 Thank you for coming. Thank you for coming. Originally started it. And if you're a grad student who drinks at a bar and consistently talks about your nerdy research topic over and over, eventually they might invite you to come and speak about it. And that's kind of how NerdNight began. Started in Boston and is spread, there's one in San Francisco, there's one in South Bay. So if you're in those areas, please go visit the pastime on your way in, but if you haven't had a chance to visit, we have food back here on the right. And we have drinks back here on the left. These guys are all really amazing people. Come enjoy them. Sit, take between each speaker. I like to read. We also have a survey up front. Most of you got harassed to take it. So if you have a chance and you have taken it, please drop it off in back. If not, if you'd like for us to know what you're thinking, we'd like your thoughts. We'd like your insights. We'd also like to harass you to come and speak with us. But we're going to be talking puppets. Been this low key thing in all of our lives. For some people, they become more than last night, who at their 20th anniversary with their company. The company gives them a puppet likeness of themselves. So you can go home and you can speak to yourself in puppet form. Finger puppets, we all make, want to give a shout out to somebody who in the puppeting world did make a difference in this area. If you'd ever been to driveway follies, they were kind of a big thing for your Oakland. Halloween time, full shutdown, and last week, they lost their founder. So the puppeting world has lost one of our own little geniuses. Having been part of all of our lives, I've been part of all of our ancestors' lives. Puppets have been around for over 3,000 years. They've been in literature since Plato. So puppets are a long-term, really important part of our communities and our artistic endeavors that we often don't get a chance to think about. So I'm really excited to learn more and to have an opportunity to really show you what they can do in our lives. So here is Victoria, and Victoria is going to talk to you all about stop-motion puppets and some of these amazing, amazing pieces of art she's been involved in. So if you'd welcome her to the stage. And I am a feature film puppet maker. I've had a love of puppets since I was 10 years old. My dad showed me the movie Alien. My mom was all, she's going to be scared, don't do that. And he explained it to me frame by frame, and I remember before Christmas came out when I was 10, and from that moment on, I was like, I'm going to be a puppet maker, and I would accept nothing else. I made puppets as a hobby, and then I ended up going to the college for creative studies and studying animation. Although they didn't have a puppet course, I ended up doing independent studies and studying stop-motion. And from there, I got hired my senior year at Leica on the feature film Coraline. I have brought with me an actual screen-use Coraline puppet. So after my presentation, I'll be sitting to the side, so you can come up and ask me any questions. And you can look at her, but please don't touch. She is not mine, and I don't want to give it back damage. I also have three original Jack Skellington heads from the night before Christmas. So let's see. That's my info if you want to look up more of my stuff. I also use the same skill set that I used to make puppets for making toys, like this giant narwhal here. This is Epic the Narwhal. He is my toy mascot, because narwhals are awesome. And what I'm going to play next is I didn't actually work on Paranorman, but Leica has made a short, like, two and a half minute film about the entire puppet making process, and I felt like it was a really good thing to show because it's going to explain, in a very quick fashion, what my entire presentation is about. It's basically just theme music that's missing, but right now they're injecting silicone, and then they're putting ice propyl to remove it from the mold and clipping it back. Now they're going to make the costume. And then that's all 3D printed head mechanics that have eye blanks and a mechanical system to control the face, and then replacement faces. And then mostly it's all, hey Norman, hey Norman, hey Norman, so sorry about that. But so when you make a puppet, you've got to start with the design. This is done usually on core line. They had multiple artists that did multiple renditions of what core line should look like. Henry Selig then picks three or four, and they have somebody do test sculpts. From the test sculpts, they'll decide on what kind of style or look they want the film to be. And then they'll bring in secondary sculptors who will then make all of the puppets to match that determined style. Here is the final core line puppet. So you can see that they kind of evolved, but they all then have the same consistent look. This is the ghost kids. This is the very first sketch of the ghost kids. And this is how they evolved into the actual puppets. Another example, this is from Planter's Peanuts. And you can see that was the artwork, the sculpt, and the final puppet. This is one of the hardest puppets I've ever had to make in my life. It was quite complicated because he was all in the mold as one piece. But from here, once you have a sculpt, or if you decide you want to do it 3D printed, you can do a 3D digital 3D printed out, and then mold and cast the same way. So you can do traditional or 3D printing. Then you have to make a skeleton or an armature. Once you have a skeleton or an armature, and this is done usually three different ways. You can have a wire armature that's really simple. You can have a ball and socket armature, and then you can have like a hybrid armature like you see on the peacock. The peacock had a wire neck, a 3D printed skull, and then ball and socket joints throughout the rest of the puppet. And then I do the center core line is what I have with me today. So if you have any questions about specifics of joints or things like that, and walk you through it. Here's some more examples of armatures. Mr. Pina, that is actually a repurposed armature from the PJs. And then that is a mermaid tail. Sorry, I'm really nervous, so sorry if I'm going through things really. Thank you. Here's another example like I was talking about of a 3D modeled mermaid. So this mermaid was 3D modeled and then 3D printed and molded. So we didn't actually use any traditional sculpting in this sense. What's really great about 3D printing is it enables you to scale up or scale down. So when we made this mermaid, she was actually made way too small and then we had to reprint the entire puppet at a larger scale. But you can see in the center is her armature like I talked about or her skeleton and she has the ball bell in the middle is really important because that is what an animator will use to grip the puppet when they animate. So they'll place their fingers on the two sides of the ball bearing basically and then it allows for them to move the rest. She had a complete wire torso from her arms and her neck and then she did not have a replacement face. She had replacement expressions. So she had one flat face and then stickers that we could stick on to change faces. Which is basically when you wanna save money and you don't wanna print 10,000 faces like Coraline. And then her tail and her torso are all made out of silicone and her hair was actually made out of embroidery floss which I'll get into hair a little bit more specific in a minute. And then here's more detail about the tail. So you can't just make silicone over the skeleton and armature because it will be really heavy. You usually wanna put some kind of foam and then clip it back and do what's called skinning. You put a thin layer of silicone, you force it to cure and then you put silicone around the rest of it. So her tail, I actually back painted the colors into the mold first and then layered her tail color by color in reverse instead of painting on top of it. And the reason why for this is that if you paint on top, the colors are really hard to get in silicone so you wanna put it in the mold first and get better detail. And then here's another example of the full process for, this is Sophie from Antique Claws. So you can see her replacement face and then she had eye blinks that you use a needle, you stick it in the center of the eye and you can kind of move it around and then replace the faces. You always wanna have something on the face similar to the ball bell on the tail that allows the animator to grip. In this case, her ears were in the hair so we had to put side temples that the animator could grip to get the faces on and off. And, all right. And then here's the other types of faces. So while there are 3D print replacement faces and there are stick on faces, there are also mechanical faces. James and the giant peach and both Corpse Bride had mechanical faces, which mean that they have a series of metal petals that have a silicone or foam latex skin on top and then the animator can then push on those little bits in a specific manner. What was really cool about Corpse Bride is they actually had a gear system similar to a Swiss watch and you could put an Allen key in the back of the head, turn it and it would force the face to smile, frown, all the expressions. They were probably some of the most sophisticated faces ever made for stop motion. Pretty incredible. And you can see on the top right you have the most lo-fi version which is like robot chicken style with stick on eyes and again, sticker expressions. So you really can make puppets in any way. It's really up to the animator to sell it. So this is explaining more about that skinning process that I did with the mermaid tail. This was called the beaky character from Phil Tippett's Mad God and the inside of the puppet, I used makeup wedges and athletic tape, wrapped it and then skinned it in silicone. I used dragon skin then with naphtha. Dragon skin is the name of a silicone which is kind of awesome. And then again back painted the colors into the molds and then cast the final and then they were able to like stick the hairs and stuff in. What's great about silicone is you can actually break a needle head and force hair into the silicone or sew through it. So you can get really cool textures and hair on top of silicone. But this basically explains more about skinning process and specifics of it. You're into that kind of thing which you are, because you're here. Here's the body of sping from Coraline and I wanted to show that the different types of puppets and like for her bottom she had foam latex and her top was again silicone. The reason you do this is you wanna, again, every puppet needs to be lightweight to move. Silicone is heavy, armatures are heavy. So you wanna use anything that you can to lighten the puppet and in this case all of the inside of spink was cast foam latex that was then clipped back and skinned. This is machete. I just thought it'd be cool to have machete in here. Oh, sorry, all right, hands. So that was my specialty on Coraline as I made all the hands. I really nerd out about hands. I could talk about hands all day but I wanted to show in this photo the different types of mold making. So you can have resin molds, you can have silicon molds, you can have plaster molds and each mold blends a benefit to the material you're using. So if you wanna cast foam latex you use a plaster mold because it will suck the moisture out of the foam latex. If you wanna cast silicone, you can do it in a silicon mold but you need a lot of release so it doesn't stick to itself or you can use a TC 1530 resin molds which is pretty much the most durable molds you can have. So when you do things like hands you wanna use an epoxy steel mold because it allows for 40, 50 castings because you go through like 40 hands a week on Coraline. Job security. All right, this shows the process of from foam latex to final puppet. So you can see in the right corner that's what the puppet looks like when it comes out of the plaster mold and foam and then it's clipped back and a very thin skin and then the silicone is laid on top. And let's talk hair. All right, hair is, there are infinite possibilities for puppet hair. For Coraline she had synthetic hair but you can also use hemp, alpaca, as firm remains on Mars that was all embroidery thread and then in silicone hair. When I can't hire a hair maker I'm not very good at hair myself so I go silicone cause that's what I know. So this is how you make silicone hair. You would make a 3D printed master pattern then you would make a box. You would encase that box in silicone. You would make a wire insert and so her bangs actually have that little wire look and worm thing and that allows for the animator to get some secondary motion out of a block of silicone and then I cast her hair in silicone and then add highlights. So you have to do shoes. Shoes are also my favorite. I really like making puppet shoes. These are all really tiny about an inch big but again you can do a sculpted master, a 3D printed master. The boot happens to be a 3D printed master and then I like to back paint the shoe so how I was explaining about back painting is you actually back paint into the molds using a syringe and then you back paint color at a time. So like for this little shoe he actually had like that blue logo. I back painted that with an 18 gauge syringe letter by letter. Same as this shoe like the gold eyelets were painted in first, cured with a heat gun. Then the brown was painted in and then the white for around the shoe. So every detail of the shoe is done meticulously layer by layer. What's great about stop motion is it utilizes so many basic artistic skills in a way that really appreciates the craft and creates magic. And I think that magic lends itself on screen to something that's unlike anything else. For the boots I used embroidery thread that's wax and I actually stitch it like you would a real shoe but just really tiny. All right, so again here's some more examples of shoes cause I like the shoes. For the Coraline Green Wally is so another job that's unknown about is like the ninja of stop motion is the Silicon Seaming Department. The Silicon Seaming Department's job is to remove the seam that comes out of the molds so that you don't know that it was cast in a two or three part mold. So here for example you can see this is what needed to be removed and sanded. Once that's removed then you have to go in and age the shoe so that it breeds as realistic. So there's an entire team of people whose job it is to not exist on film. Let's talk costumes. So one thing about costume is you have to make sure that the costumes are to scale. If you put your puppet's hand next to the seam and it looks too large, it's gonna not sell the magic. Sorry, I can't talk well. And so you really wanna spend time making sure the fibers are really tiny or the right size or to scale. And if they're not then you wanna make sure that you find or create your own fibers that are. So like the sweater for example, that was an actual hand knit sweater. This lady took tiny little needles and made them into her own crocheting needles and crocheted this tiny little sweater. And she made her tiny little garden gloves. Those were by hand, crocheted by someone or knit I'm not sure. But it's incredible that that's like beyond. And then again here's some examples of the whole process. So like you've got the artwork to the puppet to the inside of the hand. This was really cool because this was a tribute to the Raph's brothers who worked at Pixar and were a good friend of Henry Selick's. He wanted to add the movers as a tribute to him and his brother and all they had done for him which I thought was really cool. And then here are some of the ghost kids. I went through that way faster than I meant to. Some townies, these are from planters, some butterfly characters. These were some of the smallest hands I had to make. Their hands were the size of my pinky nail. This is the mole from the planters holiday party commercial. He says, you like nuts? It's pretty good. It's pretty good. These are some more of the secondary characters from planters. I just really like that turtle guy in the middle. I'm not gonna lie. And then I wanted to talk a little bit about the Coraline dolls. So one of the coolest things about working at Lake on Coraline is I got to work on the doll prototypes for NECA which was something I didn't know a lot about when I started working at Leica was how to make toys and how to make toy prototypes. What I didn't realize then is that this was gonna lead to a huge love of toys and this beautiful giant narwhal, Epic the Narwhal. So I will now talk about the same process for our puppets but for toys. So again, you start with artwork or a sketch and then you convert that to a sculpt. In this case, we made a 3D print and we created his screw system for making a mold right on the sculpt itself all right on the 3D printer. And then that was encased in silicone or you can do it traditionally with wire and toothpicks like I've done here. And another, these are also 3D printed screws and I like selfies so sorry about that. And then here's a close up. These are one of my giraffe characters but again, all on a 3D printed sprue. And then you box that up and you pour silicone around it and you do what's called a jeweler's cut. You take a pair of ring splitters and you split the mold and then you take an exacto or a scalpel handle and you very gently cut back and forth and then this allows for you to open the mold. The reason this is called a jeweler's cut is this is the same technique they use when traditionally making jewelry. And that's what the mold looks like open, close up. And then you're gonna put a two part polyurethane plastic into the molds. I use a syringe so the vent system I created the reason for that is that you have an in and an out so you inject on one and the vent allows it to travel through and back out and then you put it in a pressure pot and it forces the additional air that's trapped in the mold out. There's it going in the pressure pot. It's a messy job. And then after it's done, you peel it open. It's like Christmas. Every time you cast something, there's like a 50-50, it's gonna turn out and when it does, it's super exciting. Here's the drafts all cast and like again, similar to seaming in film, all the plastic toys come out with the seam so they'll have to be seamed as well. And that is a little octopus guy. And then here's a pile of my toys, post-seamed, ready to be painted and assembled. And you gotta wash everything, cascade. They all need to get a bath. And then you paint. And these are the final toys. So the shark and the narwhale. Thank you. So the shark is actually only an inch and a half big. And the two narwhals in that photo are five inches and one and a half inches. So my toys started out very, very small and then I went very, very big. And then as a promise, there's a cat because you need to have a cat. He's always helping make the toys. So, and that's all I got. But, and so now I've got time. Does anybody have any questions about film or any? So there's actually a person's job. Oh, sorry, okay. So she asks, what do you do for quality control? How do you make sure there's consistent color, continuity, et cetera? There's a continuity specialist, just like in regular film for Stop Motion, whose job it is to make sure that if there's a tearing costume in scene 13, there's a tearing costume in scene 14. For silicone, you actually tint the entire batch of silicone for the entire film at the beginning so that every casting comes out the same color consistently. The same is true of costumes. They'll typically print all of the fabric ahead of time so that, or they'll buy out all of the fabric at a store as much as they can, like the entire bolt so that they don't run out during production. The question is when you're making an armature or a skeleton for the inside of the puppet, how closely does it mimic real anatomy? It depends on the film and the look that you're going for. If you're having something like Gumby where it's like, you can kind of get away with whatever, if you're doing something like Coraline, Henry Selick really specifically doesn't like something called banana fingers, which is when the fingers lose the articulated bends and they look like a banana. So I was actually, on his second film, The Shadow King, which is what brought me to the Bay Area, I made hands that had tiny articulated bones and were anatomically accurate to a real hand. So it really ranges based on the need for animation. Okay, so the question is, how many separate movements do you have to create and how many puppets do you use? So every film has to have 24 frames per second, so that means 24 separate movements, 24 separate pictures per second for every film. A good week in animation for one animator is 36 seconds of animation. Because that is really slow moving, each puppet will typically have multiple characters. So Coraline, for example, had 18 Coraline puppets on stage at the same time, always. All right, thanks guys. Is that not the coolest job that any of us never knew existed? Victoria Rose has brought us a whole new understanding of some of our world. So, and she's gonna be down here. She's got some examples of some of her amazing work if you wanna come look and not touch. And we're gonna take an eight to 10 minute break. Please grab another beer, grab some food. Talk to your fellow nerds, I know, I know that's kind of pushing it, but we'll be back in eight to 10 minutes talking about HIV. So Alison Federer's gonna talk to us about how HIV treatment basically is versus evolution. And by stopping evolution, that's actually how you get treatment. And so I was trying to think how to intro this talk and I think it's really, you hear about HIV and HIV treatment and antiretroviral treatment and I think you get that macro view but it's important to remember that these are important things and these are real people and real numbers. In fact, as of 2017, we have almost 37 million people in the world with HIV. But this is actually a good story in the sense that we're actually getting closer and closer to a big number of those people being treated with ART. So actually as of December 2017 in the entire world, we had 59% of people are actually on antiretroviral therapy, this multi-drug therapy. And you know, that's a good number but what's really cool is there are groups working on getting this number bigger every year right now. And even just from 2016 to 2017, we had 2.3 million additional people get on ART and that is awesome. And just to show you how far this has come, I mean in 2005, the number was 7%, okay? So it's 2018, so in 2019, right? 2019, we've actually really made those numbers a lot more positive, right? We've actually made a good start on this journey but there are still a lot of people left to treat with all these antiretroviral drugs and so Allison's gonna talk about these treatments and I just wanted you guys to get a sense of the scale of what we're talking about when we're talking about treating with multiple drug regimens. So here's a list, there's many different lists but I took one list of all the different antiretroviral anti-HIV drugs and all the different doses that are offered in various combinations to treat HIV infection, okay? So hold on, I have another good fact, one more, then I'll get to that slide. 2005, there were 1.9 million people that died and only, quote, only 1 million as of 2016. So again, the numbers are getting better because of all these drugs that help to treat HIV but it's a lot of drugs and it's a really complicated treatment. So here's a list of all the drugs right here, all these here, you can't possibly read those, don't sweat it, there's no quiz but it's all these, all these different doses, wait, hold on, there's more, it's all of these right here, you're getting bored, don't because it's all of these right here, it's all of these right here, it's all of these right here. So when Allison's talking about these multi-drug treatments, like again, these are really complicated questions and how do you actually get it? Each person's individual strain of HIV and how do you actually figure out what the best treatment is? Because you have a lot of options. Dr. Allison Federer had received her PhD in biology at Stanford. She now works at UC Berkeley. She was actually the initial recipient of the prestigious Milner Prize by the Milner Center for Evolution. Please welcome Allison Federer to the stage. As Scott said, my name is Allison Federer. I am a Miller Fellow in the Department of Integrative Biology at UC Berkeley and I'm not gonna be telling you anything that is sort of cute or funny today, but I still think it's an important story to share. I'm mostly gonna be focusing today on the amazing adaptive potential of HIV. I'm gonna be talking how we as humans have been trying to stop HIV from evolving and how HIV sometimes gets around us and evolves anyway. And all of this work is joint work with Plunie Pennings at San Francisco State and also in extensive conversation with Dmitry Patrov at Stanford. So I am an evolutionary biologist and many people would date the origin of my field back to Darwin and his famous journey to the Galapagos. So Darwin was a prolific naturalist and he wrote about all types of organisms. But one thing that he had a particular soft spot in his heart for was birds. Now if you read Darwin's extended works, it becomes pretty clear that the dude really likes pigeons. But the thing that Darwin is actually best known for, the bird he's best associated with is the finch. These finches which spread out to different islands on the Galapagos and have different size and shaped beaks that correspond to the different types of seeds that are available on these islands. And it's easy to imagine how Darwin saw these things and was able to postulate his initial theories of descent with modification. Now I don't work on evolution of finches on islands, I work on the evolution of HIV in people. But similarly to how finches evolve, how finches go to new islands and begin to adapt to their environment, HIV moves into new patients and begins to evolve within them. And it's really this adaptive capacity of HIV, its ability to evolve that's at the root of why it's such a problem. It's the reason that we don't have a vaccine that we can use to prevent people from becoming infected. It's the reason that our immune system can't shut it down. And it's the reason that when we treat HIV with drugs, those drugs often fail due to the drug evolution and drug resistance. And it's primarily on this third point that I'm gonna talk most today. Now, Darwin initially posited that evolution was the slow and gradual process. But we're coming to learn that in a lot of systems, HIV in particular, evolution can happen really quickly. And I wanna illustrate just how quickly that happens, thinking about drug resistance. So although HIV initially transferred to humans probably somewhere in the early part of the 1900s, it really became a problem among humans in the 1980s because that's when the epidemic really took hold of our population. And it was initially so devastating because we didn't have any drugs that we could use to treat it. The first drug for treating the first drug for treating HIV which is to say AZT or Zidavidine was introduced in 1987. And it was an extremely hopeful moment. But although the virus initially declined in the presence of the drug, it quickly bounced back within single patients due to the evolution of drug resistance. A single nucleotide substitution, so going from an A to a T at a particular position, meant that the virus was no longer suppressed by this drug. And far from being a rare occurrence, drug resistance happened in nearly 100% of patients in just six months. So evolution was extremely fast and extremely predictable. So it's worth stepping back and trying to think about how it's possible that HIV evolved so quickly. And we can imagine a particular patient and do some back of the envelope calculations. So if we have a patient and inside that patient, there are a lot of viruses that are floating around. If you introduce a drug to this patient, you can ask, all right, how many of these viruses are gonna be resistant to this therapy? You can zoom in on a particular virus and see that as this virus replicates, it has a certain probability of making a mistake of substituting that T for an A in a particular position and becoming drug resistant. So we can ask if each of these viruses has a probability of, say, 10 to the negative fifth, which is about the mutation rate in HIV of becoming drug resistant each generation. Even if there was no drug resistance at the start of this generation, how many drug resistant viruses will we see at the end? So although this number, 10 to the fifth, one in 100,000, seems like a pretty small number, it's actually a pretty high mutation rate compared to, say, the mutation rate in humans. And you have to remember that although this is a low rate, each individual virus has a certain probability of making this mistake, and the viral population sizes inside people are huge. So if you have each of 10 to the ninth viruses with a 10 to the negative fifth probability of becoming drug resistant, then you find that actually after a generation, there are 10 to the fourth variants within a person that are already drug resistant. This is sort of the basal material that natural selection can use to increase drug resistance and frequency in the population. So it's not really surprising to us that drug resistance is able to happen so quickly and so predictably. So if we look at this picture from the 1980s, it's all of a sudden makes a lot of sense. Luckily, if we zoom forward to the 2010s, we see that things have changed fairly substantially. Now drug resistance is a relatively rare occurrence and this is awesome. This is an amazing thing that we have somehow moved from a state where drugs were going to fail in all patients predictably to a place where patients can take antiretrovirals and remain with low viral loads and live normal, healthy lives. It's amazing. And the reason that we've done this is because now we treat patients with combinations of multiple drugs simultaneously as Scott was mentioning in the introduction. And the mechanism of this is that each of these different drugs targets a different viral pathway. So no single mutation is able to confer resistance to all three drugs. And this has been an extremely powerful weapon in terms of slowing down the rate of drug resistance evolution in HIV. Now, there are a few questions that come to my mind when I look at this picture. First, how exactly has this transition happened? And second, when drug resistance still does emerge nowadays, how does that happen? And to think about that first question, we can go back to this picture and ask how does it change under the context of multidrug therapy? So as, and this is sort of the conventional wisdom in what we think about in terms of why we think three drug therapy works. So if you have a single mutation, it's still the same probability that we talked about before, 10 to the negative fifth. But now in the context of three drugs, even if this yellow mutation confers resistance to this yellow drug, it's still suppressed by two other mutations. It still can't replicate in the presence of the red or the blue. So what this means is that the virus is not actually probably going to be able to propagate its descendants. What you need to do is you actually need to wait for three drug resistance mutations. And the idea here is that without three resistance mutations, you shouldn't be able to replicate. Now, this has a much lower probability of happening because you need not just 10 to the negative fifth, but 10 to the negative fifth cubed. And this is an astronomically small number. This is a quadrillion. And so even if you have a population size that's pretty large, your expected number of variants becoming resistant each day is 10 to the negative sixth. Or put another way, that means that you need to wait on average about 1 million generations before you see your first triple drug-resisting clone. Alternatively, you could say more than 2700 years until drug resistance evolution emerges in the context of this triple therapy. So this is great. This is an amazing thing. It tells us that probabilistically we should expect that drug resistance never happens in any patients. Of course, we saw on the last slide that that's not quite true. So I'm gonna show you some data from a cohort of patients in British Columbia who were infected with HIV and had no drug resistance mutations and were tracked over time. And what you see is that among patients that were given this particular type of drug, 3TC or FTC as part of a combination therapy, they increased in frequency. This is a cumulative distribution. So it tells you after each period of time how many of those patients have acquired drug resistance to this particular drug. And you can see a couple of striking things. One, it's not zero. And two, there's this linear increase over time. Clearly, we're not as good at suppressing drug resistance as we think that we should be under our model. Now, if you add on other drugs, you see that the rates of these things vary. These are different classes of drugs that are generally combined for a combination therapy. But it's sort of not as nice a picture as we would hope in many cases. So what's wrong? Why is there drug resistance that continues to emerge? Even though we think that it should take 2,700 years until a single patient becomes drug resistant. And to think about this, we can think about what parts of our model we might be getting correct and what parts we might be getting wrong. So here, one thing that might be the issue is just the rates. Somehow drug resistance is more common than we expect. So maybe the population size is larger or maybe the mutation rate to the fully drug resistant state is higher. If that's the case, then there are other predictions of our model that we can test. So for example, we can see what the distribution of drug resistance mutations within patients is. So if you give a yellow, a red, and a blue drug, how many patients are resistant to just the yellow one, the red one, the blue one, the yellow and red one, and so on. And what we see is that based on our prediction, what we would expect is, okay, drug resistance is pretty rare. Most patients probably live up here. But in the case when drug resistance does emerge, they should probably live down here. They should have three drug resistance mutations. Now, is this actually the case? If we plug some numbers into this, 3TC and D4T are nucleoside reverse transcriptase inhibitors and the funniest thing I've said all night. And Nelfinivir, get this, is a protease inhibitor. And so what we can do is actually, this is a common first line therapy that would have been given in the mid-1990s. And we can see that sure enough, a lot of patients are up here, no drug resistance at all, that's awesome. But if you look at patients that do have drug resistance mutation, you see that they're actually not distributed how we would have expected them to be. We see that a lot of patients, while some patients do have triple drug resistance, some patients have single drug resistance and some patients have double drug resistance. And there are a few weird things about this plot. I was surprised to look at it for the first time, which is that firstly, drug resistance seems to arise sequentially. You get a single drug resistance mutation and then a second one and then a third one. Now there might be flow on this chart from here directly to here or here directly to here, but based on the intermediate states that we observe, it seems more parsimonious to expect that patients are first getting one mutation and then a second one and then a third. The other thing that's weird about this is that patients always get resistance to 3TC first and then D4T and then NFV. So there's this weird non-uniform flow through this network. And this isn't at all predicted by this combination therapy of three drugs and needing three drug resistance mutations to be able to spread. So can we step back and think about our original model and how the data doesn't actually really fit it very well? First, we think that drug resistance should take a long, long time to emerge and it should be extremely rare. Yet we see that drug resistance still emerges under combination therapy. The second thing we would expect is that if a patient is drug resistant, they should be resistant to three drugs simultaneously. Yet we see that drug resistance seems to spread via single mutations. And further, there's this additional weird observation that they happen in a semi-predictable order. So what else could we say about this population? How could we update our model to try to figure out what's going on? So this picture that I've shown you of HIV is a little bit of a simplification. So I've drawn this as one big bag of viruses and three drugs over on this side. But in truth, HIV is split into a series of sub-compartments. Different populations of viruses inhabit different organs and there's some amount of migration that's connecting these different populations. And one of the projects that I don't have time to tell you about is actually tracking viruses across these different compartments using genetics where we can figure out migration rates and sort of better characterize this intrapatient population. The other simplification that this picture makes is that although you're taking these drugs orally, not all of the drugs are going to get to the same place at the same time. So there might be certain places like the blood where all of the drugs are able to get easily. And then there might be other places, for example, the central nervous system where only one drug is able to get. And this is a particular problem with the central nervous system actually because the drugs have to cross the blood-brain barrier which is difficult for them to do. So if this is the case, then we all of a sudden can start to conceptualize how it might be possible that single drug resistance mutations can still spread in HIV. So you get a mutation in a particular place and if that mutation happens in a spot where there's only monotherapy, we know that HIV actually is pretty good at evolving drug resistance in this situation. And so you might see this drug resistance mutation spread in this compartment. Then it might only be one short step away to finding a different compartment with a slightly larger but not too much of a jump in terms of its drug profile. And so it can migrate there and begin to evolve anew. And if you look at how this fits with the data, it actually seems to conform in many ways. We know that 3TC has a relatively good penetrance profile, especially to the central nervous system. And this can help us understand something about the way in which the ordering of mutations can tell us about the processes that are going on inside our body. So what would happen if we took Nelfinivir and we replaced it with a different protease inhibitor, one that's better, one that gets into the brain? Well, if that's the case, even though we haven't changed the drug profiles of any of the other drugs, all we've done is we've added a Lopinivir that now gets into the central nervous system. We can see what happens to patients under this condition. So we see that, sure enough, there are more patients that don't have any drug resistance at all. But what about the ones that do? We see that, so we would expect that because 3TC is now protected in some way by Lopinivir, there's less movement from this compartment to this compartment. And in terms of onward movement from this compartment, there's actually none at all. So within this particular study, what we've seen is that updating the therapy to use Lopinivir fundamentally alters the speed of movement through this pathway in a way that makes sense with this idea of spatial compartments. So Lopinivir, because it's able to get into the brain, is able to protect things here. And there's some strange kind of counterintuitive observations that fall out of this. One of them is the fact that you're actually most likely to get drug resistance to your best drug, not your worst drug, because your best drug is getting to parts of the body that your other drugs can't. So in some ways, it's not sort of the, you're not worried about the best drug that you're being treated with, but the worst ones. Because the worst ones, if they're not able to cover for the best ones, are still going to result in treatment failure and drug resistance evolution. Another sort of interesting thing that comes out of this is that if you're designing treatment profiles, you wanna find combinations of drugs that have maximally overlapping penetrance profiles. In some ways, it's better if no drugs get to a particular compartment than one drug gets to a better single compartment. Because there's no selective pressure if there's not at least one drug present. But there's not going to be able to be replication if there's, so you won't get any selection if you only have a single, if you have no drugs, but if you have too many drugs, it's gonna be too hard for the virus. So this is in some ways telling you about how HIV can evolve via breaking down a complex evolutionary problem into smaller, easier to tackle sub-evolutionary pieces. And there's some nice theory that's been done about this in sort of a totally mathematical framework by this paper in TNAS from a few years ago. Okay, so there's still a lot here. This is only a single example, but we have been seeing a lot of consistent features of this example across other therapies. Similar predictability in the orders in which mutations accumulate and single mutations accumulating at a time and non-zero probability of an ongoing evolution. We've come a long ways, so there's a lot still to figure out. We need to understand where the virus is hanging out, where the drugs are hanging out, what are their concentrations? How do they co-move together? And so we're, this is, I would say definitely not a done deal, but it's a promising way forward in terms of interpreting data that doesn't actually quite fit with this conventional model of how triple drug therapies work. However, we have seen a big improvement. So when triple drug therapies were first introduced in 1995, they still actually had a relatively high evolution of resistance. And now we're seeing that where we sit in 2019, this rate of drug resistance has gone way, way down among patients who are being treated with the newest and most effective therapies. And it's worth thinking about how in the context of our model, we can explain how these observations have happened. Why is it that three drug resistance mutations or three drugs given simultaneously was not the solution in 1995 that it is in 2019? Well, one of them is that our drugs have got better penetrance profiles now. We're better at making sure that drugs can get to all of the places they need. And in that way, protecting each other from single monotherapy compartments where drug resistance can continue to emerge. Second, the drugs have longer half-lives. So they can last longer, so just in the same way that I've described the spatial heterogeneity, there can also be temporal heterogeneity. If you're taking drug A and drug B and drug A lasts a long time, but drug B quickly declines, you can have temporal monotherapy in the same way that you have spatial monotherapy. Finally, and I guess related to this point, there's better adherence. We've simplified the way in which these drugs are given into fewer pills that you have to take less often with fewer adverse side effects. And this has been great in terms of making it easy for people who are HIV infected to take their drugs in a consistent way, which allows us potentially to keep the drug levels more constant in more parts of the body. Okay, so to just back up and tell you what, I hope that I want you to take away from this talk. So the first thing is that HIV can evolve extremely rapidly and in general evolution can happen very rapidly. The types of processes that Darwin described can actually happen on much shorter, faster time scales. Evolution is still going on within the lifetime of humans and even much shorter than that and it would be unwise to ignore this. The second thing is that triple drug therapy was not the silver bullet for HIV that it sometimes made out to be. It was actually a gradual process of improving these various aspects of therapy that has decreased the rate of drug resistance over time. And this is an important lesson to remember if we're going to be applying the sorts of lessons that we learned from HIV to other types of systems like cancers where multi-drug therapies are increasingly being used. We need to think about how different drugs are penetrating into solid tumors and whether this is something that can actually help evolution in some ways. The third thing is so effectively we don't want to just look at the example of HIV interpreted naively and not learn the important lessons that it has to teach us. The final thing is that studying this example in HIV can help us figure out how populations solve difficult evolutionary tasks such as when they're being attacked by three drugs simultaneously. We can use the sort of reasoning in places where we might want to facilitate evolution as opposed to prevent it. So for example, in a rapidly warming world or fastly acidifying oceans, we might think about the way in which we can split hard evolutionary tasks into smaller, easier ones in a way that we might be able to allow populations to keep up with their changing environments. Sorry. Finally, I just want to say that our ability to treat HIV, to keep it suppressed for long periods of time is a triumph of evolutionary medicine. It's amazing that we can do this. I think that now it's time to look back on this success and think about what are the actual things that have brought us here? That have brought us from 1989 when everyone failed via drug resistance to 2019 where if you're taking your therapy you have a relatively low probability of drug resistance. And think about the lessons that that can teach us both in basic science in terms of evolution and also in medicine. Thanks. So the question was, wouldn't it be the case that transmitted drug resistance should largely be, that HIV that's transmitted between people should be drug resistant? Shouldn't one person get three resistance mutations and that just is able to infect other people? It's a great question. There are a few reasons why that doesn't happen. One of them is the fact that HIV, because it can kind of go in one direction so fast, can also go in the other direction so fast. And in the absence of these drugs, which are generally deleterious, they're bad, they quickly revert back to their old forms. A kind of another thing that complicates the matter is that HIV reverse transcribes itself into the host genome and stays there. So it effectively has version control. It can always go back to a previous form. And so even if you evolve drug resistance, you can always, and then you switch your drug therapy and then you switch it back again, you can kind of go back and see previous forms, which means that it's really easy for these non-drug resistant forms to reemerge. Finally, most people actually transmit HIV before they know that they have HIV. The viral load is highest at that point. And if you're on therapy, you actually have a really low probability of transmitting. And so what that means is that most of the time HIV is transmitted before you're actually treated. So there's no drug pressure that's forcing you to have these drug resistance mutations in the first place. That's a great question. It's not something I know a lot about. And in some ways, oh, sorry about that, yeah. So the question is, in the introduction, Scott showed a slide that had just huge dollar amounts next to each of the HIV drug names. How are these treatments being funded? And the short answer is I don't know, so I'm not gonna try to speculate too much. It is extremely expensive and a lot of the fact, a lot of our ability to treat HIV is predicated on the availability of these drugs. And I would say that the biggest problem in terms of people facing HIV today is actually the socioeconomic problem of getting access to these drugs and being able to pay for them as opposed to the probability of HIV evolving drug resistance under those drugs. But you're right, it's very important. Yeah, thanks. So the question was, what are the mechanisms that these drugs use in order to prevent, what are the drug resistance mechanisms? So what do drugs target and what are the mechanisms that HIV uses in order to, what are the drug resistance mutations doing? Is that right? And how does that impact the probabilities of evolution of resistance? So HIV is a little bit of a weird case because almost all of the mutations are just single nucleotide mutations that have huge effects. And normally in evolutionary biology, we spend a lot of time thinking about mutations that have small effects and how they accumulate and work together. Whereas in HIV, it's pretty well characterized what these single large mutations do. So they sort of affect different aspects of the HIV viral life cycle. So some of them target the stage where HIV integrates itself back into the host so they target this integrase protein. Other ones target the protein that allows HIV to cleave itself into multiple portions and actually go on to be an infectious particle. And those are a different class of drugs as well. The one that was discovered and the one that's most commonly used, nucleoside reverse transcriptase inhibitors are effectively a substitute base pair. So when HIV is making a copy of itself, it's extending itself along, this drug acts as a phantom nucleotide that gets added into the HIV genome as it extends. And then it has the wrong end. So normally you're able to sort of link each of these nucleotides together in extending the chain and this is basically, it doesn't have the right end. So additional ones can't loop on which prevents the HIV from replicating. The way that these particular mutations get around this problem is the fact that sometimes they make just random nucleotides to drop off this extending chain, which means that HIV has a second chance to try again and keep extending. And this kind of gets back to your question in terms of why it's a deleterious mutation. It seems like it'd be a bad thing to have your chain getting disrupted all the time unless you need to for the purpose of circumventing a drug. Can you repeat that? Yeah, awesome. The question is how is PrEP related to antiretroviral therapy? PrEP is pre-exposure prophylaxis. It's a two drug combination therapy that you can take before you're infected with HIV. And the idea here is that if you're taking PrEP all the time, if you're in a situation where you feel like you might be at risk for getting infected with HIV, if you're taking this two drug therapy all the time, then if a virus gets into your body, the idea is that PrEP is going to be able to be there to counteract the virus before it's able to seed a full-blown viral infection. And it is an amazingly effective option for preventing HIV acquisition. If you feel like PrEP might be a good thing for you, you should definitely, definitely look into it. And this is, I will mention this kind of ties back to some of the news about CRISPR that you may have seen floating around where this particular scientist, CRISPR, the CCR5 Delta 32 deletion into some babies in China. And the purported reason for doing this was to prevent HIV infection. And this is sort of raises a whole quandary of ethical issues in terms of genetic engineering of humans. But the idea of this is actually to make you less susceptible to HIV. And I think that there are definitely less permanent, less risky methods, including something like PrEP of preventing yourself from becoming infected. And it's not worth going out and CRISPRing your babies to prevent it. Let's hear it for Allison. So if you have more questions for her, she'll be hanging out here. We'll have the puppets in the back. We're gonna take about an eight minute break and then you can learn how to have great sex when you're old, please. Welcome back, welcome back, welcome back. My name is Rick Karnesky. I'm the co-founder of this magnificent show. Thanks for coming. How many of you have been here before? I can still vaguely see you. A few of you. Do you guys like the earlier start time? That's really good to hear. So that suggestion actually came on last year's feedback forms. It took us a year to implement, but we did actually listen to the four of you who wrote that down. So the most important thing I have to say to you is fill out these forms. If you put your email address up on that top line, yes, we may send you a reminder or two about our monthly event. We only send two emails a month. But also we will draw one person for a free Nurnite East Bay for a year. So it's the best perk we give out. I think it's totally worth it, please. And even if you don't enroll, like all that stuff on how we can improve the show, we love it, we listen to it, just let us know. I'm kind of delaying now. And again, if you haven't yet gotten food from them, pick it up please. I know that someone had paid for it. Thank the Oakland Public Library who's back there. You can see that I'm just kind of delaying because I have no idea, like we have to introduce topics and the whole like geriatric sexuality topic is not something I'm kind of well-adversed to talk about. Not yet. Thanks, Scott. I like that optimism. And let me tell you, when you type in a septuagenarian sex into Google, you don't get like the greatest of the results. But I kind of ran with it. And I'm like, you know, should I tell them about, you know, the oldest prostitute still making a shit ton of money in Britain? Like, I mean, that's pretty good. It's kind of inspiring. So what's hilarious about this particular story is that there's this like British X Factor contestant, Katie Weissel, and she's this woman's granddaughter. And she got onto the X Factor and it was like, my crazy prostitute grandmother who's like totally ruining my career. And then the grandmother shot back, no, my no talent granddaughter who's like on TV is ruining my career. I can make a way more than $250. That could only get so far. So I thought I wanted a little bit more, thought I wanted a little bit more Freddie Mercury. Yeah, who wants to live forever? And so before we bleed into the next speaker, I think Laura's gonna give a great talk. I did want to kind of talk about negligibles in essence. And so that's all about how to stop getting old without really trying. And I'm gonna tell this in kind of three vignettes. And so the first vignettes about Lucretius. So Lucretius lived a long time ago, 99 to 55 BC. You could see that he only lived about 40 years. He's Greek. He's an atomist. So he sort of bought into the whole democracy's thing that there is like some base unit that says, Louis, you could go. He actually got in a lot of trouble with not only the Romans, but also the Christians. They're usually not on the same side, but they're like screw this atomism bullshit. Also he doesn't like old people very much. He basically said that the reason that we get old and eventually die is to make room for the young people. Pretty sure that these two people were pissed off at him about that too. If we jump ahead a little bit, Hippocrates. 460 to 370 BC. This guy lived a little bit longer. So maybe he knows what he's talking about. He's also Greek. Father of medicine. But he still doesn't really get old people. So he said that the reason that we get old is the gradual consumption of the innate heat and the inevitable loss of body moisture. So that's kind of this story. That's why we get old. Okay, modern age. Hey, Flick. So he was born in 1928. He's actually still alive. That's pretty good, right? Not Greek. Can't everything. Microbiologist. So he basically said that there's a limit on cell division. So he measured it in human cells. He said human cells divide between 40 and 60 generations and that's it. And so that kind of established like at least one basis for aging. But then if you look at it, some things end up living a lot longer than us. So here are sharks that live for 400 years. Clams live for 570 years. That's actually a really sad story. So I had heard like a radio lab episode about someone inadvertently killing the world's oldest tree, like a scientist, right? Unfortunately, the same thing happened to the world's oldest animal organism. So there was like a really old clam. Some scientist was looking at it and he killed it. So that's no good. Hopefully that screen comes back. I did. Obviously, there's non-negletal senescence for our main projector. Just quickly move along. Good, we're back. No more talking about clams. Even the projector got depressed. Lobsters though, 100 plus years for a lobster. And so there's this great advertisement and lobsters are really interesting because not only do they live a long time but their fertility actually increases with age. And so you could have these decades or centuries old lobsters that are still breeding. So that's pretty cool. Like this is kind of what we shoot for as far as like old sex. Be a lobster or be a tortoise. So this is, outside of the sharks, since we kind of killed that oldest living clam, this is the oldest living tortoise. So he's 186 years, now he's 188 years old. This is the world's oldest tortoise. And he was kind of in the news lately because he's still breeding too but then they looked at who he was breeding with and it turned out that it was also a dude. So they thought that he was mating with this Frederica but they looked a little closer and it was Frederick. And I don't really know why that kind of made the news. Like, you know, he's in captivity, what do you expect? And he also had a second tortoise mate who was a woman. So he's really a bi tortoise, he's not a gay tortoise. And the other thing is I think the media like focused on the completely wrong thing here. They focused on the sex of this tortoise. What they really should have focused on is age. This 186 year old was making it with a 26 year old tortoise. Like what the, anyway. With that brief diversion, I'd like everyone to welcome to the stage Dr. Laura Perry who is going to talk about how old people have sex. Thank you. And that will definitely be the end to the bestiality discussion. Good evening perverts, very nice to see you. Happy to have you here. So my name's Dr. Laura Perry. I'm a primary care doctor at Highland Hospital and I'm also a geriatrician. Which means that I specialize in folks who are slightly more mature. So he decided that we agree with Hippocrates and his predecessor. We essentially have two options. We can either die young or we can get old. And I know that because this is a Bay Area audience we probably believe that we're all going to participate in some form of cyborg immortality where we're just brains and jars attached to the matrix. Well on the off chance that humanity continues to operate in the same way that it has for several hundred thousand years of its existence I'd like to talk a little bit about what it means to age. And the hidden agenda of this talk I wanna be honest with you is that I may or may not have used the promise of sex talk as a premise with which to lure you here so that I could talk about what it means to get old. So during this talk I'll mostly be talking about what aging is with just a little bit of time for all of you who really want it to learn a little bit about how aging impacts our sexuality and our sex lives as we get older towards the end. So first things first, what is aging and what do I do as a geriatrician? So in primary care we have a model called the biopsychosocial model of health which is considering the fact that it's not just our physiologic realities that impact our wellbeing and how we're doing. But there's also our psychological health, our mental health and the social context in which both of those exist. So what geriatrics adds on are two other domains. The cognitive domain which is how well your brain is doing and how it's changed over time. And what we call the functional domain which is how do these different parts add up to enable you to do different things and throughout your life and what might you now need assistance with, what might you be totally incapable of doing on your own anymore? So I'm gonna go through each one of these different domains and talk about what aging is from each of those perspectives. So biologically humans are incredibly complex organisms. I remember once as a medical student I was sitting around with some of my friends enjoying some fine California agricultural product and we were just kind of sitting and talking about what we were learning and I realized we're just all fractals, man. And I think it's really kind of true that we have this layered complexity beyond complexity with repeats and different waves of things moving in and out. But with aging, what happens is that complexity evolves over time. As a population, we become more complex. Babies are all kind of the same. Babies are great, don't get me wrong, but one baby is pretty similar to every other baby that's out there. But there's a saying in geriatrics that when you know one 80 year old, you know one 80 year old. As we age, we just get more different from each other because we've accumulated these different experiences that impact us physically, psychologically, socially. But the counterbalance for that is that the gain in complexity among a population also represents a loss of complexity among an individual. So the human body is this just incredible marvel of complexity. Every single data point that you're able to measure is under the control of so many different factors. So I'm gonna give you the example of blood pressure. And that's defined as the force with which blood moves through blood vessels to reach the different organs in your body that it's feeding, whether it's your brain, whether it's the muscles in your legs as you're walking, whether it's your kidneys to make urine. But in particular, I wanna focus on the brain. When you go from lying down to standing up, your blood pools into your legs. And so your body wants to counteract that blood pooling and maintain the same pressure that was going to your brain, which is very delicate. And so to counteract the effect of that blood pooling in your legs, these fast acting factors like the sympathetic nervous system, which is from epinephrine, that'll kick in right away. But the thing is that your brain's very delicate. And if only the fast acting factors were at play, then your blood pressure would skyrocket and your brain would protest vis-a-vis a stroke. So the less fast acting factors start to kick in and eventually the slower acting factors. And so what you can see is that there's these incredible oscillations of blood pressure that happen in a young person where it shoots up when you go to standing right away, but then it kind of bounces around and is sort of trying to gradually reach this target by these constant micro adjustments from all of these different factors. But in aging, a lot of these different factors change in different ways. Some of them operate more slowly. One example is antidiuretic hormone, which is the hormone that controls how much water you do or don't retain in your urine. So that just acts a lot more slowly than it used to. Some of them are less effective than they used to be. So for example, epinephrine, you get a lot less bang for your buck out of epinephrine than you used to when you were young. Some of them take a lot longer to clear, like cortisol, your stress hormone. And the example that I've seen is that my grandparents are still stressed over some of the family strife that happened over Thanksgiving. And I think it's because that cortisol is just taking a while to kind of clear out of their system. And some of the effects just occur less overall. Older people have a lot less thirst mechanism. And it's why they're more prone to dehydration. So when you add these all up together, you get this kind of loss of this beautiful fractal-like complexity when it comes to the overall additive effect of how blood pressure responds when a person goes from lying down to standing up. The oscillations, as you can see, they're larger, they're a lot less smooth, and they happen a lot less frequently. So clinically what this means is if you have an older person who's on a combo of medications that interfere with some of these different factors, they're more likely to pass out when they go from lying down to standing up if they're outside on a hot day, for example, than a younger person would. All right, so that's the biological. Now let me move on a little bit to the psychological. So I practice here at Highland. Anyone, anyone familiar? All right, thanks, give a little love. So Highland is the public hospital, it's a county hospital. And it caters to one of the most diverse patient populations that you'll see in any hospital in the entire country. My patients, at last count, spoke 30 different languages. And I'm caring for patients who, I guess you could say my specialty is that I specialize in people who have seen some shit. They've almost all experienced trauma. And whether that's in the form of gun violence, in the community here in Oakland, whether it's as an immigrant who's fleeing from a war-torn country, or physical, emotional, or sexual abuse from someone that they know personally. So with aging, the effects of trauma over time can kind of take three separate roads. So first, you could process it, you could heal. And that can be done through a variety of different modalities, whether it's working with a therapist or another type of counselor, whether it's through yoga or acupuncture, or many different modalities that help to take that traumatic event and turn it just into a bad memory, rather than something that's kind of hijacking. The second option is that it confessor. The physical effects of trauma really come hand in hand with psychological effects. What it does is it creates this rift between your physical reality and your mental experience. One of the most common new ways you might see that is, for example, in a returning war veteran who's quote-unquote hyper-vigilant, where an everyday event gives them this kind of exaggerated, startle response. They're essentially a constant fight or flight type of reaction. And that can have nasty health effects when it accumulates over time. Or it can recur. And that's particularly true in communities that have been exposed to structural violence or racism. So often recurrent trauma happens to a lot of the patients that I see who grew up here in Oakland and have seen members of their community institutionalized through the prison system or in my patients who have fled from war-torn countries and just got re-traumatized when they were going to the next place where they ended up and then re-traumatized once they came here to the United States. So what that ends up looking like is this entity that I call end-stage trauma disease. I have one patient who had the terrible misfortune to flee from a civil war in her country only to end up in a country that went into its own civil war just a couple years later. While she was in that country, her husband died of cancer and she wasn't able to bury him for three weeks because it was too unsafe to leave the house to go to the cemetery. So she lived with her husband's corpse, watching it decay while she was too afraid to leave the house. She's constantly calling the clinic in a panic over some new symptom. It's been chest pain, it's been ankle pain, it's been dizziness, it's always something. And she'll get the million dollar workout, the MRI, the stress test, the x-ray and everything turns out normal. And I think a lot of this has to do with this rift that's been created between her inner psychological life which is clearly, incredibly tormented by this trauma that has taken over her and the reality of her physical body and one becomes representative of the other and essentially what I've sort of come to believe is that one of the major important parts of how aging changes our psychology is what do we do with our shit? What happens to our trauma and do we take care of it and are we part of a community that allows us to do that? As the psychological aspect demonstrates, the social environment in which a person ages also makes a huge contribution to what their life is going to be like. And in this country, I'd say that there's two major social factors that disproportionately affect older people as compared to younger people. The first one is loneliness. The US and Great Britain have in common that there's these much larger proportion of older people in our population who are living alone as compared to in other countries of the world where older people tend to live with extended family. So in the UK, this has provoked this huge public health campaign to combat loneliness. They have volunteers, they have paid programs, they have ways of getting people out of their homes. In the US, our approach is a lot more haphazard and poorly funded. There's some places where the area agency on aging is really well organized and well integrated into the rest of the social safety net in the community. Here in Oakland, we really struggle. Highland does not do a good job of communicating with the Department of Public Health and with the area agency on aging. So I think each of us is individually doing some good things, but we're so disorganized and poorly funded that we can't get ourselves together to work on this problem as a group. And loneliness has some really big consequences. The largest study that looked at the effects of loneliness in older people showed that older adults who I self identified as lonely were 45% more likely to die over a six year period than their peers who said that they weren't lonely. The other social factor that really impacts older people in this country is ageism. In the US, we absolutely worship youth. This image is from the Dove campaign for real beauty which was lauded by everyone as being so inclusive. Look at all the diversity that we're seeing here, all these different types of bodies of different colors and shapes and sizes, but the oldest woman in here looks like she's maybe 40. Ageism remains the final acceptable form of stereotyping and prejudice that we as Americans are willing to tolerate without question. It's the only form of bigotry in which we are prejudiced against our future selves. I think about it, if I were to stand up here and make an openly racist or homophobic joke, I would become very famous in a very bad way, very fast. But I'm willing to bet that at least some of you out there in the audience were expecting me to make jokes about depends or dentures or something else that really uses older people at the expense of their shame for our humor. And when it comes to something like incontinence, that's already typically the person's greatest source of shame, and then we use it to make jokes at their expense, and it's a great way of taking that isolation and loneliness that the person's already been experiencing and magnifying it profoundly. Thank you. All right, I'm off of my soapbox. So now I'm gonna kind of move on to some of the other domains that make me a little bit different, specifically from another type of primary care doctor. So I wanna talk about the cognitive, and I think it's pretty obvious that the brain changes as we get older, and some of these changes are normal and happen to almost everyone. Older people need a lot more time to process instructions on how to complete a task, which is why they get so frustrated and vice versa with the people at the genius bar when they're going in to get their iPhone fixed. That feeling of why did I walk into this room? That only becomes more common as you get older and older. My advice is stop multitasking now. Because it only gets more impossible with age. And one of the things that becomes more difficult too is that question of did I get this information from my daughter or did I read it in the newspaper? All of this is normal aging. And finally it can be a little bit more difficult to abstract and there's a little bit less flexibility in thinking. But that's in contrast with some abnormal changes that happen in cognition with aging. Whether that's forgetting recent conversations. If you're talking to your parent and find yourself saying, I just told you this two days ago and they're like, I have absolutely no idea what you're talking about. Getting lost, that's not normal aging. It's not the same thing. Newly impaired judgment. If you have someone who was always rock solid and suddenly is making really bad decisions about their finances, for example. And personality changes. These are things that should be considered alarming and just a public service announcement. If you meet an older adult who happens to be experiencing any of these things, they should get a cognitive test. It's really easy to brush these things off as oh, so and so is just getting old. But that is not just getting old and needs further investigation. All right, so when you put that all together, how do all of these four domains add up in the form of function? What I wanna know is what can this person do on their own? So when you go to the doctor's office, you probably have to fill out a questionnaire that asks a whole bunch of questions about symptoms. Do you have any fevers? Do you have any headaches? Are your teeth loose? Are you constipated? Blah, blah, blah, blah. So this is sort of the geriatrician's version of that. I wanna know what can you do for yourself as a result of all these biological, psychological, social and cognitive things? What are you needing help with? And what are you no longer able to do for yourself at all? Because that allows me then to help prescribe a potential remedy, whether it's hooking someone up with services, whether it's getting them connected to a therapist, a physical therapist, a psychological therapist, a social worker, getting them some kind of equipment or getting them into a community program. All right, so now that I've given you the skinny on what aging is, Jane Fonda and Lily Tomlin are here to remind me that I did promise a little bit of talk about what it means when it comes to sex. So let's get down and dirty for every single domain. So that loss of biological complexity that I was talking about, that actually does kind of provide some form of lease in the terms of fewer hormonal swings. Hormone levels stay steadier, and so your sex drive tends to be relatively constant as opposed to having changes over time when you're older. On the other hand, that increase in complexity among the population that I talked about, that essentially means that sex lives really very wildly among the population. That's certainly been my experience in taking care of patients. I've had plenty of patients who have told me, you know what, that part of my life that's over and done with, and I'm okay with that. I've had a number of male patients who have come to me asking for a prescription for Viagra solely so that they can jerk off. And then I've had a number of other patients who have asked me if I can fix them up. Because, so there's really even more, I would say, diversity of sexual experiences in the elderly as there are in younger people. On the psychological side, many older adults go through an event that we call the life review, in which they think back to important milestones and decide sort of how they feel about them. And so for older adults who have that unprocessed trauma that I was talking about, this can actually mean reliving and re-experiencing early life sexual traumas in a way that can sort of re-intensify the experience of them. But on the other hand, for others can have a real sort of reawakening of their sexual selves. There are more and more stories of older adults coming out of the closet for the first time and experiencing sort of the new awakening, having looked back at their life and said, you know what, I never got it the way I wanted to, and you know what, it's now or never, baby. On the social side, the loss of romantic partners and close confidence can take a big toll on the sex lives and sort of increase that loneliness that I was talking to. But at the same time that there are deaths of peers, there are also deaths of inhibitions. And more and more older adults find themselves sort of asking for what they want for the first time, giving fewer fucks to get more fucks, as we might say. On the cognitive side, you know how I talked a little bit about decreased mental flexibility? That means that sex tends to be a little bit more rootinized. Every Wednesday at noon, no problem. Same position every time, no problem. Everyone's happy. So it tends to bother people a lot less too than I think in our youth's sort of constant change, obsessed culture. People tend to have more satisfying sex lives, even if they're the same sort of rootinized over and over again. On the other hand, the development of dementia that I talked about can bring about some major controversy around what consent looks like. In Spain, nursing home residents have a bill of rights that actually includes a bill of sexual rights. So what can a nursing home resident expect to be allowed to do and how do you provide them with a nurturing environment? On the US, on the other hand, our attitude towards nursing home sex is a little bit more like panic when the husband of the demented wife comes to visit. We haven't really figured this out. So I think as we struggle with consent as an entire community, this is something that particularly affects those who have impaired decision-making capacity. I don't have any easy answers for that at all. And finally, the overall change in functional abilities can mean a lot of challenges for the actual mechanic of sex, but the good news is people will persevere. I had a patient come visit me a couple months ago, and we spent the entire half hour talking about how was she gonna be able to do it with her oxygen on? And so we came up with some different strategies of longer-length oxygen tubing. We're gonna reposition it in a certain way. There's certain positions that are just off limits because oxygen tubing is gonna get bent, but we know what? We figured it out. We figured it out. People are creative, and they're motivated, and they make it work. All right, so what's the moral of the story? Here are my take-home points. If you wanna have a great sex life that lasts until your dying day, you've got to experience healthy aging overall from a biological, psychological, social, cognitive, and functional perspective. And to do that, here are the evidenced-based recommendations on how to age well. Oh my God, guess what? Exercise, a doctor telling us to exercise, shocker! So there is, in fact, a magic bullet that makes every disease better and prevents almost all diseases, at least from getting more severe, and that's exercise. Yep, it's true. All right, don't smoke. For all of those of you who are fans of California agricultural products, I'm not gonna say don't do it, I'm just gonna say don't light it on fire and then put it in your mouth. Find other ways. Next, maintain your important relationships, and I can't emphasize this enough. If you wanna prevent yourself from getting lonely in your older age, you gotta keep up with those people who matter to you. Your family, your friends, your romantic relationships. Invest in those now and keep investing in them over time. Keep learning new things, and whether that's the comma sutra, or whatever else it is that's going to keep your brain flexible and hopefully keep you in that normal, healthy aging category. And that's anything, whether it's learning a new language, learning a new musical instrument, but challenge yourself to constantly grow cognitively. Manage your stress and process your trauma, so every single one of us has crap that's happened to us. And one thing I will say is, if you want it to not impact you in a way that's going to cause that rift between your physical and your mental self, deal with it. Get your ass in therapy. Whatever it is that you need to do to heal, if the first therapist doesn't work, go find another, and then another, until you finally start dealing with it and it doesn't overload you and own you. And finally, be lucky. I can't emphasize this enough. Have the good fortune to not be born into a war-torn country or a war-torn city or community. Unfortunately, that's just the reality of things is that aging here in Oakland is really different than aging over in Mountain View. And the people who are from this community are beset by a lot of factors that are out of their control that do cause early aging and a lot of times early death and changing quality of life. So keep that in mind when you're thinking about what kind of a citizen of the world you want to be and the ways in which we've each been lucky you're not lucky. All right, that's all I have to say about that. Three questions. Three questions. Or if you Google it, possibly four questions. Yes, how do you define old or what does that mean? That's a really fraught question I'd say. So typically, a geriatrician's cut off is 65 and up. That has to do honestly with insurance coverage more than anything because that's when people become eligible for Medicare. But just like I said, aging is really defined by complexity in the population. And there's certain disease processes or conditions that cause kind of an acceleration in aging. Some of the things that are proven to do that, homelessness. Someone who's in their 40s looks functionally like someone who's in their 70s when they've been living on the streets. On the other hand, CEOs with access to organic bullshit vegetables and things like that and all sorts of different exercise programs they tend to look in their 80s functionally like they're in their 50s. So there's not really a number that I would say you're definitely old when you hit X. Is this a question or is this like a statement of fact? Taking a lot of drugs once you get old. Oh boy. Pull the audience on this. Come up a lot when people ask me about medical marijuana and particularly for my patients with dementia there's increasing attempts to use marijuana to help with agitation and confusion among Alzheimer's patients. And my sort of personal practice has been to say if you tried it when you were younger, sure. Like you know, actually probably it could be beneficial and I've had one patient who it's been the only thing that has calmed her down enough where she wasn't trying to escape from her nursing home constantly. But on the other hand, I would be pretty reluctant to just throw a bomb into someone's pretty altered brain chemistry and just sort of see what happens. It's kind of like trying to fix your TV by hitting it with a hammer. I mean it might work. But it might do something entirely different. One more. Call your parents. Call your aunties. Call your uncles. Go visit your neighbors. Don't forget that we all, it takes a village to raise a child and it takes a village to care for your elders too. Yeah, go check on your neighbors a lot. Thank you. Let's give it up for Laura. She'll probably be around kind of in here if you have any last minute questions. I would like to point out that we are happy to help you with at least this bullet. And we would love your help with that bullet too. So if you'd like to be up on the stage and get free beer in order to tell everyone here what you know, talk to Scott, Ann Ray or me, Rick. We'd love to get volunteers. We always close the show with a calendar of events. There was way too much for one page this month. Nerd Night Silicon Valley is relaunching their tomorrow. It's a bit of a drive, but that's exciting. You should check back with them every month. SF Beer Week is also starting the first week and a half of February. Fantastic time. Best part of the year is at Tremor in Berkeley, the last day of that festival. You should definitely go or you can drink beer for like $45. I hear this guy's like on Radio Lab or something and some reason there are still tickets for sale. UC Berkeley has a lot of great events over the next month. This is my favorite. They have a Valentine's Day show about houseplant botany and I thought it was really curious because the octopus literary salon, The Slame Day, also has a botany like romance talk. So great minds think alike and all that. We're back here next month, last Monday of the month. We have three fantastic talks. One's on Albany bulb. One is on ecological networks and the last one is on the science of athletic recovery. Thanks again to all of our speakers, Victoria, Allison, Laura. Thanks to the Oakham Public Library, Club 21, Mr. Ray Ben, of course all of you. See you next month.