Howdy how's it going? My name's Davy Chappy and today we're going to be going into a parallel world where I decided to teach people how to play the world's great, good role-playing game, Pathfinder. Specifically, I'll be going over the first edition because I am not qualified to talk about second edition. I am qualified to talk about Starfinder though, so maybe one day that one dude in the comments who always asks for a sci-fi game will finally be satisfied. I gave you Star Wars, what more do you want from me? As always, keep in mind that the majority of this is just my opinion, so if you feel like I could never understand the complexities of fantasy role-playing, feel free to play your games however you want. But with that out of the way, let's begin.  Originally published in 2009 and getting a completely overhauled second edition in 2019, Pathfinder runs in the same system as third edition D&D, making it a very easy alternative for fans of third edition who are looking for something else to try, because Pathfinder can be very easily summarized as D&D 3.75. In fact, my first introduction to the concept of role-playing games was by going to my school's D&D club, playing third edition once, and then immediately switching to Pathfinder, because my dirty little secret is that I like Pathfinder more than 3.5. It makes sense though, Pathfinder came out way after 3.5, after fourth edition got released and people realized, hey, wait a minute, this is bad, so with the benefit of hindsight from seeing exactly what 3.5 did well and what the player base wanted to see done better, and after the botching of 4e made people yearn for something that was similar to 3.5 but just updated, Paiso, the company behind Pathfinder, pretty much had the secret to a better game laid out for them, with the perfect circumstances to make it popular. This technique did not work so well for them the second time around, but hey, we're here to talk about the first edition. Now, call me presumptuous, but I'm going to assume that your role-playing experience is limited to 5e, and if it is, then you have a ballpark understanding of how Pathfinder works. All the core mechanics are here. The game is the same, yet different. AC is reflex saves, bonus actions are swift actions and don't do as much, feats exist but are way weaker, but also come around every two levels instead of four, a million different subclasses are instead a million different classes of their own, and all of your favorite classes, like the Wizard and the Barbie, were recasted as either buffed or nerfed versions of their 5e counterparts, depending on whether or not you got magic. If you think that magic is powerful now, you really have no idea, because magic used to be busted. Also, Pathfinder was the game that gave us unlimited cantrips, because even though 4th edition did it first, nobody played 4th edition, so we're giving the credit to Pathfinder. As far as the reasons why you would want to play it over 5e, one of the biggest criticisms of the world's greatest role-playing game is, for all of its simplicity that managed to bring in a massive new fanbase, the game is just that simple. There are like three real choices that you have to make in 5e, your ace class and your subclass, and I guess the afterthought of the background counts too, so four things. This is a huge advantage for new players, but once you're not a new player anymore, you might find yourself restricted by the solid walls of character creation, and Pathfinder represents the exact opposite of that. With Pathfinder, almost every level brings a list of choices that can make it so that your character feels unique to you, and a lot of the fun in the game is mixing and matching all the different options to create the strange Frankenstein's monster of your imagination. There is a huge reward for going through and memorizing all the different options, because the difference between a normal character and an optimized character is crazy wide. You can look up the Godzilla for this concept taken to its extreme, but there are plenty of rewarding combinations besides that. Plus, the core premise of Pathfinder isn't all that dissimilar from 5e, so outside of the culture shock that you'll get from the specific mechanics being different, you actually do have a good base of understanding the game before you even play it. Of course, there is a flipside to that coin. It's no secret that while Pathfinder isn't complicated to learn, per se, it is by no means the open door that 5th edition is, and the amount of options available to you from the get-go is a huge contributor to that. I remember trying to learn the game when I was a kid.  Meanwhile, my friends would be making character named Titan, the man who could kill gods. If you're playing casually, you better hope that your friends are fine with playing casually as well, because there is no hand-holding here.  You're better off making a bard and having its special power be that it has a long line of relatives that look and act exactly the same. And speaking of making a bard, another reason to try out Pathfinder is due to its diversity in both race and class options. Not to say that they're better or worse than D&D, but there's plenty of creative ideas rolling around for your paths to find. Like the Samsonan, a race of blue people who reincarnate when they die so that their soul always lives on through the ages. Or the Ratfolks, small-sized mouse beats that like to hurry scuttle around and steal your metal shinies. In fact, the races of Pathfinder often come with swappable racial features, much like how the Skag tried to do with the half-elves and the tieflings. And every race has a variety of classes that they're naturally attuned to, giving them some mechanical bonus for playing them. Although to work that out, you kind of have to decipher Pathfinder's unapologetic terminology. As for classes, there's all the classics, and then there's things like the Blood Ranger, one of many hybrid classes that casts polymerization on two classical classes. In this case, taking the Barbarian and the Sorcerer and giving the resulting child so many anger issues that their blood literally boils like a red lantern. Also, if you like the idea of subclasses like the Samurai, Pathfinder makes a lot of those subclasses into its own class, with its own gimmicking mechanics, although that's not unique to Pathfinder. It's actually a very new thing for variations on the same base idea to be made into archetypes of one main class, which has the drawback of some classes being lame as hell if their gimmick isn't very useful. But all the different mechanics means that you're more likely to find something that's tailored to you, and since they're not subclasses, you don't have to just grin and bear it if the main class has a feature that you don't like. Another notable change from D&D is that the world that it all takes place in is a mismatch of dozens of different ideas from all over pop culture, thrown together in a melting pot like the lies we learned from Schoolhouse Rock. See, where D&D has many different worlds like Greyhawk, Dragonlands, and the only world that's been given love in five years, the Forgotten Realms, Pathfinder went in the direction of having a catch-all world where everything from every book could be absorbed into one world. You can check out the lore for yourself, but the gist of it is that Galarian was the name of a continent where everybody was good and happy until the singular god of humans went and died, and what was widely regarded as a bad idea, without him to keep things on track, every single bad thing that could happen did happen, from the implosion of empires due to politics to tears in the fabric of reality that annihilate all the barbarians to motherfucking pirates that just start coming in and saying, your booty is mine. Due to the melting pot nature of trying to cram all of your stories into one confined space, pretty much every adventure you can think of could be had on Galarian, and every book released by Pathfinder is set in this incredibly conflicted continent, and the setting was loved so much that it was reused for Starfinder, wherein it reached the natural conclusion of all this chaos and just blipped out of existence.  Overall, Pathfinder is a good alternative choice for those of you who like 5e, want something very similar to 5e, but want it to be more complicated or just have a different range of choices for you to pick from, and who knows, maybe in the future I'll talk about the second edition of Pathfinder, although to get that done I might need to call in some help from a friend. Buuuut that'll about do it! I hope you enjoyed this video, be sure to like, comment, subscribe, ring that bell to keep the notifications coming, and maybe support me on Patreon so that I can make my entire life revolve around Pathfinder. But yeah, Davie out.


Thank you. Is that working? Okay. So thank you. Welcome. I am Wana and before I'm presenting Myself how smart and beautiful I am and how much I achieved I want to tell you a fact You will all agree. It's 4 30 in the afternoon Everyone Would argue that? Another fact at 4 30 afternoon Energy might be a little so and so so the first thing the first Activity that I wanted to Propose you is to ensure that you have a neighbor X to you so you're exactly that you're not alone and And it it will be nice if you are in a pair. So at the your table Yeah, your pair. Yeah, so two four six Okay now this topic is called Change for the perspective on change. So it's about change. So the first thing I want you to experience is Something about change Simple experience and I invite you to change. This is an exercise. I really love a change something on yourself This is and I'll give the example because we need to give you the example. Don't we this is something that I wanted to do So change something on yourself. Yeah, I change Okay, did you Did you succeed Okay, are you happy with your change? No Well now what I invite you and that was a thing to have a pair being in pair turn to one of your neighbors and Change something on her or on him, which means can we have an an example? Who is some some of the the people that help me Of some of the one of the volunteers. Can you come and help me? We'll do a demo Can I change I need to change something on you? Yes, please Yeah, I changed something on him and you can do the same on me Okay, I don't know you change something on me Look at me. You need to change me No, you change me So That's what the demo so you turn to your your neighbor and you change something on him or her Okay, so you do it so you could change that or whatever you wanted Please do please do please proceed it don't ask them go and change don't ask for permission and Also, don't ask the person to change herself.  How how does this second part of the exercise felt? Okay It felt okay That didn't fail you're okay so and so No answer Did it feel awkward Yeah so this is my super short exercise about change and they if it is this This workshop is kind of the backlog of the takeaways if there's only one first takeaway is That you can't change someone else People change themselves and if you change someone that is an aggression Well, yeah, it feels awkward from the people that is changed, you know because When I tell change something on me I was like what will he change and for for him Oh my god, what will I change and it's also a cultural. That's why this is a little bit provoking It's also a cultural matter in this exercise was the level of my own intimacy space How that I enter in that space and that is true at the team Organization and corporate that so if there is one takeaway from my Workshop today is that you can support if you are change agent You can support people to change themselves, but you don't change If you can change that it's more than a aggression okay We go we We can start still with me. Oh no. I am pretty after that take first takeaway Presenting myself. I'm one of Runko. I'm coming from France. I love to the team dynamics and leadership and I am using systemic constellations and Design thinking for collaboration lots of things. So I I like to present myself as an agile Leadership and business DJ that mixes whatever practices make people proud of their outcomes So that this is for me now The second takeaway I'd like to you to have from here And I say if after that you don't like the session you can go but you have a second takeaway is that organizations are made of People and people What's What's the quality of all people that are in the organization is that you will you will agree with me or not? We can argue they are alive A fact So if they are alive, they are living Systems and because organization are made out of people organizations are also living system like the individuals and Because organization are living system and that is my second takeaway they change like living system That means they emerge they They are born they grow they decline and then die and The fact is what the us as Us people and also organization We have a bias About that truth Which is it that we live for we we believe that we'll live forever and we act as if we live forever And that's the same case with organization They act as they they live forever in the format that they they are in at a certain point so now After the second takeaway, which is organization of our living systems I would like you to Have this first activity Discuss with at your table in an agile journey adoption. What do you think is needs to change first? Two minutes on that. Yeah, you can write it there Could have done also a cloud, but I prefer that you have a conversation Just just have a conversation and then you'll tell me two minutes Okay, it was just that this is the warm-up Table if you can throw at me some words and conclusion what element Leadership Mindset Opinions Openness to become more open that's okay from those those tables what structure of Okay New did you find something open? Okay, so what was already said? willingness to achieve To change the willingness to change. Okay, so this this was a little bit of a generic question Theoretical philosophical now Maybe that's the The next question will have another answer in your professional environment right now in your organization Either the one that you work with in or we work with if you're an independent consultant What is need what is need to be changed to change first? Maybe it's the same answer. Maybe it's another one another minute Based of working now, let's yeah, let's discuss between with your pair For one minute Okay, okay once again, it was really a quick conversation Some answers for each table yes yourself, okay Thank you for that What else other table? Yeah Okay creates psychological safety on other table your boss Okay, what was the problem with your boss? Okay Other things Mindsets experience on going back to the the first question yeah business agility so the The business being more agile So you see here something else from this table that We you stick with leadership the actually I was thinking Which it's a good question once What it needs to be changed in leadership? Okay, so okay, so the leadership should Hold the why of the change that's okay. Okay, so This is our sum Answers so you see there's about mindset that Managers also lead leadership So you see you we come back to the the same basics and what you what I observed I was between the two questions actually that Not exactly the same answers because the first one is a more wishful and The second is more concrete you know concretely for for me what in my what I observe in my organization so Now okay, so all these things that you said you need to change What's the problem sorry resistance? fear resistance and Why is that? Stepping stepping out of the comfort zone is kind of linked of fear because out of the comfort zone is dangerous But what it's I want to say is there's a balance when we change there's unbalanced between the decay and the growth of a new system and the fear is also and Resistance is normal and that will come it's normal because a System doesn't want to decay as we don't want to get decay I'm I'm not very sure that every there's a human being that Can't wait to become very old Not sure you all get old, but I'm not sure that I know anyone that said oh I can't wait to be 80 So Me too. I mean I'm included in all this So that's that that's unbalanced between decay and growth. So Having said that What I wanted to share with you This is a model that I discovered and I find it so useful for the idea today is to experience it I presented I think it's a model of change that is based on the cycle of life thing that in it's called the two loops just simple as that two loops From the Burkana Institute Margaret wheelie and Deborah freeze Have defined it at the point in time There's a dominant system and that's also in the organization and there is an emergent system to look the one that is dominant and another one that Emerge and that will bring change because you know, we also change continuously I don't know the numbers and I didn't I prepared for that that came to me that you know how how many Selfs die and are renewed in our body every day. There's million. I don't So Yeah, that's that's at each moment in time. This is what's happening Now let's talk to to to really embrace change. Let's zoom a little bit on the dominant system and when you talk about the dominant system what is Can be blurry is where are we in the dominant system because we said that as living system systems are born grow Arrived at their peak decay and die and When we are in the system, it's very hard to see at what point of the life that system is and The system that is powerful it works is What I was saying before is at that peak We have this delusional sense of permanence. We were successful It won't right So we think that will live forever. I told that's why I was saying we want to live forever and be young and beautiful If you have a time in your life where you you thought that you were happiest we think that will stay at that moment forever and That's what happens with system and society It's one of the reasons so that Society or organization don't want to change that they are their peak and they think That this will be real and true forever But at the same time at that peak zone While the dominant system has the delusional sense of permanence There was it's called the pioneer start those that see That the system is not right anymore it's like the agile manifesto in 2001 those were pioneers at that time and Normally, they are kind of isolated I don't want to talk for forever They are kind of isolated at the beginning isolated initiative, but say this system has a problem They kind of see the starting of the decade But they are As a separate voices and also Very hard to believe in those voices there What Starts us to happen is that those pioneers start to connect together and One if it's one thing that this model of tulips Does wants to do is to name those pioneers connect them together and then nourish So it looks it looks maybe two very easy, but it's powerful name Name a movement a movement without name. It's powerless Think of agile if you didn't have a name At all, how would that be successful now? This is look simple, but name them Connect them so they become stronger and nourish them so they become they they can get even stronger and then There's the emergent Oops. Oh, yes, sorry There's the emergent system that will Start to to grow. So this is the second loop the emerging loop Normally to have been emergent so dominant emergent What happens to the new system now than? Here With the pioneers Right now in that moment, you know dominant system the peak They saw what what is the dominant system? Do once want to do exactly exactly why Exactly, it's a self-defense Exactly, yeah, yeah, it's fear, but actually it's normal that this is really one of my messages is that if you're you're Frustrated that the change doesn't happen is that it's really a living system logic the dominant system Sees the pioneers as a threat and What are they what in a living system? What does it does it activate when there's a threat? defense Immune system So the immune system of dominance system Stands to active so they can smash the pioneers and In organization what what is blame? It doesn't work I said fear-driven behavior. It doesn't work in our environment because that that that too many meetings, whatever Whatever arguments it has Now after Connecting the the pioneers the idea is to create coherent patterns for the the new system First connecting them and then see what are the patterns? You know what those pioneers can have as a common Way of working scrum was one of them. Let's say a pattern You know the first are giles doing so and so it's true that it was A lot of initiatives at the moment. There's something that happens that it creates coherence and the the emergency system is more powerful and they have patterns and they have a Shirt purpose and the cause that Makes them stronger Okay, so now That's all this was a little bit of theory now. I would like to Make this concrete for you because it's really a model and as I saw that for to to Reinforce the new emergent system. There are three things that To in this mode to be done name connect and nourish and The exercise I'm inviting you to do it's an individual exercise and you have it on the handouts It's not exercise number one is after so you skip exercise a number one that will do or not do I don't know and there's a list of questions and there are these questions What is the change that you want to see in your organization? In your own environment name, what's the tribe of pioneers? Who are those ones? How can you? help them connect better and What are the ways that? You can nourish them more So they don't die as Umbrians, okay, is that clear? So what I suggest You yet take three minutes to answer the questions and then five minutes to To share With your group. Okay, something like that eight minutes. So Okay Yeah Yeah, three minutes to capture five minutes to talk May add two minutes bonus if necessary is that clear maybe it's The time to start sharing The idea of sharing is also to get inspired by other People's idea Yeah, I think it's it will be a good time to start sharing the others what What were your ideas? at a table all table with you one for one or Or prepare I see pairs organise. Oh, it's the best for you Do you want to join another table? Yeah It's it's pure me pioneers you talk about the pioneers those that are willing to change the system So it's not people that you want that they change they are already in they are the change triggers Okay. Yeah, that's that's For the moment. So I hope you had good conversation And you've got inspired by the ideas of the others I Listen a little bit of the discussion here. I hope it was clear The idea is that you name connect and nourish the pioneers Those that want to ignite the change. So it's not about convincing them They are already convinced it just need to reinforce them. If not the dominant system Will say kill kill kill Okay, so this was The first exorcist for for the pioneers and that's why I say if that's another take away from this workshop is This one if you identify part identify pioneers that want the change in organization Connect them and nourish them Where we go on Yeah, yeah, of course, yeah, yeah, yeah Absolutely you can yeah, they have a common intent and they're doing little things all they feel that they can't do it That's why you wanted me to nourish them. They are not it's like an embryo and they are not Um Strong enough yet, but they have that intent. That's also why if I'm lucky Well, it doesn't work anymore. No, it's it's this thing that Well, no, I don't want to accept this This is a Microsoft thing It's in the middle of presentation. It has absolutely some updates to do or whatever and then luckily it's not there, but It's working again, thank you you're you're you're my hero Actually, I wanted to come here back through this slide What I would say, you know, it's creating a shared purpose That intent they have an intent if you connect them at least to have a that shared purpose It's motivating and it's the same thing with this within a society that have today It's all this voices that are stronger stronger about the climate change, etc but when it it started it started like What what does society said about them that they are kind of pirates that are Activists yeah, yeah activists illegal, you know in England the The people in UK the people that are activists for climate change Actually, they are trained To how to act when they will be put in jail Because as it is stronger they will they say they occupy sites, etc So the the system of they all they are disrupted the what the actions are illegal So one of the training is that prepare them how to act when they will be charged So it's a way to connect so now as I said there are this There's one form of resistance I just wanted to have a focus on that is when the new emergence system starts to be Powerful enough There one of the form of the resistance is to copy it copy the copy the new but based on the old logic And hey, we are also doing the same thing and because I use this This Activist for climate change That is now stronger and stronger one of the form of resistance Which is copying is the greenwashing everyone's green and But those are Copy the new which is not innovation innovation Thinking differently is by the pioneer and by in the emergency system. What is said in this model of two looks also we said that This change is a disruptive change which might not be a good news There is no way to say that's that's the the line the dotted line there There's no way to say I will easily step from there. There's disrupt that it needs courage There's not there's no path between them It's and it's also because of this This way of behavior as a living system as the New the pioneers the new system is detected as a virus The dominant system the old system will activate its immune system. So There's no dialogue Okay, and That's The hard moment and that is the second part of the exercise is that okay the the dominance System grew it was steward and then it decays after the peak and This is the the hardest experience to have from dominant to dying from being at the peak of its splendor to Decay but what is What is important about decaying system is and That's a message to pioneers or change agents is Compost what we what life does and we we are very bad as Human species is at composting By the way, and that is a Side comment. We are the only speed a species that creates garbage Garbage meaning something that no other Life type of life Needs to leave all other species create something that that is used by Others but we create garbage Why and our organization also we forgot to compost what does composting means in this is Taking those old behaviors and see How they can nourish the new one? Because we have this tendency and pioneers can have this tendency to say all of that is bad and That creates even more resistance, of course and What What the the the two models loop says for another three actions so for for the emergent system and for the pioneers it was name name connect nourish and for the dying system another three actions is Hospice so hospice the old system so can it can die It's the support that today composted so take what is good to feed the new and Also, the third one is illuminate is illuminate the path So it can be safer for for the the people to cross the chest from the old to the new and What is really a very very important and one a question Which it's kind of a rhetorical right now, but we'll have another exercise How can we provide? Compassion to the dying system. This is something that we forgot a way to Disactivate that immune system is to To provide compassion Which means what? Saying that the the way that that system acts is normal because It wants to stay safe Or do you say that the problem is your manager in this water? I say well that manager is behavior is normal Because it's what he knew that was the success path he had so this is so it's part of the dominant system and And And really the compassion is very important. So to compassion and hospice what means is a Support the dust of the smooth Transition so the smooth dying of the the dominant system I will present you the questions and will be the second part of the exercise what actions of compassion Toward the people in the dominant system that I believe in that dominant system Can you put in place so they can feel less threatened? The second one is to To protect also what are usually in in in the dominant system and you know when in the transformation always have sponsors or People that actually are in the dominant system don't feel safe enough to be pioneers Not anyone wants to be Greta Thunberg But there are people that support Would protect the pioneers so The second question is who are in the dominant system protectors of the pioneers? Who do you identify in your organization the the pioneers and what are the ways? to illuminate the plot the path Toward the new and that can amplify also the pioneer work So that to create the the this new eventually this new safer engagement You know we talk of the psychology is safe. So What are the ways and I think you I I invite you to the Second exercise. Yeah, sorry The second exercise on your hands out. You have this question and Equally, I'll ask you to reflect five minutes on answering this question and then share and Is mutually inspire yourself? Yeah, exactly Oh, that's what was the first exercise So go back to see how you nourish those pioneers now. Yeah, the second exercise is how you support those people that say We try to transformation. They have the transformation fatigue Or or it's also an avoid me avoiding behavior No, that we don't change because we know all change we changed all the time. So We I'm really invited to reflect on that and at the end of this session, I'll give some answers eventually So, so if I understand, well, they're different protectors Yeah, yes, but now what I invite you is to reflect on your Current organization so not don't think theoretically generally it's in your organization who can be you know So if you have an international organization think what who do you do in identifiers protectors? locally or at the head office or Or or offices other offices of head offices in India Okay Another five minutes to go. Well, I I'd invite you to start sharing So you can get inspired by the others So I I hope you had good discussions and I would like to invite you to a third round Of discussion in which the wisdom of the group is At service of one person which means one of one in each group can present his or her situation and Then you you have a bigger flip chart paper and that person writes down or with bosses on that but the the ideas That the others in the group can give him or her so they can Nourish their pioneer and can also illuminate and amplify their work So that the people in the dominant system can become willing to engage on the new path So focus on that Is is the instruction clear or not? Yeah, so one one person described the situation and the others in the group gives her or him ideas To answer that person don't reach this situation. Okay. It's a way to So the group is at the service of one person And if you had time we could do all the people but pick one In your group. Okay That will the be the gift that the each group will give that person Yes, oh, it's the idea is that one of one of you presented her or his situation and Both the other two of you give them answer Suggestions with that second question mainly how can okay, so It's the gift that you're giving. I don't know. I don't know where it comes from, but it's nice Yeah, the idea is to have a map for the person that For the one that you are working for so the idea was that one of you present the situation and the other helps them helps him to And they put There with post it or you write on that map. What are what were the the ideas that you've got? that was simple Sorry, not necessarily like that. It's just the answers to the questions that you can put ideas on post it Like brainstorming, you know, no I Will keep it simple It's about two minutes left, so ever if you didn't finish it. It's okay Okay, I'm sure I'm sure that you can I invite you even to continue the discussion outside and give Give the the feedback. I just wondered Wanted to say how how did it feel to work and give ideas to one of your Colleagues, thank you Woody. How was it? Yes pioneer the one that has initiatives to change is the rebel The one that says I don't would aid it couldn't be No matter who that's what I was giving the examples of Greta Thunberg She's a 15 year teenager in terms of legitimacy on politics or Science She had none, but she observed That the dominant system is cracked. So that's what it's not a role In in the organization and thank you for that that question is that person that is the rebel Whatever the role is yeah That was the thing. But yeah, thank you for that that question. Okay, so I I would like to go guide you for mom and Another set of concepts real quick because this is huge and I'm really passionate about I Hope you felt well to either receive ideas from your parents at table or To be at service of someone usually it's it's quite nice So what happens is that as I said these two loops that are kind there's no link. There's kind of disruptive The path to one system to another is painful is it and it's chaotic There's no right way. So that's why the questions that I asked you are pretty open I don't tell you do this this and this it's just For the pure pioneers name them connect them nourish them for this dominant system find the protectors Illuminate and hospice to create so that's our own hospice is really important for me compassion and Compost Compassion for the people that don't want to change. It's normal. They defend themselves and compost recognize that The dying system will also nourish the there's something good Look up what is good in the dominant system And sometimes is hard mainly when we have very strong beliefs and I give an example as well the industrial system, you know the the Petroleum extract industry That it's it's a it's a decaying system and This challenging question what what is good? How do we compost what this is the system brought in terms of I don't know Well being for me, I don't know. I'm not I don't Want to give answers, but that's the mindset There's always something good that can nourish the new system but the the path is chaotic and because it's chaotic it's once again a threat and you and it's it's hard to go in and Yeah, I won't have time to really go through it Deeply and I knew it, but I still wanted to to Present that that the way to cross this chasm is to decode to this deconstruct our own beliefs Because pointing to someone else's belief that our wrong is easy deconstruct my own beliefs not that easy and A way that I want to offer it. It's it's from a model from Dave Gray For the liminal thinking so thinking at the borders is that say that reality is at the same point somewhere and We interact with with that reality and then we have an experience and that experience combined With our relevant needs because we each one of us needs so we create a story about it and that story is our set of assumptions So we have an experience That answers to some some needs we have so we create assumptions and On that assumption we create something that is called obvious our own reality. How is that?  I have an experience. This has happened So now I know this is true and What happens also is that if someone else had the same type of experience and same time of needs as me There we create the collective obvious and that's what it's called the self Sealing bubble of beliefs as shared beliefs group thinking And the group thinking is that it's a set of beliefs of one group and Guess what other groups have their own self sealed bubble of belief like Pioneers will have the there's dominant system have their set of beliefs and We create here our own reality it's what is obvious and there's a gap and the one way to The live the threshold to set to pass from the set of beliefs that we have To set of beliefs be is what is called us that liminal space is being aware of this model and deconstruct them Question always what is obvious? I'm not entering into details Because it's all a process that I have here, but question what is obvious for me I said what what are what are the assumptions? I'm doing what are my needs? What is the experience and this is a way to to go from the set of beliefs a to the beliefs be? Because this is the threshold because when we deconstruct our beliefs what's happening? What's happening and an idea? Sorry, yeah Yeah, we we don't have any assumptions anymore and what does that mean? Sorry Insecurity exactly void chaos. I don't have my references Self-doubt so a lot so that's very complicated. It's an awkward not easy Place to be and that's also an invite you to compassion and also to self-compassion by the way So what is called as the resilient learning is is happening in in the liminal space and Another model I will I want to share with you because I'm working with this It's the theory you change curves saying that change doesn't happen in a linear Way, I I mean at a and I want to be at b. It's more like that I'm Getting rid of my beliefs. I'm present to reality You know the top of reality because I don't have any assumptions Any judgments? It's a hard place, but I don't and then new behaviors and no idea emerge and the way that we go to be Is like that? We renounce we I love to say that we you can't bring something new If your space is already packed with them, so you need to renounce the something so that was oh What I wanted really to it's a it's the same thing It's a way to say how do we cross that you is and the liminal space What is my obvious? What are my assumptions? So it's exactly what I've told you about the on the slide the needs What are my needs? How do I feel my needs and that let's see? what things that Actually are dangerous as I said I for me and make me in insecurity and make me have another type of beliefs It's also a way to have compassion saying hey I have made the assumption of that needs maybe the other group or the dominant system had the same needs Guess what just that they have others made other assumptions But if we meet there were we have the same needs Then we can construct something together. It's a way by the way to to Manage conflicts So that's that completely other topic so with that Yes, because it's the last session a Way to go through the that you What I wanted to do is to make that exercise number one on your hands out which is here and connect to our own body Real quick exercise Just to end the session and an experiment transformation. It's called the stuck exercise It's the same like this one and think of some situation that you might be stuck with and please Please if you want to stand because we need that If that's okay with you to stand I invite you to stand I Invite you to stand It's a more complex exercise, but we will do it individually and now Think at a situation where you think you're stuck. You don't know how to solve it Is that that our body knows that has a lot of of ideas and try to make What's called a sculpture take a posture that that is That illustrates that stuck We say it's an exercise that invites you to to put your brain down and and tapped into other Other resources so Everyone that has absolutely no stuck no situation that I can give some of mine Okay, so I think of one of mine and this is I'm trying to do a demo of that so And then have a posture This is mine Not with my brain is what just thinking of it. It's like that and try to stay with it Staying in a stuck situation is not sustainable so stay as long as you can and then Let your body move It will move or and we you'll finish with another one. So let me This is my second and this was for me my second sculpture the second posture and what I invite you is to put a word that comes to you without thinking on the first one and on the second one and That is all and that will tell me if you've got any ideas how to get unstuck afterwards, okay? Is that okay? I? Let you do this exercise I Let you do this exercise for you right now Then I will applaud you think of it It's a work with yourself stay as long as you Can and then let your body move and put a name a word on the new And all of you have a word for the new posture Yes Sorry believe relief Discomfort the second one, okay So I'm not sure because I really wanted to you can do it with yourself. You can do it also by in triads so three people are together and The others also give a feedback what they felt about About this I know it looks awkward, but it's you know deconstruct them our beliefs one of our beliefs is that the body is a taxi for the brain and Actually, it's not true. So you have a lot of A lot of information that the body has and this was a way to invite you at the end At the end of the session to connect with with another type of change Okay, I think this is This is kind of all there's a There's a minute Some minutes left. I wanted to offer you as a conclusion about change this Quote that is one of my favorite In saying that all change passes by three phases The the stages the first one when it's ridiculous You know the exercises we've just done when I say tap in the intelligence of the body in our Culture professional culture that this is ridiculous right now I've made you Do a ridiculous exercise didn't I? the second phase is When it's dangerous is violently opposed because it's dangerous. You know, it's the dominant system that starts to react Because it's dangerous and the third stage when it becomes Self-evident everyone does like that Now I just wanted to finish with this Connect with me I'm doing this type of Workshops longer and You're interested Please connect with me and I think we still have some moment for reaction questions violently reactions Yes, yeah, Mike So for everyone, I'm not sure if you'll understood the last exercise so what Anna John could it was, you know, she did a somatic exercise in this somatic exercise what we do is like our memory resides in our body and What we are actually trying to do is tap into it and our body knows a lot of things just not just our brains and When we were in a uncomfortable position, I could like you know for an example we could say, okay In an uncomfortable position, I can say, okay I am having a lot of challenges for agile transformation in my organization, okay The body is in an uncomfortable position. You are just thinking of that pain and once when you are coming into another position Which you feel is relaxed Okay at that point of time your body and your mind will start throwing some ideas actually if you put some Efforts into it and you will get us one or two nice ideas from there So that was actually a very beautiful exercise to you know, actually tap into our own learnings Thank you. Thank you. Thank you. Thank you so much for that It's true that I I saw this and I didn't have time really to create the safe space for you That exercise might have been awkward, but you have it in the handouts and it's exactly that The body inspire your mind Thank you Other questions In terms of representing the emergent system, yeah, why is there a dip because the dominant system also emerged earlier, right? Exactly, but the idea is that it's really to to make them different Actually, the dominant system was an emergent system Before but it's it's a choice of representation. We are here now in the dominant system And you know the dominant system. It's a way to represent that it decays It's it's only that it's only a way to represent, but you're right the dominant system was an emerging system Yeah, it's just about experiential this is more of enlightening thoughts for us because what I felt is more from Structural or non-living perspective only to approach the Transformations, but how we connect these things with the living organisms one seat as a living thing. That's a very different perspective I got it from you. Yeah. Thanks. Yeah. Thank you Any other question any other question? Okay. Thank you. Have a nice day. We have now time for networking and dinner Enjoy. Thank you. Thank you. Thank you. Enjoy your evening


When Alexander the Great Idiot was moving towards India on the way, was Persia, ransacked the Persian empire, killed every male member of the royal family, went in search of this man sitting there with a heap of bones, this happened. When Alexander the Great Idiot had this dream of conquering the whole world, but at that time in history, the important part of the world, and even today is, but at that time it was significantly so, was everybody wanted to conquer India because of the wealth and the culture and the most prosperous nation on the planet, all these things. So he was moving towards India on the way, was Persia. So he ransacked the Persian empire, killed almost all the male members of the royal family and then he wants to leave, move towards India. But he needs somebody, a vassal king to manage that. Somebody who's puppet will manage the kingdom for him. You can't just pick up somebody and put them up in those days, they must be of the royal family otherwise people will not gel with that. So he started looking but unfortunately he had killed every male member of the royal family. Then somebody said there is one prince who left the family long time ago and he spends all his time in the graveyard. The Persian people have this, that they're dead, they neither bury nor burn, they're very smart people, even today, they're very smart people. Why waste firewood on the dead, fuel, why pollute the earth by burning, why take the labor of digging holes in the earth, just leave it for the birds and other scavengers to eat the meat. Then the bones alone you bury which is easy because after hundred people have died, one colossal digging you have to do, easy. I'm just saying, this is their way, this is their tradition. So this young prince left the family for years, he's been just sitting in this graveyard watching these bones trying to realize something. There's a whole tradition in India that yogis, first part of the training is they're sent to the cremation ground, we'll sit there and watch. So Alexander went in search of this man, so he was sitting there with a heap of bones. Alexander said, see I will make you the king, you just be there as a king, I will take care of everything, my soldiers will manage everything, my people will manage everything, you just be the king, sit on the throne, wear the crown, we'll take care of everything. Then this prince looking at a heap of bones here, like a disappointed vulture, because vulture is disappointed if the bone doesn't have meat. Like that he's looking at it and says, see so many have died here, many of them killed by you and some are rich, some are poor, some are royal family, some are ordinary people, some are high, some are low. I've been trying to make out through these bones which one is high bone, which one is low bone, which one is royal bone, which one is ordinary bone, which is a rich bone, which is a poor bone, I'm not able to get it, can you tell me? Alexander looked at it, this is too complex for me, he just left and went away, there's too much for him. The most precious thing is your life, it is slipping away. You are thinking this and trying to find explanations for the drama that's happening around you, time is going away. If you could stop time and discuss how your husband is not okay, we can do it. Your time is going away, but we are investing time in things that we don't care for. If you knew time is going away, you would not invest in things that you don't care for, isn't it? So, I'm thinking of providing, creating a device, we are working on it right now that every day it's reminding you, oh you are fifty years of age, fifty percent of the sense of time are gone and as you see it is just going away. You see in the old hour glasses, that was just telling you the hour is getting over. This we make it a little enlarged to see how your life is getting over all the time because if you sit it goes away, if you stand it goes away, if you do something wonderful it goes away, if you do something nasty it goes away, you did nothing it goes away. This is the nature of time and life. If you want to rise above the time process, there is a way, but that also you must dissolve in a way otherwise as long as you are a slave of time, it's best that you are conscious that time is slipping away, there is no time in this life to do anything that genuinely does not matter to you. Yes or no?


Good morning. This is the second lecture on the visual system. Ralph and I thoroughly enjoy teaching this part of the course. We enjoy teaching the whole course. We enjoy teaching this part of the course because we get to swap off lectures and to alternate between Ralph and myself. So you get a feeling for the variations in among how neuroscientists approach topics. So on Wednesday he talked about the process from the retina to the visual cortex. Today I'm going to talk about the first part of the process, the retina and the detection of light. And then on Monday Ralph is going to talk about a higher level vision. Then Wednesday I will talk about the motor system and Friday about the olfactory system. And so we have fun switching off topics and giving you interesting perspectives. Today we talk about the visual system and there are actually six topics involved in the visual system. First of all, I'm going to talk with you about lenses and optics, then about the photoreception event, then about the retina itself, connections to the brain and master switch that actually controls a good part of differentiation in the retina. And finally the time frame for evolution of the major features. So the topics for today are actually two. Photo transduction in the retina of course is one and also evolution of the eye is another. The motivation here on evolution is that we actually, except for John Allman's course on the evolution of on evolution undergraduates actually do get only a limited exposure to evolution as a concept. And this is a field that's changed rapidly in the last decade or decade and a half because of the enormous amount of data available from genomes show very clearly that genomes are all related. But we get this countervailing set of arguments from people who don't believe in evolution. And do any of you have friends who didn't do not believe in evolution. As an undergrad, you had friends who did not believe in evolution. One particular Mason, you have friends who don't believe in evolution. You encounter one at a cocktail party. Here are your arguments. Mostly chapter 26 of candle talks about the first topic photo transduction and it was partially written by our own Marcus Meister. In terms of the evolution of the retina, we quote Dubjanski, a great 20th century biologist who said nothing in biology makes sense in except in the light of evolution. There are many ways to solve a problem in biology. And in order to know, to appreciate how an organism does it these days, we ask how it evolved. The key point in evolution is that all modern biological processes evolved from related processes. So we are not talking about the origin of life here. We are talking about evolution after life appeared. A way of saying that in molecular terms is that every modern gene evolved from other genes. Specifying that a little bit more precisely, we say that every gene has an orthologue in related species and most genes have paralogs in the same species. I'm going to explain to you what I mean by orthologs and paralogs, but basically we'll get into it in great detail. But because all vertebrate eyes are quite similar, the hung for orthologs is very straightforward and it's successful in every case. And in fact the two organisms share many orthologs is very powerful evidence for the idea that they evolved from a common ancestor, which is of course a central aspect of evolution. So let's give as an example of orthologs and paralogs the globin genes. These are the proteins that carry oxygen in the blood. We are going to talk about the human on the right and the mouse globin genes on the left. We're going to go back about 700 million years to the point where in the common ancestor of humans and mice, there is a single globin gene. The globin is the protein that eventually binds the heme that carries oxygen. The record suggests that roughly and very roughly 500 million years ago, before the present, there was a split, a transposition separating the alpha and the beta globin genes. Because this happened before humans and mice split, vestiges of that split remain in mouse genomes and in human genomes today. So the orthologs, well let's talk about paralogs first. The paralogs then are related occurred because of the split. So the split produced paralogs, related genes, usually with related function within an organism. Now there was another split between the fetal and the adult beta genes. Again, before the common ancestor of humans and mice gave rise to the two species. And there was another split right here between the delta and the beta genes, again before humans and mice diverged. However, after the divergent, there was a further split only in humans between the gamma G and the gamma A globin, which was not present in the mouse genes. And so we see that if we understand common ancestors and splits and descent, we can explain most of the genes in a complex family like the globin genes. So we have orthologs, which resemble each other across the species, the beta globin, mouse beta versus human beta. Paralogs resemble each other distantly or closely depending on when they diverged within a species. A good example would be the human epsilon versus the human beta. There's also the mouse epsilon versus the mouse beta. And then we have this more recent divergence in the human lineage that produced gamma G versus gamma A. So these are the concepts which we put into molecular terms, into protein terms when we discuss evolution. We discuss orthologs and paralogs. Let's now go to the specific topic for today, which is how the retina works and what this tells us about evolution. So first sub-topic is lenses and optics. The lens, of course, has an index of refraction greater than that of water, and it can therefore bend light. And the reason it has an index of refraction greater than water is that it has a high concentration of protein. Actually remarkably, the high concentration of protein occurs in all animals, but there are various proteins that subserve this function. Many of them are called crystallines because they are in the lens. Some of them are also enzymes. They perform various functions in other tissues. Apparently, to get a crystalline, really the only requirement is that the protein should have good stability so that it can be present at high concentrations. And it also should have no prosthetic groups or attached groups, such as vitamins, that might absorb the light. All we want is a high index of refraction. We don't want a colored lens. To give you an idea of the protein concentration, this cell is 22% protein. And I said in lecture one that it's 4 millimolar protein, and you can work out the idea that a typical protein, you can see it right there on your gel from your biochemistry lab course. It runs at around 50 KD, 55 KD. Average residue has a molecular mass of 110, so we can go back and forth between 4 millimolar and 22%, which is really a remarkably high concentration of protein, and a lot of cells metabolism goes into generating proteins and keeping them fit. And so I told you that crystallines come from various, or are various proteins in various species. If we look at a typical picture of the gene regulation, we see the coding region. We see a promoter. Here is the coding region of a crystalline. Here is the upstream factors, the Tata box, the transcription factors, the RNA polymerase that you learned about and by 8 by 9. There are a lot, and as you know, the non-coding regions of the genome are very much larger than the coding regions. So there are lots of non-coding regulatory regions in most animal genomes. They can be folded in ways that we don't completely understand yet to activate the RNA polymerase to transcribe the crystalline, to transcribe a protein. In the case of the common protein, the common transcription factor that I'm going to talk about later in this lecture, it is one of the transcription factors that binds to an upstream regulatory region of DNA and activates RNA polymerase. So what do we learn? Existing proteins used for various functions, probably the use in the lens came later than the use in other tissues. And it is also a fact that you learned about gene sharing that several distinct transcription factors can share activation of a protein and could activate that protein independently. And here in the case of crystalline is a great example of that. So we've got the lens and we've got the optics. We know how the lens has accomplished its high index of refraction. What about the aperture? That's part of the optics too. So the aperture mechanism is actually controlled by smooth muscles. There is a nerve from the brain, releases acetylcholine, makes a muscarinic synapse. The smooth muscles are around the iris. When acetylcholine is released, the smooth muscle, the acetylcholine activates muscarinic receptors. It contracts the smooth muscle cell, which is connected by non flexible fibers to the aperture itself. So the contraction leads to a smaller pupil. Now, people who don't believe in evolution say, this is just such a wonderful process. It must have been created. I want to remind you that in fact, innervated smooth muscles control many organs in the body. They control the diameter of blood vessels, the peristaltic activity of the intestinal tract, the diameter of the bladder neck. Many of these smooth muscles are controlled by muscarinic receptors. If any of you have friends who get their eyes dilated when they go to the ophthalmologist, the dilation of the eye involves atropine, which comes from the plant atropa belladonna, meaning beautiful woman, because in the old days it was thought that a beautiful person had wide eyes, dilated pupils. So this is where atropine comes from. And so in each case, the nervous system has evolved circuits that extract and integrate information from sensors and employ smooth muscles in a homeostatic loop. So if at this cocktail party, your friend, a new acquaintance says to you, the eye is remarkable because it has evolved to control the aperture. You can say to your new found acquaintance, well, so has this fainter. Okay, so moving on from the lens and the optics to the photoreception event, photoreceptor organs have actually evolved independently. About 40 times. And in each case, they respond to the visible spectrum, which is an eponymous statement that is a photoreceptor response to visible light. But it's always between 400 and 700 and maybe a bit in the near UV. So how do we explain the fact that the limited part of the electromagnetic spectrum, which goes out from, of course, x-rays through radio waves? How do we explain the fact that eyes come back to this limited part of the spectrum? Well, infrared light, remember E equals h nu, infrared light is insufficiently energetic. It cannot provoke the cis trans isomerization that actually is part of the photochemistry of vision. Shorter wavelength UV light is too energetic and it might damage organic molecules. You've seen clothes get bleached. You've seen you've got sunburns, etc. So there is a reasonably friendly part of the electromagnetic spectrum that is energetic enough to do photochemistry, but not energetic enough to do damage. And that's what we call the visible spectrum. As Ralph Adolphs told you the other day, the photoreceptor cells in the rods and cones in the retina actually receive their photons from what appears to be the back. That is, light goes through the entire retina before it arrives at the photoreceptors. Well, that's okay because the retina is transparent, so you don't lose much energy in going through the retina before the light gets to the photoreceptors. There are two types of photoreceptors as Ralph explained the rods and the cones and their distribution varies across the retina between the fovea, which is quite dense and has primarily rods, and the rest of the retina, which is specialized for a larger visual field. The rods have free-floating discs. They're not actually free-floating, but they are separate physically from the plasma membrane. The rhodopsin, the visual pigment, is on those discs. The cones have invaginations, which causes the vast increase in area. But again, there's rhodopsin on these greatly amplified amount of membrane. In each case, of course, the greatly amplified amount of membrane provides room for lots of rhodopsin molecules within a single cell so that each of those photons stands a pretty good chance of being caught absorbed by a rhodopsin molecule. And then the nutrients come from a connecting cilium that goes to the nucleus where the proteins get made. And then one selective advantage of the fact that the rods and cones are on the other side of the retina is that they conduct another layer of cells, epithelia, which keeps the outer parts well nourished. If we look now at the rhodopsin, there are actually, here's a good example of paralogs. So there are four paralogs of rhodopsin in the human genome. They obviously evolved from a common ancestor. And each rhodopsin interacts slightly differently with the common molecule retinol. And these slight differences in the interaction with retinol change the absorption spectrum of the retinol so that we have the blue absorbing, the red absorbing, the green absorbing cone pigments. The cones are specialized for color vision and a much broader absorbing rod rhodopsin, which is specialized for black and white vision. So there are lots of mutations that change the spectrum and these mutations are mostly clustered in the membrane in the region that in fact interacts with and slightly tugs at the retina. The chemistry, the initial event in photoreception is rather simple. The retina, vitamin A, bound to the rhodopsin is in the cis configuration, which is metastapal. And you can see there is this conjugated part of retina so that it absorbs light in the visible part of the spectrum because it's nicely conjugated. When cis retinol absorbs a photon, it undergoes an isomerization, a photoisomerization, changing it to the trans configuration, which is more stable energetically. So each time a rhodopsin molecule absorbs a photon there's a good probability that it will undergo the isomerization. This then leads to spontaneous dissociation of the retina. So now the retina is free and the rhodopin, the activated opsin is also free. Then there are enzymes associated mostly with the epithelium that regenerate the 11 cis retina that requires energy back into the, sorry, that trans back into the 11 cis. This requires energy and then we go back and reload the rhodopsin, get ready for another photoreceptor event. But the key millisecond time scale photoreception event is right here. It's the light induced isomerization. Now we have discussed about a week ago the usual G protein coupled receptor pathway. And I mentioned that rhodopsin is in fact a GPCR, a G protein coupled receptor. The usual pathway begins in the membrane then moves to the cytosol and then if it is activated for long enough actually moves to the nucleus. There are a couple of key differences in the GPCR family that have the selective advantage of being able to respond more rapidly to visual stimuli than other G protein coupled families. First of all, in the membrane we have the receptor, seven trans membrane helices, just like a usual GPCR. It activates a G protein, again, standard GPCR. It activates the one G protein family that we have not discussed in detail, neither I, Q nor S, which we discussed in detail, but GT. And actually this was the first G protein alpha subunit studied carefully. T stands for transducent and it transduces the signal from photons to activating the effector. We discussed the fact that G proteins have effectors, either channels or enzymes. In the case of the vertebrate visual system, the effector is an enzyme. We also discussed the fact that enzymes make intracellular messenger. And in the case of the retina that intracellular messenger is cyclic GMP. Unusually this messenger activates an ion channel. But the first few parts of the GPCR pathway involved for vision should, you should pardon the mixed metaphor, ring a bell. Although they take place more in the cytosol than in the membrane. We talked about the beginning of the GPCR family pathway. We have a neurotransmitter or hormone that binds to the receptor that activates the G protein that activates an effector. And we said it at fastest it's 100 milliseconds. That's about how fast the visual system is also. Now, the difference is that in the usual G protein coupled receptor family, there are lipid tails on the proteins to keep them in the membrane so that they can all encounter each other rather quickly. However, in the rods and cones, there is a limited cytosol between the discs or between the folds in the cones. This limited cytosol allows the rod or the cone to lack the lipid tails on the downstream members of the family. So, for instance, G sub T transducent is a cytosolic G protein. It doesn't have a lipid tail. And the enzyme effector is also cytosolic. It doesn't have a tail. However, because of the fact that the space between discs is so small, there's not many places that these enzymes and proteins can diffuse to. So, they are close enough so that it says though they were in the membrane itself.  So, they're not membrane bound, but the membranes effectively restrict their motion so that we can get a high density of these proteins and of the rhodopsin and they can still interact within milliseconds. So, less than 100 milliseconds and very close to each other, much less than a micron away. So, that's a slight difference in terms of membrane embedding versus cytosolic arrangement. Now, remember we said also in our G protein lecture that we make intracellular messengers and that this involves transfer of a phosphate group. So, it involves energy and that intracellular messengers get made and bind to proteins. We also said in these intracellular messengers typically are either calcium or cyclic nucleotide. We also said in the previous lecture that these messengers can themselves in a few cases activate ion channels and I promise to get back to you with that. Well, here we are with that example. In a few places intracellular messengers activate ion channels and that's where we're going today. Among vertebrates, the intracellular messenger for vertebrate phototransduction is cyclic GMP. Not cyclic AMP, but cyclic GMP. Just reminding you here's guanosine. Here's guanosine triphosphate. Cyclase is cyclic GMP. There is as we learned in a previous lecture always an enzyme that hydrolyzes cyclic GMP. It's a phosphodiesterase and hydrolyzes it into cyclic, into simply GMP, not cyclic GMP. Now there's a lovely twist here. This lovely twist is the opposite of what we think most of the time in the nervous system. In the photoreceptor we begin with high cyclic GMP. It opens ion channels, keeps the plasma membrane depolarized and keeps glutamate release at the synaptic terminal high. The result of photoisomerizing right now in the activating rhodopsin is that actually we activate the phosphodiesterase. This reduces the cyclic GMP concentration. It results in closing an ion channel in the outer segment of the membrane, the outer segment of the photoreceptor where the disks are. And so this transiently hyperpolarizes, not depolarizes like in a synapse, but hyperpolarizes the entire plasma membrane. So just a reminder that in previous lectures we talked about the effector enzyme, the cyclase, making a cyclic nucleotide, breaking in another enzyme, phosphodiesterase. We talked about the fact in previous lectures that the phosphodiesterase is often inhibited by caffeine, and AMP itself is not very interesting. We also mentioned in a previous lecture that the analogous system, which occurs in the retina, having an enzyme, a cyclase, making cyclic GMP, getting hydrolyzed to an uninteresting molecule. And it is, in fact, the phosphodiesterase, which is the effector for GT for transducing. I also gave you this little puzzle to tell me which commonly used drug can also inhibit a phosphodiesterase. Indeed, a paralog of the phosphodiesterase expressed in the retina is expressed in other places in the body, and that paralog is inhibited by Viagra. And the package insert for Viagra says that Viagra may cause a perception of bluish haze or increased light sensitivity in some patients. So the selectivity of Viagra for a particular phosphodiesterase subtype is not perfect. Okay, so then we also study this system using the excised inside-out patch, that aspect of the patch clamp, which allows us to pull the patch away from the cell while the gigaseal remains mechanically intact. We can still measure channels opening and closing, and now we can ask whether, in fact, those channels are indeed opened by cyclic GMP. Sure enough, when we add cyclic GMP to the bath, the channels open very nicely. So this was really an experiment done in the mid-80s, was really the first hint about the transduction process of photoreceptors. The idea that in a normal photoreceptor, channels are open. When phosphodiesterase gets activated by light, the channels, the cyclic GMP gets hydrolyzed into an uninteresting molecule, GMP, and those channels close. So transduction process receptor going to GT activates the enzyme, which decreases cyclic GMP. So if we look at the membrane potential of a photoreceptor, it looks, as one gives a light pulse, it actually looks electrophysiologically opposite to most neurons. When we activate rodopsin, we actually get a hyperpolarization. That hyperpolarization is caused because channels close. Sodium channels close. This is transient, takes typically a good fraction of a second, sometimes much faster, and then the hyperpolarization goes away and we go back to the resting potential. So, rodopsin absorbs light, cation channels close in the plasma membrane of the outer segment, hyperpolarizes the entire cell. This hyperpolarization relays visual information to the synaptic terminal made by the photoreceptor cell onto subsequent cells, and it slows the ongoing release of glutamate. So we have a challenge for the photoreceptor. It has to release a whole lot of glutamate all the time. And apparently this challenge is subserved by a specialized organelle called the synaptic ribbon. So here is the cytoplasm of the photoreceptor. Here are the post-synaptic processes downstream from the photoreceptor. So it is a photoreceptor to horizontal cell synapse. There are an enormous number of synaptic vesicles in the photoreceptor terminal waiting to be released. They apparently get lined up on the ribbon and they get nicely moved toward the synapse and get released at pretty high efficiency in large numbers. Of course the calcium channels that control the release are right down here. Those calcium channels are continually activated because the cell is continually depolarized. It sounds really funky, but that's the way the cell does it. And it takes so much energy actually that a typical photoreceptor cell turns over its entire sodium concentration every 20 seconds or so. So that photoreceptor cell has to have lots of ATP, lots of nourishment, works very hard. Alright, we have talked about the phototransduction cascade. I want to talk about two aspects of that cascade. Amplification and adaptive and homeostatic mechanisms. We know that the retina is a remarkable organ because it adapts. When it's fully dark adapted, many species can detect one photon hitting per photoreceptor cell. That event registers. Not one photon in the retina, but one photon per photoreceptor cell. On the other hand, when fully light adapted as in bright sunlight, species can accurately analyze light at intensities about 10 to the 10th fold higher. So there is not simply one adaptive homeostatic mechanism that underlie these phenomena. There are several of them at the photoreceptor level, at the circuit level in the retina. And probably the adaptation is complete by the time that impulses get to the central nervous system. Now, I have a few Henryisms. One of my Henryisms is that I don't like the term homeostasis or adaptation. Because we inevitably tend to assign our favorite process such as memory or learning or addiction and say that it occurs because of homeostasis or adaptation. Actually, that tells us nothing. Homeostasis, adaptation, compensation, these are not mechanisms in themselves. They're really adjectives. So the best way to talk about these processes is adjectives. So we talk about homeostatic mechanisms and adaptive mechanisms. And one of the goals of neuroscience at the circuit level or at the cellular or molecular level is to understand the adaptive and homeostatic mechanisms. But if you say, well, this process occurs because of the homeostasis, you've actually sort of defined homeostasis rather than defined how it works. Moving on. So the amplification, first of all, that allows a single photon to generate a perception occurs because after the rhodopsin is activated, the receptor can activate about 500 transducent proteins. So in the space between disks, 500 transducent proteins can be activated by a single activated photoreceptor. So that is amplification. Then the phosphodiesterase, which chews up cyclic GMP, is fairly efficient. It has a turnover number of around 4,000, 5,000 per second, which is about as fast as the cyclic GMP molecule can find the phosphodiesterase. It then gets hydrolyzed while it's activated. So we have another amplification. And the third application is that each millisecond, each time a cyclic GMP molecule binds to a channel, each millisecond that it's open, the cation channel in the rod can allow the flux of about 10,000 ions. So this amplification occurs at several steps. We understand the amplification when the system is at its most sensitive, that allows a single photon to be amplified by a factor of 500 in terms of transducent, a multiplicative factor of 4,200 in terms of cyclic GMP molecules. And then for each of those, we interrupt the flux of about 10,000 ions for every millisecond that the channel closes. What about adaptive and homeostatic mechanisms? Well, those are more complex to describe, and I'm not going to describe them all. But one of them is that transducent itself, which is not shown here, hydrolyzes GTP to GDP and shuts itself off just the way any protein does. So that is, we get some adaptive, we get a shutoff of the transduction right there. Another part of adaptation is that the activated receptor also gets deactivated. And the way this happens is that a kinase called rhodopsin kinase appropriately enough, which phosphorylates proteins, remember a kinase takes ATP, takes the terminal phosphate of ATP and puts it onto a protein, thereby making ADP in a phosphorylated protein. So this phosphorylated C-terminus mostly of rhodopsin binds another protein called apparently appropriately enough arrestin. And a rhodopsin molecule that is capped by arrestin can no longer interact with the g-protein. So rhodopsin kinase helps to terminate the event as well. And then we also remember that guanylate cyclase has to synthesize new cyclic GMP from GTP. It is partially inhibited by calcium at concentrations greater than around 75 nanomolar. So these are cation channels, they flux both sodium and calcium. So typically the tonically open channel sets calcium in the cytosol at around 500 nanomolar. But when the cation channel closes, calcium continues to be pumped out via the usual processes, calcium pumps. And this lowers calcium to around 50 nanomolar, and it activates the denominal cyclase. We start off here at a high concentration of calcium. The channel closes, no more calcium is flowing in, it gets pumped out instead. This activates guanylate cyclase, we make more cyclic GMP. So that's another homeostatic or adaptive mechanism. There are lots of these in the photoreceptor and in the circut downstream. With the result that over the time scale of seconds to minutes, you can adapt to varying light intensities. So we've talked about the photoreception process, let's now go on to the topic of the neurons in the retina. Here is a picture very similar to the one that Ralph showed you. The rods and the cones with their outer segments facing outward. Then there are two layers of synapses, the so-called outer plexiform layer and the inner plexiform layer. Remember we're going in toward the center of the eye here. In between those two layers, there are cell bodies of several types of neurons. There are the horizontal cells and you can see why they're called horizontal. There are the bipolar cells, you can see why they're called bipolar. And after the inner plexiform layer is the ganglion cell. The ganglion cell in the retina is unique until we get to the ganglion cell. We are dealing with cells that do not fire action potentials. They don't need to, everything is within a few hundred microns. They just do graded signal processing. But the ganglion cell feeds the optic nerve millimeter to many millimeters and it does have sodium channels. But in general we've seen these processes before. They have paralogs all over the body. So glutamate, the major transmitter, we've seen it before. Other neurons in the retina make dopamine. We've seen that before. There are paralogs of dopamine allergic cells in the handlebar moustache that I like to tell you about, for instance. Some neurons make acetylcholine. We know about neurons that make acetylcholine. In the retina there are also inhibitory neurons that release GABA. So in short, the person who says to you at this hypothetical cocktail party, the eye is this wonderful complex set of cells and mechanisms that must have been intelligently designed. You reply, no, there are paralogs to genes and processes that occur elsewhere in the body. Channels, receptors, transporters, we've seen them all other places. I won't go in detail into the types of cells in the retina, but if you'd like to learn more about it, you could work in Marcus Meister's lab as a surf, for instance. So we move on now to connections to the brain. You've seen this picture before. They talk about Roger Sperry's experiments in 1948 involving goldfish. You remember that Roger Sperry cut the nerve leading from the optic nerve that those cells that conduct impulses, individual fibers go back to their original destination. Dorsal retina projects to the tectum. The posterior retina projects to the anterior tectum and vice versa. The tectum in higher animals is called the superior colliculus. So when he saw that fibers go back to their correct place, he postulated a so-called chemo affinity between the nerves and their target cells. These were very important experiments, but in terms of what the neuroscience community believes, they may not even have been Roger Sperry's most important experiment, because he then went on to conduct the Nobel Prize-winning split brain experiments that we know very well that form modern ideas about the specializations of the two hemispheres. So these chemo affinity type interactions lead, of course, to the maps. Maps are not unique to the visual system. We see them in the somatic sensory system. We see them in the auditory system. They're probably unique to nervous systems, but they are ancient. In fact, as far as I can tell, visual maps arose at least 500 million years ago. And Ralph has discussed visual maps already. He will discuss them in greater detail. So here is a creature from which we diverged about 500 million years ago. It is Lemulus, the horseshoe crab. You can't find any horseshoe crabs on the west coast of any continent, but horseshoe crabs are on the east coast of many continents. This may be Woods Hole, Massachusetts. It might be Recalbote Beach in Maryland, just hundreds and millions of Lemulus horseshoe crabs. This is about a foot across. The females are larger than the males. They have compound eyes with omatidia, very much like other vertebrates. They find their way around reasonably well. And they have maps from the retina to the brain. Now, remember that Sperry's chemo-affinity encouraged us to find molecules that subserve chemo-affinity. For the first couple of decades, all we found was chemo-repulsion. Ralph has told you about efferens and effkinases, which keep molecules away from each other and help to form maps. But in fact, over more recent years, actual chemo-affinity has been discovered. And I told you about the search for chemo-affinity, for instance, in the fly visual system. The fly is an arthropod, so is Lemulus. So there are maps in Lemulus that are reasonably similar in their molecular basis to the maps in Drosophila. But Drosophila is this wonderful genetic animal that allows us to find many types of molecules. So here would be the Drosophila nervous system, the retina, the lamina, the medulla. There are maps at several places in the Drosophila visual system. And I told you about the experiments from Kaizen's laboratory about a multi-gene family in which gene products can interact selectively with other gene products and form the kinds of chemo-affinity maps that allow us to have a precise visual system. So we've discussed this in our lectures on development. All right, where are we? We are at topic number five, which is master switches for eye development. I mentioned the PAX6 gene earlier in the talk, and this is a transcription factor that produces some of the components of the eye. Markably, one can take, and of course in Drosophila, PAX6 is called EY stands for eyeless, because a Drosophila with an interruption of the PAX6 gene has no eye. Well, you can do the opposite experiment, which is to take the primordial cells that are going to give rise to the adult eye in Drosophila. You move it to the leg, and the Drosophila generates a primitive eye spot. And so this is one of the classic experiments in Drosophila that you can move one organ to another. And in fact, you can simply induce EY, PAX6 or eyeless, in this spot and get a primitive eye. So there clearly is a master switch that goes part of the way toward controlling all of the gene activation in the eye. And remarkably itself, eye formation is so similar among organisms from arthropods to vertebrates that you can take a human PAX6 orthologue. Remember now these are orthologs because they have the same function in two species, not paralogs. And a human PAX6 orthologue will induce a primitive eye in an EY mutant and eyeless mutant Drosophila. So orthologs have an important role here too. Now the final topic is that your mythical friend or your hypothetical friend at the cocktail party will say, alright, that's fine, I believe it, but all of this evolution is so complex that it would take much more than the billion years we have available. Actually, the time frame for evolution of the major structural features, and remember this has happened independently, probably 40 times, might take only a couple of hundred thousand years. And so one can show a, or postulate, a series of intermediate steps in the development of the eye that each have use. So one starts with photoreceptors right here and a little dimple in the skin. They can receive photons. And then every intermediate step in which gives you better photoreception. So put the little photoreceptors in a curved spot, you can get better imaging. More and more curved, better and better imaging. Then a primordial simple lens gives better imaging and so on and so forth. And so we don't have to postulate an intelligent design of a complete eye. We can actually see the selective advantage of individual parts. So you can go to this website, which is now several years ago, about the estimation of the time required for an eye to evolve. And what I've just showed you is a summary of the possible intermediate steps in evolving an eye. I think this is the most pessimistic estimate. So we've gone all the way through the evolution and the parts of the eye. I've showed you orthologs and paralogs with other species. And I'll be at office hours this afternoon. Have fun with the midterm.


We're going to do one more example of finding all complex zeros of a polynomial. So this is the second example on your sheet. What we first want to do is look at the graph just like we did before in order to find any real zeros. Remember, while you look at the graph to look for the multiplicity of the zero based on how it hits the x-axis. So this one, since it has a fourth degree, it's a fourth degree polynomial, at the most it will have four distinct zeros. So we'll fill in our blanks with four. So I want you just to pause the video a second and look on your graph to find any zeros of the polynomial. On my graph I found zeros at negative three and one and both of those zeros were just single roots because it went straight through on the graph. So if I have a zero at negative three that means my factor is at x plus three and a zero at one gives me a factor at x minus one. So what I'm going to do is because these two zeros did not appear on the graph that must mean that they are imaginary zeros. And so I'm going to use division in order to reduce the original equation and find the remaining zeros. So I'm going to use synthetic division and I'll first divide by x plus three. So I'll place all of my coefficients in order and then complete the division. Remember to always multiply by the number in the box and then add when you go down. And one good way to always check your work here is the remainder should always be equal zero equal to zero because you're dividing by a factor. So that means it should fit in perfectly. Now with what I have left I'm going to divide by my second factor x minus one and I will just complete that addition here or that division. And what I have left here is one zero twenty five. What that stands for is the equation x squared plus zero x plus twenty five. And since I'm trying to find zeros of a polynomial what I'm going to do to finish this problem is set this final equation equal to zero. And I can solve that in any way I want since it's a quadratic there are lots of options. But here I think the best way to solve that the easiest to me is just to get the x squared by itself and then take the square root of each side. So the square root of negative twenty five is a positive or negative five i.  If you don't want to do that one by hand you also could use the quadratic formula by hand or you could use the program on your calculator.


Welcome. I'm Steve Bell, President of Queso Global, based in the United States, and I'm a consultant that's focused on the ICT industry. I've been fascinated by innovation, strategy, and technology around the industry for a number of years. I'm moderator for the panel session Telecoms Innovation is Going Over the Edge. Is it time to pivot? We have some interesting panelists that can provide some non-traditional perspectives. From the IET world, we have Mr. Jeffrey Hanine Jaleel, VP and Global Head of Telecom Equipment Vendor Verticals for Wipro Technologies from India. From a developing world perspective, we have Mr. Charles Matadone, Head of Internet and Value-Added Services for Vodacom Tanzania. And finally, from the innovation area, we have Dr. Ali Jazeiri, Head of Innovation and Technology Transfer Section at the World Intellectual Property Organization in Switzerland. And apologies to all of those gentlemen if I mispronounce their names. So, what are we going to look at? Primarily, the mobile telecoms industry has been at the epicenter of change for the last 32 years. Exponential growth took the industry from zero to 10% in 19 years so that by 2000, we were set for a new millennium. And in the next seven years, we basically grew the penetration rate to 50%. As we go into 2013, as all of the ITU statistics show, we're approaching a 96% penetration rate. Not only has the industry connected the world, and in many cases, it's provided access to the internet for the first time via mobile. Mobile phone has become an indispensable aspect of daily life to billions. As Francis Cancross in a famous book, The Death of Distance forecast, geography borders and time zones have become irrelevant to the way we conduct our business and our personal lives. And I think she's being proved right. However, with near-saturation growth rates have also fallen, and the lowest levels are being achieved in developing countries. So the mobile telecom world is being subject to the same forces of change as the internet business model collides and disrupts the status quo that's been in existence for the last 30 years. All of a sudden, there is an uncertainty about going over the edge of the internet-flat world described by Thomas Friedman into an unknown world. One thing's clear, though. As Albert Einstein said, the thinking that got the industry to where it is is unlikely to get it out. Equally, as my experience shows, those efforts at change will meet with resistance as internal silos act as an immune system to kill new ideas. So what's to be done? The words we use to define something represents the world we see and as we share those words, they tend to both unify and defy and divide the ecosystem and participants within the ecosystem. As the ecosystem expands and new members join, this can become an issue. Clearly, those that came from an internet background have a different worldview and a unique perspective on where things will evolve and develop too. I read the phrase, voice calls are no longer the preferred communication mechanism between people. To me, it became clear that the language we use defines the horizons of our imagination. From a telecoms perspective, this can be seen as a negative, but from an internet perspective, it's a golden opportunity. So the challenge is to shift the mindset and to focus less on the delivery of comms and innovatively focus on something else that leverages the assets that have been put in place, the layered technology developments of the last five years and the new ones that are emerging are most importantly, the changes in global consumer and business usage needs and patterns. What I hope the panel will explore is the colossal change that's happened within this concatenated timeframe where people have less time but more choice. We hopefully will look at cross-pollination, what can be learned from both worlds, borrowed and morphed. How will we create a world 3.0 where the real impact of an interconnected world at a local level and at a context level starts to be explored? Clearly, mindset, myopia and perception. For instance, telecoms. Is it tele or comms? Tele literally is at a distance, but it's also a combining form, telephone, television, telemetry. So is it time to pivot? Given the convergence, it implies a focus on innovation to combine capabilities and services to enable engagement over distance. So what did the tele consumers and the tele enterprises really mean? Another colleague of mine is running several panels, Martin Geddes, and he talks about the technology of flow. But it's not just about the technology, it's about flows within an interconnected world, new technology flows of info, voice, data, media between people, devices, things and the cloud. What's the value and the relationship within the freemium model from the internet world? What becomes of the business model in the 3.0 world? What's the essence of the mobile network operator in the future? Capturing customer value as opposed to holding customers captive, maybe one of the challenges. Boundary blurring, as we look at how the ICT industry has impacted health, banking, education, agriculture, transport and with the internet of things beginning to emerge onto the world stage, the interrelationship of the internet of things with people and devices. The interconnection is a new frontier. 99% of the world's things are not connected, whereas 96% of the people are. So there's an abundance of opportunity. Developing versus developed world rates have changed. The impact of the existing infrastructure holding back the developed world and the lack of infrastructure being a need-based drive for innovation and acceleration in the developing world. Customer engagement, the utilization of big data and open innovation to create value on both sides of the telecom and the internet world. And finally, people and organizations. The telecom industry was full of visionaries in the early 90s. Now you've got a lot of accountants. Where are the mavericks? How do we capture the startup mentality and the understanding of trying to recognize when standards make sense, but do it try and fix it makes even more sense. I have little fear about innovation in this converged industry. The only issue is who are the players and where does the innovation come from? There's abundance of opportunities. Success will ultimately come from a focus on the consumer and the business, fundamentals and defining value-added capabilities around security, access, simplicity, resilience, unification of options, frictionless interaction, harmonized services and curated content and media. So in conclusion, the panel is about the need for new mindsets and the re-evaluation of the telecom landscape. Chiefly because the current map and strategy don't fit the territory that's been ripped up by powerful convergence forces over the last five years. I think it's going to be a fascinating panel. I think that the discussion that evolves will be very stimulating and I look forward to the questions that it generates from the floor and I hope you will join us on Friday, November 22nd at nine o'clock for the panel. Thank you very much.