about compliment.


[User] Please transcribe this text

[Assistant] And then I'm going to move into thinking about the cellular innate immune response.


[User] Please transcribe this text

[Assistant] Uhm, more commonly known as the inflammatory response.


[User] Please transcribe this text

[Assistant] So if you, uh, recall from Friday, we were talking about the compliment cascade when we left off.


[User] Please transcribe this text

[Assistant] We saw that there were three different ways that we could initiate the compliment cascade. All three of them come together.


[User] Please transcribe this text

[Assistant] And once, uhm, we have this C3b activation, we can get, uhm, a number of different downstream effector functions, either, uhm, the membrane attack complex or lysis, which is lysis, opsonization or inflammation. And we went,


[User] Please transcribe this text

[Assistant] All the way through the classical pathway and the lectin pathway last time and I had introduced to you the alternative pathway.


[User] Please transcribe this text

[Assistant] But I also told you about a problem with the alternative pathway, which is where we left off last time.


[User] Please transcribe this text

[Assistant] Alternative pathway has to do with the structure of the protein C3.


[User] Please transcribe this text

[Assistant] C3 has, uhm, a thioester bond in that protein, which is unstable. It's under a lot of strain.


[User] Please transcribe this text

[Assistant] Uhm, and it will sometimes spontaneously cleave.


[User] Please transcribe this text

[Assistant] Leading to this very reactive, uhm, nucleophile being produced.


[User] Please transcribe this text

[Assistant] If the closest thing is water, then we make this inactive C3b and no one cares ever again. But if the closest thing...


[User] Please transcribe this text

[Assistant] On some other type of biological molecule, then immediately that C3b nucleophile is going to attach as it shows here to a pathogen surface.


[User] Please transcribe this text

[Assistant] In terms of thinking about how we deal with microbial pathogens very quickly.


[User] Please transcribe this text

[Assistant] We didn't really have to do much of anything to prep to get, to uhm, start the alternative pathway of complement fixation on this pathogen surface.


[User] Please transcribe this text

[Assistant] It happened pretty much immediately as soon as the pathogen was there. We immediately kind of stuck a little sticky of C3B on it to start destruction. So that's fabulous. But the problem is that.


[User] Please transcribe this text

[Assistant] OHs and NH2s are found in all sorts of biological molecules, including on your cells.


[User] Please transcribe this text

[Assistant] And so just like we have this ability to immediately stick a C3 onto pathogen surfaces really quickly.


[User] Please transcribe this text

[Assistant] We also can potentially stick C3s onto the surfaces of YOURSELVES.


[User] Please transcribe this text

[Assistant] Uhm, and I told you last time that that in fact does happen. You are getting C3 deposited on your cells right now.


[User] Please transcribe this text

[Assistant] Uhm, happily none of you succumbed to the membrane attack complex over break, or over the long weekend. Uhm, so something must happen to all- to make sure that that does not occur.


[User] Please transcribe this text

[Assistant] The answer to what will happen is that all of your cells


[User] Please transcribe this text

[Assistant] Express a variety of compliment inhibitors.


[User] Please transcribe this text

[Assistant] So, there are complement inhibitors.


[User] Please transcribe this text

[Assistant] That can inhibit every single step of the alternative and the classical and the MVL pathway. These are some examples


[User] Please transcribe this text

[Assistant] So here you can see, uhm,


[User] Please transcribe this text

[Assistant] This I and H factor that sort of inactivate C3. You can see uhm, one DAF that


[User] Please transcribe this text

[Assistant] Gets rid of, uhm, deposited compliment. You can see another one, MCP.


[User] Please transcribe this text

[Assistant] And even a final one, CD59, that gets in the way of the membrane attack complex when it tries to form. Basically every single step


[User] Please transcribe this text

[Assistant] Of the compliment cascade that we talked about has some kind of inhibitor that is made by your cells.


[User] Please transcribe this text

[Assistant] And so right now C3 is attacking to all of your cells and your cells are brushing it off and basically inhibiting it as soon as it comes on.


[User] Please transcribe this text

[Assistant] Well, microbial cells don't have the ability to inhibit C compliment in the same way. And so they are actually getting attacked.


[User] Please transcribe this text

[Assistant] You may hear this and think that this sounds incredibly inefficient. Uhm, and in a lot of ways, yup.


[User] Please transcribe this text

[Assistant] And the immune system is incredibly inefficient in so many ways.


[User] Please transcribe this text

[Assistant] One of the reasons why we have realized that complement, um, plays a role in certain types of diseases, particularly in different types of arthritis.


[User] Please transcribe this text

[Assistant] Is that, what's really important from these titles, from the title of this slide and the previous, is it says, our cell express complement inhibitors. Bone surface is a surface in that cell.


[User] Please transcribe this text

[Assistant] And so for example, your joints don't have any complement inhibitors. And the complement can actually start to build up in the joints.


[User] Please transcribe this text

[Assistant] Place where we've seen that this, uh, whole situation breaks down a little bit.


[User] Please transcribe this text

[Assistant] Uhm, the one other thing I want to point out about uhm, compliment


[User] Please transcribe this text

[Assistant] Uhm, I could have pointed the same thing out about other antimicrobial peptides. Uhm, but I can only say so many things.


[User] Please transcribe this text

[Assistant] Uhm, is that there are patients who have


[User] Please transcribe this text

[Assistant] There's missing C3, missing C3, missing 1, 2, or 4, missing 5 through 9, missing any of these other components. So there are patients that will have mutations where they are missing a particular complement protein.


[User] Please transcribe this text

[Assistant] Uhm, in most cases, those patients seem to have particular susceptibility to some types of bacterial pathogens.


[User] Please transcribe this text

[Assistant] Uhm, it's not necessarily all, it's a little bit weird.


[User] Please transcribe this text

[Assistant] Uhm, this is one thing that we realize when we think about immune genetics, is that the immune system sometimes like overlaps and covers for itself.


[User] Please transcribe this text

[Assistant] And there will often be like one pathogen that it can't deal with if it gets rid of a protein.


[User] Please transcribe this text

[Assistant] But a lot of other ones it can deal with, with the overlap. Uhm, so there are certain types of bacteria, these patients.


[User] Please transcribe this text

[Assistant] Uhm, have trouble with. Uhm, and this is one particular type of disease. There also are some uhm, patients who are missing the complement inhibitors.


[User] Please transcribe this text

[Assistant] And those patients have autoimmune like syndromes, uhm, where they are starting to see some complement, uhm,


[User] Please transcribe this text

[Assistant] Problems happening, compliment, attack happening on themselves. Yep.


[User] Please transcribe this text

[Assistant] No, many people have no deficiency at all. Um, most people have a complete, have sort of the standard compliment cascade as I've shown you, but there are some patients whose disease


[User] Please transcribe this text

[Assistant] I'm guessing that you asked that because you wanted to know why people get sick.


[User] Please transcribe this text

[Assistant] Oh, so most people have the whole perfect compliment casket.


[User] Please transcribe this text

[Assistant] Okay, so what we've been talking about when we talk about antimicrobial peptides is sort of this immediate innate immune response.


[User] Please transcribe this text

[Assistant] And the key thing is that all of these antimicrobial proteins, uhm, that are present in this humoral response are pre-formed. They're already there. You don't have to transcribe or translate them. They can start working the minute the microbe gets into your body.


[User] Please transcribe this text

[Assistant] Sometimes they do the job and completely eliminate the microbe. And then you live happily ever after. Sometimes they don't.


[User] Please transcribe this text

[Assistant] If that microbe is not completely eliminated by those antimicrobial peptides in that first few hours following infection,


[User] Please transcribe this text

[Assistant] Then the next layer of the innate immune response starts to play a role.


[User] Please transcribe this text

[Assistant] This you can see is happening from about 4 hours after infection to about 4 days. Uhm, and,


[User] Please transcribe this text

[Assistant] Here, we're going to start seeing cells doing something to act against this microbe. We're still in the innate immune response.


[User] Please transcribe this text

[Assistant] But now we've got cells, and those cells have to be activated and have to do some stuff before they're ready to kill the microbe. And so that's why it takes a little while.


[User] Please transcribe this text

[Assistant] Compared to those preformed proteins.


[User] Please transcribe this text

[Assistant] As we talk through this process today, we are going to see two key types of cells that are going to be involved in this process. One of those cell types is the neutrophil. The other is the macrophage.


[User] Please transcribe this text

[Assistant] I'm representing my neutrophils and my macrophages.


[User] Please transcribe this text

[Assistant] You learned about these last week, you saw them in lab a bunch last week. If you look at uhm, this figure from your textbook,


[User] Please transcribe this text

[Assistant] There's something that you might notice about these two cell types.


[User] Please transcribe this text

[Assistant] So you can see it tells us the function of these two cell types in this figure.


[User] Please transcribe this text

[Assistant] And what do you notice about the function of the cell types in these two, in this figure?


[User] Please transcribe this text

[Assistant] They're the same. They both say thigocytosis and killing of microorganisms.


[User] Please transcribe this text

[Assistant] When we learned about these cells last week, we learned about them as both cells of the innate immune system. They're both myeloid cells.


[User] Please transcribe this text

[Assistant] Oftentimes, students really want to


[User] Please transcribe this text

[Assistant] Switch neutrophils and macrophages around and think that they're the same thing. They're actually not.


[User] Please transcribe this text

[Assistant] And as we talk about them today, we're going to talk about some things that are unique about them as well.


[User] Please transcribe this text

[Assistant] So it is absolutely true that both of them, uhm, do a lot of phagocytosis, and phagocytosis and killing of microbes is a big deal for both of them. They are both innate immune cells, but they've got some big differences.


[User] Please transcribe this text

[Assistant] And the process that we're talking about is uhm, the process that most people think of and know of as inflammation. So uhm, you know some things about inflammation. Uhm, I told you on the first day,


[User] Please transcribe this text

[Assistant] That we've got some situations where immunologists have, people made observations about immunology a really long time ago.


[User] Please transcribe this text

[Assistant] Uhm, with inflammation, that is very much true. Uhm, inflammation was first described by the Romans.


[User] Please transcribe this text

[Assistant] Uhm, who talked about there being four cardinal signs of inflammation. Four things that happen to you.


[User] Please transcribe this text

[Assistant] That uhm, or how you know inflammation is going on. So.


[User] Please transcribe this text

[Assistant] Pain! Exactly. Uhm, so redness, heat, swelling, and pain.


[User] Please transcribe this text

[Assistant] Uhm, the Romans called those ruber, cowler,


[User] Please transcribe this text

[Assistant] I was trying to make sure I was doing it in the same order that you guys said them.


[User] Please transcribe this text

[Assistant] And all of those things are actually related to the processes we're going to see with functions of innate immune cells.


[User] Please transcribe this text

[Assistant] And so we're going to be talking through this process. I will largely be using an example like the example we're seeing here where we have some nice healthy skin.


[User] Please transcribe this text

[Assistant] My professors in, uh, grad school always wanted to talk about this as what would happen if someone slammed their hand on the podium very hard.


[User] Please transcribe this text

[Assistant] And got a wound, so I don't know why we're slamming your hands on the podium, but if I slammed my hand on the podium and got a cut, this is what would happen.


[User] Please transcribe this text

[Assistant] You've likely heard the word inflammation before. I'm sure you've heard it. If you went out and talked to people who were non-scientists about inflammation,


[User] Please transcribe this text

[Assistant] They would probably tell you that it's terrible.


[User] Please transcribe this text

[Assistant] They would say all sorts of bad things about it. They'd tell you it was the worst thing ever. If you watch, uhm, TV you'll see lots of types of products that are going to get rid of your inflammation. Especially to, you know, get rid of your wrinkles and things.


[User] Please transcribe this text

[Assistant] But one thing that I want you to know is that inflammation is in fact an important physiologic process.


[User] Please transcribe this text

[Assistant] If you did not have any inflammation at all in your body, it would be really, really, really bad.


[User] Please transcribe this text

[Assistant] My guess is that on Friday, we'll get to some of the reasons why inflammation can be a bad thing.


[User] Please transcribe this text

[Assistant] It is how you deal with infection, tissue injury or tissue stress.


[User] Please transcribe this text

[Assistant] In order to have defense, repair, and restoration of homeostasis.


[User] Please transcribe this text

[Assistant] Because of really macrophages. So we're going to start out with some macrophages.


[User] Please transcribe this text

[Assistant] These macrophages live in lots of different tissues in your body. So in my skin example, there are currently macrophages living in my skin.


[User] Please transcribe this text

[Assistant] So we're gonna start out with the macrophages that live wherever. If we were having lung inflammation, it'd be the lung macrophages. If we were having brain inflammation, it'd be the brain macrophages. Here it's gonna be some skin macrophages.


[User] Please transcribe this text

[Assistant] Because it's from chapter one, it's a little oversimplified, but we're going to use it. You can see there's a cell hanging out in the healthy skin and that it, here it's called an effector cell. It's the skin macrophage. So here's our skin macrophage. It's just chilling in the healthy skin.


[User] Please transcribe this text

[Assistant] Bacteria introduced, perhaps because of this wound that we got, I guess we have little like, are those like stones or something? I don't know. But we get some bacteria. Now,


[User] Please transcribe this text

[Assistant] Those macrophages are going to be activated.


[User] Please transcribe this text

[Assistant] And are going to start this process of inflammation.


[User] Please transcribe this text

[Assistant] And so the first thing that we want to think about in this process is how in the world do the macrophages know that there are bacteria present?


[User] Please transcribe this text

[Assistant] Uhm, so, if the macrophage is going to be activated by the bacteria and start doing something,


[User] Please transcribe this text

[Assistant] Then that macrophage has to know that there are bacteria present. They don't have eyes.


[User] Please transcribe this text

[Assistant] So we have to figure out how they understand that there are these bacteria present.


[User] Please transcribe this text

[Assistant] The way that they do this is that they have lots of different receptors on their surface. Also, uh,


[User] Please transcribe this text

[Assistant] Inside of the cell as well, though we're just seeing them on the surface here.


[User] Please transcribe this text

[Assistant] Found only in bacteria or microbes. They are things that are non-self.


[User] Please transcribe this text

[Assistant] So the macrophage has these receptors that are going to help it


[User] Please transcribe this text

[Assistant] Detect things that are non-self. Say this, this doesn't belong here. This is not me, uhm, in order to start this process.


[User] Please transcribe this text

[Assistant] And that receptor is recognizing things that are


[User] Please transcribe this text

[Assistant] Sort of unique to microbes. It's a pattern that many microbes have.


[User] Please transcribe this text

[Assistant] The macrophage will have many pattern recognition receptors, not just one.


[User] Please transcribe this text

[Assistant] So that it can detect many different microbial patterns.


[User] Please transcribe this text

[Assistant] You can also see that here with many different microbial, uh, many different pattern recognition receptors.


[User] Please transcribe this text

[Assistant] These pattern recognition receptors are things that are characteristic of broad classes of microbes. So this is not a situation where


[User] Please transcribe this text

[Assistant] You're going to have a receptor that only recognizes SARS-CoV-2 Omicron and not SARS-CoV-2 Delta.


[User] Please transcribe this text

[Assistant] Instead, this receptor might be recognizing RNA viruses.


[User] Please transcribe this text

[Assistant] We're recognizing some broad class of microbe. And so what you can see here is that the brown microbe, the yellow microbe, and the purple microbe


[User] Please transcribe this text

[Assistant] They all have something in common that hits the same receptor. They all have the same pattern.


[User] Please transcribe this text

[Assistant] This is pretty useful because uhm, you don't need quite so many receptors to recognize all the microbes.


[User] Please transcribe this text

[Assistant] Also pretty useful because uhm, we tend to see recognition of


[User] Please transcribe this text

[Assistant] Structures that are really important for the microbes biology. Things that the microbe can't


[User] Please transcribe this text

[Assistant] Uhm, that really helps uhm, us not have to worry about microbial evolution.


[User] Please transcribe this text

[Assistant] We also have a name for that part of the microbe, the pattern that is, uhm, recognized.


[User] Please transcribe this text

[Assistant] The field has changed terms here.


[User] Please transcribe this text

[Assistant] You might see a couple different terms. This is the official, most up-to-date term. Uhm, A, the last, uhm, so it's MAMP. The P stands for pattern, because it's the pattern that the receptor recognizes. So that goes together.


[User] Please transcribe this text

[Assistant] But then the rest of this is a microbe associated


[User] Please transcribe this text

[Assistant] So it's some part of a microbe, some molecule that's on a microbe that makes up this pattern.


[User] Please transcribe this text

[Assistant] In the past, we used to refer to these as PAMPS instead of MAMPS.


[User] Please transcribe this text

[Assistant] Because we would say they were pathogen-associated molecular patterns, but now we realize they're not just on pathogens, they're on other microbes too. So we went to microbe-associated molecular pattern. But if you see PAMP instead of MAMP somewhere, they're the same thing.


[User] Please transcribe this text

[Assistant] Uhm, and this just shows you some examples.


[User] Please transcribe this text

[Assistant] Of some types of maps, again we'll talk about some of them a little bit more.


[User] Please transcribe this text

[Assistant] Uh, later on, but you can see things like LPS, which is in the cell wall of many bacteria, or peptidoglycan, which is in the cell wall of many bacteria.


[User] Please transcribe this text

[Assistant] There are some that are particular types of nucleic acids that are found only in certain microbes.


[User] Please transcribe this text

[Assistant] Heptidoglycan. And so having one receptor for each of those things is going to be great in helping the cell to recognize


[User] Please transcribe this text

[Assistant] Something that is definitely foreign, definitely not us.


[User] Please transcribe this text

[Assistant] And something that gives you recognition of a broad group of pathogens that cannot easily, that we can't easily mutate around.


[User] Please transcribe this text

[Assistant] Two things that we're going to think about happening.


[User] Please transcribe this text

[Assistant] So here you can see some PRRs on the surface of a macrophage. You can see microbes being recognized with those PRRs.


[User] Please transcribe this text

[Assistant] And the result in this case is that the macrophage is going to do phagocytosis.


[User] Please transcribe this text

[Assistant] I mentioned before phagocytosis is important for our macrophages. So the macrophages going to do phagocytosis.


[User] Please transcribe this text

[Assistant] It's going to start to destroy that microbe.


[User] Please transcribe this text

[Assistant] Uhm, I will point out that there is a figure very similar to this in your textbook in 3.4. Uhm, but for some reason they wanted to add, they added like two more complicated factors.


[User] Please transcribe this text

[Assistant] I was like, I don't need to show them the complicated version. We're going to show them the simple version first. So if you look at 3.4, it's like an evolution of this. Uh, but.


[User] Please transcribe this text

[Assistant] There is one other big thing that will happen when a macrophage uses its PRR to detect a microbe.


[User] Please transcribe this text

[Assistant] On the left, you can see the thing I already just told you about. Phagocytosis.


[User] Please transcribe this text

[Assistant] Is that we see signal transduction from that receptor?


[User] Please transcribe this text

[Assistant] And our cell will now start to transcribe and translate some new proteins.


[User] Please transcribe this text

[Assistant] And so we're going to see this transcriptional response and this response of making these new types of proteins.


[User] Please transcribe this text

[Assistant] This is the thing that's really unique about the macrophage. So remember I told you that there were macrophages and neutrophils? They both do phagocytosis. Everybody wants to mix the two together.


[User] Please transcribe this text

[Assistant] The neutrophils kind of just do phagocytosis.


[User] Please transcribe this text

[Assistant] The macrophages do phagocytosis and the signaling stuff. Uhm, so they're like the smart ones.


[User] Please transcribe this text

[Assistant] It can lead to a bunch of different things.


[User] Please transcribe this text

[Assistant] Some of them help the macrophage get better at killing microbes.


[User] Please transcribe this text

[Assistant] Uhm, but the third type are the ones that we're really gonna care about for the rest of our time today. They're also shown here.


[User] Please transcribe this text

[Assistant] Little proteins that get made that are known as inflammatory cytokines.


[User] Please transcribe this text

[Assistant] So our macrophage is going to start transcribing.


[User] Please transcribe this text

[Assistant] And secreting them. So you can see there are little triangles that get secreted from the cell.


[User] Please transcribe this text

[Assistant] You might guess inflammatory cytokines are involved in


[User] Please transcribe this text

[Assistant] Inflammation, which is what we're talking about now. They can, as this points out, uhm,


[User] Please transcribe this text

[Assistant] Actually also help out with an adaptive immune response.


[User] Please transcribe this text

[Assistant] We've now seen our macrophage in the skin recognize bacteria that have come in.


[User] Please transcribe this text

[Assistant] And produce inflammatory cytokines.


[User] Please transcribe this text

[Assistant] Uhm, because of the signals they had through those PRRs.


[User] Please transcribe this text

[Assistant] So the next thing that we can think about in this process is what


[User] Please transcribe this text

[Assistant] Those inflammatory cytokines will do.


[User] Please transcribe this text

[Assistant] There also are a few different cytokines that can be made here.


[User] Please transcribe this text

[Assistant] Some of them are officially inflammatory cytokines.


[User] Please transcribe this text

[Assistant] Our messenger molecules in the immune system. They're the messages one immune cell sends out to talk to others.


[User] Please transcribe this text

[Assistant] That's really the easiest way to think of cytokines. Here we're talking about inflammatory cytokines. The message they're sending is inflammation.


[User] Please transcribe this text

[Assistant] You will see on a subsequent slide that I also do mention chemokines.


[User] Please transcribe this text

[Assistant] There is a reason why I mention chemokines. Hopefully it will click as we go. Chemokines is


[User] Please transcribe this text

[Assistant] The word actually means chemotactic cytokine. It's a cytokine that makes something move.


[User] Please transcribe this text

[Assistant] There are ridiculous immunology cartoons, uhm, that sometimes, I have like,


[User] Please transcribe this text

[Assistant] So many of these that I'll put in random places I'm just realizing this would be a perfect place for one of them that I did not do. Uhm, but it shows a cell making chemokines.


[User] Please transcribe this text

[Assistant] And the cell says, my chemokines bring all the boys to the yard.


[User] Please transcribe this text

[Assistant] Those cytokines and chemokines being produced in the skin?


[User] Please transcribe this text

[Assistant] There are some effects that happen on that specific location, uhm, of the, at the skin.


[User] Please transcribe this text

[Assistant] And so, you've got two panels here. Sort of a before and an after.


[User] Please transcribe this text

[Assistant] Left and the right. And you can see some of the effects in that specific location. So those effects are not necessarily happening throughout the entire body. They are just happening at that specific location. They are the local effects.


[User] Please transcribe this text

[Assistant] One of the things that you can see is that this, um, blood vessel that is nearby in the skin changes its diameter. So it goes from kind of skinny to much wider.


[User] Please transcribe this text

[Assistant] So we see a change in blood vessel diameter. That's called vasodilation. The vessel dilates.


[User] Please transcribe this text

[Assistant] So we actually get a change in permeability of the vessel wall.


[User] Please transcribe this text

[Assistant] Why might it make sense to dilate or make that vessel bigger?


[User] Please transcribe this text

[Assistant] Help out. That means more complement proteins can come and help out.


[User] Please transcribe this text

[Assistant] So a lot of it's to allow cells, um, to actually get to that location. It will also allow things like a sort of bathing in the complement proteins and things like that. So again, you're letting.


[User] Please transcribe this text

[Assistant] So uhm, the permeability thing potentially could, uhm, and so you really hope that you have other aspects of the immune response that are trying to keep those bacterial numbers low. Uhm, if you completely opened, you opened all the doors, sure, you'd get some, you could get bacteria in the blood. Uhm, that's why you've got a lot of things going on here at once.


[User] Please transcribe this text

[Assistant] Also realize as you're bringing in more blood to this site and bringing in more of the liquid to this site, the site's going to get warm because the blood is warm.


[User] Please transcribe this text

[Assistant] This site is also gonna get swollen because you are pushing more liquid there. This site is going to get red as you get some of this additional blood flow.


[User] Please transcribe this text

[Assistant] And so all of those cardinal signs of inflammation are direct results of those inflammatory cytokines and chemokines.


[User] Please transcribe this text

[Assistant] Um, you do also get some pain with this. The pain is also involved in signaling, um, on local nerves from those inflammatory cytokines. So I'm not going to go into the neuroscience of.


[User] Please transcribe this text

[Assistant] Some of these are also going to be chemokines.


[User] Please transcribe this text

[Assistant] And those chemokines are going to be recruiting immune cells. They are going to be actually


[User] Please transcribe this text

[Assistant] Giving out the call to say, hey, immune cells, come here.


[User] Please transcribe this text

[Assistant] There is something you need to deal with right here. So we're going to be actively recruiting in cells using those chemokines.


[User] Please transcribe this text

[Assistant] One point that I just want you to know.


[User] Please transcribe this text

[Assistant] Uhm, switch the order of this for a second.


[User] Please transcribe this text

[Assistant] Uhm, there is this whole specific process that those cells go through for recruitment.


[User] Please transcribe this text

[Assistant] I'm not going to talk about the process right now. Uhm, the process actually has the same set of steps later when T cells do something, and we're gonna deal with it then.


[User] Please transcribe this text

[Assistant] But there's a set of steps. One part of that involves a chemokine and just so you know,


[User] Please transcribe this text

[Assistant] Chemokines have really specific kind of receptors. They have seven transmembrane domains. They signal through G-proteins, uhm, as you learned about in Bio250. The reason why I tell you this, because on Friday,


[User] Please transcribe this text

[Assistant] I told you about two proteins called C3A and C5A that signal through a receptor.


[User] Please transcribe this text

[Assistant] How many transmembrane domains does that receptor have? I really hope they drew it right, hold on. Okay, they did. How many transmembrane domains does that receptor have?


[User] Please transcribe this text

[Assistant] One, two, three, four, five, six, seven. The same number that chemokine receptors have.


[User] Please transcribe this text

[Assistant] So hopefully you see that this sort of links together. That while I try to put some of these things in different


[User] Please transcribe this text

[Assistant] Locations in different parts of the immune response, we're seeing a lot of the same themes over and over again.


[User] Please transcribe this text

[Assistant] The inflammatory response are what are the sort of local effects of inflammation.


[User] Please transcribe this text

[Assistant] So here we can see we might have our person who slams their hand on the podium. And they get a cut in their hand.


[User] Please transcribe this text

[Assistant] We're going to have this process that I've told you about of inflammation happening in their hand. That's where the hand is red and nothing else is red.


[User] Please transcribe this text

[Assistant] We're going to make changes to the blood vessel only in the hand. Everywhere else.


[User] Please transcribe this text

[Assistant] We're not gonna see changes in the blood vessel diameter. We're not gonna see changes in permeability. We're not gonna see recruitment of cells over here.


[User] Please transcribe this text

[Assistant] It's only just in this one local site.


[User] Please transcribe this text

[Assistant] Uhm, there are other things that some of those cytokines and chemokines can do elsewhere in the body.


[User] Please transcribe this text

[Assistant] To help support this immune response.


[User] Please transcribe this text

[Assistant] So we do also see some systemic effects of the inflammatory cytokines. Uhm, one of those effects is an effect on the liver.


[User] Please transcribe this text

[Assistant] So those same cytokines like IL-6 and TNF-alpha can move through the bloodstream.


[User] Please transcribe this text

[Assistant] They're not going to affect the vessels, but they are going to affect the liver.


[User] Please transcribe this text

[Assistant] And they are going to make the liver make some new proteins.


[User] Please transcribe this text

[Assistant] So you can see, here's the IL-6 receptor on the liver, here's the IL-6 interacting with the liver, and now the liver makes some new proteins.


[User] Please transcribe this text

[Assistant] Anybody remember here, so one of the proteins it makes is, uhm, mannose binding lectin. Anybody ever heard of mannose binding lectin?


[User] Please transcribe this text

[Assistant] Yes, where did you hear of man with binding leptin? Yeah. Inquisitive? Anywhere else? Yeah.


[User] Please transcribe this text

[Assistant] Yeah, it was one of the pathways that we learned about on Friday, the complement cascade. Uhm, C-reactive protein, also a complement.


[User] Please transcribe this text

[Assistant] related protein. Fibrinogen is related to blood clots.


[User] Please transcribe this text

[Assistant] Uhm, this is showing you some other complement components. So the liver is going to start making


[User] Please transcribe this text

[Assistant] More of those proteins we learned about on Friday. Again, because all of these things are really interconnected.


[User] Please transcribe this text

[Assistant] So the liver is going to say, okay, there's bacteria here, we probably are going to need some more complement proteins. And it's going to start making complement proteins to help out this process.


[User] Please transcribe this text

[Assistant] The part where the liver is making some of these things is known as the acute phase response.


[User] Please transcribe this text

[Assistant] Those same cytokines are going to act on the bone marrow.


[User] Please transcribe this text

[Assistant] That tells the bone marrow, hey, uhm, release any extra neutrophils you have. Send out more neutrophils.


[User] Please transcribe this text

[Assistant] So that there are now more neutrophils in the body to try to get rid of the microbe.


[User] Please transcribe this text

[Assistant] We can also see those same cytokines have effects at the hypothalamus and at fat and muscle.


[User] Please transcribe this text

[Assistant] Both of those things end up being impacts on metabolism.


[User] Please transcribe this text

[Assistant] And much of that impact on metabolism changes your body temperature.


[User] Please transcribe this text

[Assistant] Specifically increases your body temperature. Makes your body temperature a little hotter.