Megan is the assistant professor of ophthalmology at the Wilmore Institute at Johns Hopkins, and she specializes in pediatric ophthalmology and astrabismus, and her clinical work includes amblyopia, congenital cataracts, and retinopathy of prematurity. Megan received her medical degree from the University of Chicago, where she also completed a fellowship in clinical megalithics. After an internship in internal medicine at the University of Maryland, she returned to the University of Chicago for her residency in ophthalmology, followed by a fellowship in pediatric ophthalmology and adult astrabismus at the University of Toronto's Hospital for Sick Children. For six years, Dr. Collins worked for the Immune Tonus Network as an expert on ethics and conflict of interest, and today, Megan will speak on the topic doctor-patient relationship and technology. This is a lot of pressure, Mark. The last talk of the day. My talk is actually on the utilization of anti-vegetive agents in retinopathy of prematurity, which is a permutation of technology in the doctor-patient relationship, but a little different than my... Oh, can you hear me? Okay. Hi, everybody. Can you hear me now? Wonderful. So my talk today is on a little bit of a permutation of what you have on your agenda. I'm actually talking about some ethical considerations with the use of anti-vegetive agents in retinopathy of prematurity. I just want to say it's an absolute delight to be here and see old friends, and thank you so much to Mark and all the wonderful faculty from the McLean Center. I don't have any financial relationships to disclose, unfortunately, but I will be discussing off-label use of an FDA-approved medication. This may be the first time in the history of the McLean Conference that there's going to be a lot of photos of eyes. But I think in order for me to frame the ethics question for you, I need to give you a little bit of a background of retinopathy of prematurity. So we're going to talk a little bit about some visual things, and then talk about the anti-vegetive story and then ethical considerations moving forward. So I'm sure all of you remember this from your third year or second year of medical school. This is what the inside of the eye looks like. Retinopathy of prematurity is a potentially blinding vitro retinopathy. What that means is the jelly inside the eye and the retina, which is the back layer of the eye, end up undergoing some abnormal development. It primarily occurs in very low birth weight infants, and it's the leading cause of childhood blindness in the United States, as well as the cause of 20% of cases of pediatric blindness worldwide. So that is certainly a significant problem. What happens with retinopathy of prematurity is very low when infants are born prematurely, their retinal vasculature has not developed completely. Do I have a pointer at all? So when they're born prematurely and the vessels have not grown yet, they can go through various stages of what's called ROP, starting with a very early disease stage zero, going all the way to stage five. Majority of cases will resolve without needing any intervention, but there are a subset of cases that will go on to meet what's called threshold disease, which would require treatment. And the different treatment options, primarily historically, have been cryotherapy, which has been largely replaced in the mid to late 90s by laser therapy, and now some discussion of bevacizumab, which is Avastin. If left untreated, the majority of these patients would go blind from what's called a retinal detachment. And just so you have a sense of what this looks like, this is the abnormal retinal vasculature inside the eye, this is the demarcation between the vascular retina and the avascular retina, causing what's called a retinal detachment. And you can appreciate more significantly here, these are eyes that would have a very poor functional outcome. There are screening and treatment guidelines from the American Academy of Pediatrics for retinopathy of prematurity, and I won't belabor sort of the points of when to treat here, but the important thing is laser is considered the standard of care at this moment in time. Although interestingly, new treatment guidelines that came out about two years ago talked about using bevacizumab, specifically off-label for select cases. Why do we talk about using a new treatment option for ROP when we already have a standard of care? The problem is our treatment option has some limitations to it. This is actually my boss at Hopkins treating one of our babies. In order to treat retinopathy of prematurity, it's a little bit archaic, but we actually destroy the avascular retina. So this is the area of the retina that was abnormal and it's treated by applying laser burns and those laser burns will destroy the retina, which as the benefit of destroying the abnormal drive for blood vessel growth, but the unintended consequence of permanently destroying your peripheral vision, as well as causing some children in particular to become profoundly myopic. And looking out across the room, I know there's a lot of you who have myopia, but probably not to the severity of these kids. Some of these kids that I treat, they could be minus 12, minus 13 diopters of myopia. So pretty significant. Number of these kids also have strabismus for which they would require surgical correction within the first couple years of life. And as you can see from this slide here, a number of them have severe visual disability, particularly those ones with the stage four and five disease. This brings us to the question of using a new treatment modality, because we have something that works for a number of cases, but there's also a number of cases it doesn't work well for. And this is where anti-vegeteves come into the picture. Anti-vegeteves, as you might know, down regulates abnormal blood vessel development. It's been used for many years within ophthalmology, particularly as an intravitreal injection, and primarily for age-related macular degeneration, some types of diabetic macular edema, and some other type of vein occlusions. It was originally approved, of course, for the treatment of metastatic colon cancer. Its use in retinopathy or prematurity hit the literature in about 2007. There were a number of case reports coming out about the use of it both concomitantly with laser treatment as well as on its own. And the case reports were varied as far as what dose to use, how to administer it, whether the children were put to sleep to do this, or whether it was done at the bedside in the NICU, what stage of disease to use it in. And to date, and this still holds true, there's only one randomized controlled trial that has been reported comparing bevacizumab to the current standard of care. And that's a, it's called Beetrop. It's a study that was published in the New England Journal in 2011. And this was a study of 220 neonatal infants who were prospectively randomized to either receive bevacizumab versus conventional laser treatment. And the infant had a specific type of ROP, something that's called stage three plus disease. And just for kind of your interest, that's typically the basic threshold of disease when we decide to treat patients. They found that for kids with stage three plus in zone one, which is the center of the back of the eye, they had a superior outcome with bevacizumab. And bevacizumab in addition allowed for continued normal vascularization of the back of the eye. So remember when I showed you those pictures earlier of that retina that had been destroyed by laser, these kids didn't have that problem. So long-term they probably would not become as nearsighted, they would not have as many problems with their side vision. When something like this happens and whenever ophthalmology actually makes it into the New England Journal, we get a lot of media attention. And there was a mixed response within the ophthalmology community. Some heralding that we had cured retinopathy of prematurity and no kids would ever become profoundly myopic or go blind from ROP again. Others heralding more caution as this is an anti-veg F agent that despite the fact that it's administered into the eye could potentially get into the systemic circulation. And this is about a year later, interestingly, the story didn't end. We started learning that a bunch of these kids who'd been treated and who'd had a very good outcome initially three, four, five months later had reactivation of their disease. And then looking back at some of the data from the New England Journal article, they hadn't followed the kids for more than 16 weeks after treatment. And we found that most of the kids who reactivate are 16 weeks and beyond. So this has led to still some significant controversy within the ophthalmology community as to whether to use this or not to use it and how to use it safely. And this has been a wonderful opportunity for me, somebody who's both in pediatric ophthalmology and has an interest in ethics to start thinking about an ethical framework for this. And surprisingly, there was not a lot of talk within the ophthalmology community, particularly when this started talking about the ethics of using anti-vegetarian in babies. The first question that came to my mind is this research, is this innovation and what are we as an ophthalmology community doing? And this is of course from Mark Siegler, one of his papers, research involves a formal protocol, it involves protection of participants in a formalized way through institutional review board oversight mechanism versus innovations of variation in practice conducted on an individual basis and relies on clinicians' judgment and integrity. And my interest was how are anti-vegetarian agents being used in the ophthalmology community? Anecdotally, I can tell you, in this 2007 I've worked at five different hospitals and all of them do something a little bit different with regard to anti-vegetarian agents. Some actually won't let you use it at all versus others have absolutely no regulations whatsoever about whether you use it or not in a research protocol or as part of your clinical practice. I did a survey with my collaborators at University of Toronto to gain an understanding of how people are using anti-vegetarian and we distributed this to pediatric ophthalmologists and retina specialists in both the US and Canada and asked them about their experience treating kids with ROP, whether they were using anti-vegetarian agents and what we really wanted to understand was what was their institutional policy as well as their personal approach to the consent process. We found some interesting results from this survey. This is one of the tables that divides, just for your reference, both pediatric ophthalmologists and vitro retinal specialists treat retinopathy of prematurity. Historically, pediatric ophthalmologists are probably a little bit less aggressive about using anti-vegetarian agents than the vitro retinal surgeons because the vitro retinal surgeons have a ton of experience using this in macular degeneration and other adult diseases. But we asked all the participating doctors when they used it and was at first line all the time, sometimes based on the severity of the disease, which is what the American Academy of Pediatrics recommends, first line only if they couldn't do a laser treatment or salvage therapy if the patient had failed other things. And as you can see here, the majority of respondents in both the pediatric and vitro retinal group were using it in compliance with the guidelines. However, somewhat concerning was that about 10% of vitro retinal and pediatric specialists were using it as first line therapy in all cases and actually moreover offering this to patients as the new current standard of care. We asked people about what they were doing in the consent process and what they were telling patients and we gave them a list of options of different things that we thought should be included in the consent and asked both what they were currently doing and what they suggested should be included. The majority were mentioning that this is an off-label use of a medication and that there's an unknown long-term safety profile. Not as many people were talking about their own institutional or personal experience with this medication or the fact that there are risks of systemic complications when both used for other eye diseases as well as systemically. Regarding use of educational material for patients, the majority were not using any educational material to supplement their consent discussion. If they were, however, interestingly, about half of them were giving patients scientific papers and as someone who used to write a lot of consent documents for a living, essentially, this is not what I would call at a sixth grade understandable level for families. Regarding institutional oversight, most institutions don't have a policy on using anti-veg F agents. In fact, only 5.4% of respondents said that they were required to obtain ethics approval for any use of an anti-veg F agent at their institution. And the vast majority didn't have any sort of approval process necessary for off-label drugs at all. So to put this into context, this is a tough disease that sometimes does well with standard of care, but sometimes doesn't. And there are certainly some benefits to consider with anti-veg F agents. One, it's very easy to administer. You use a small vial of the medicine.  I know that makes most people cringe, but ophthalmologists are good at it. And it can be administered very quickly versus laser treatment is typically done under general anesthesia with a child asleep. Can take over an hour to do. So there's the risks of the comorbidity of that length of anesthesia. We do know from some of our preliminary data that it has a relatively good safety profile. And there's continued development of normal retinal vessels with the hope of warding off myopia and visual field loss. But we also know that there's a lot we don't know. We don't know whether this gets into the systemic circulation. We don't know if it down regulates anti-veg F both in their kidneys and their lungs. There's the risks of interestingly, if you deliver the drug too late in the process of ROP, they can actually cause them to develop a tractional retinal detachment, which is what you're trying to avoid. And probably the most salient thing is these kids get late recurrences. And speaking as a pediatric specialist, examining a kid who's about 40 weeks of age versus a kid who's 50 weeks of age is a much different exam. And as kids get older and very big, it's very complicated to examine them in clinic. Often you have to put them to sleep for anesthesia, which is one of the things you were trying to avoid in the first place. We don't know much about the risk of death with anti-veg F agents, but certainly it's theoretically possible. My collaborators on this project from University of Toronto and I published a paper recently talking about sort of how to proceed with using anti-veg F agents. The general consensus of the ophthalmology community is to embrace this new innovation. And, but we are really suggesting it needs to be thought about within a very carefully structured ethical framework. One is that it's really more of a medical innovation and can't be offered as a current standard of care, particularly as a standard of care alternative to laser treatment. And it must be held to a higher standard of consent. Premature infants and their parents must be considered a vulnerable population. The unique thing about the ophthalmologist and the relationship with a child in the NICU is we often come in either early morning or late in the day after our surgeries and we often don't meet the families. And the only time we end up meeting the families is when kids require treatment. So they don't have the same day-to-day relationship that they have with their neonatology team. And that's something that we need to work on. And I personally, when I have kids that I think are going in the direction of treatment, I make a point to meet the parents and say over the next few weeks, we're gonna be deciding whether or not your child needs treatment and I'll give you weekly updates. We have published a nine-point checklist of elements to be included in the consent document as well as a template for educational material because we felt that this was so important that the different elements be included all the time rather than practitioners using their template, a consent from their institution. In some of the elements we want included in all the checklist, of course the data from the New England Journal Study, that's the most robust data we have to date. The important emphasis that we just don't know what happens long-term systemically with these medications as well as the limited data we have on how well these kids do visually. The kids who got the drug for the first time are still very young, they're probably three, four, five years old, so we don't have a lot of information about their visual acuity as much as we will when they're eight or nine years old. These kids have the potential for late reactivation of disease, we'll need to undergo exams for a much longer period of time and importantly to mention is that this is an off-label use of medication. Of most medications used in the NICU are used off-label so I don't think that in a loan should be something to eliminate us from considering this but it still needs to be told to families. So moving forward with using anti-veg F agents, so I think it's a viable option for a specific sub-population of patients and certainly not all patients. It must involve a rigorous consent and parental education process as well as cautious long-term monitoring of these kids. This is an idea that Mark and I had talked about a long time ago when I worked with him in the Immune Tolerance Network, this idea of creating a registry of collecting information because it's still institutions may have you know five, six cases over a six month period so they're not building up a huge database quickly. It would be nice for us to pool our resources both from our US and Canadian colleagues to figure out how these kids are doing both short-term and long-term. That is the end of my presentation for today and hopefully I've stayed somewhat on time. Thank you so much for your attention and I'm happy to answer any questions. I thought you was going to use their mic. The question today, if I could plot this in my new name, Dr. Collins, if this was your baby, because this sounds wonderful and exciting but it also sounds scary.  So I would say that for a subset of patients that are too unstable for me to do a laser treatment I would use anti-veg F. But the way that we use it at Hopkins is we are doing it under an IRB approved protocol. So it's considered an experimental use of the medication. The parents have to go through the somewhat rigorous consent process of the IRB documentation as well as having a discussion with us. There's a number of kids that I have seen personally that had been treated in the community and they had never been offered laser treatment. This has just sort of been, this is the new hot thing on the market which unfortunately ophthalmology is a little victim too at times of we're great innovators and have a lot of technology and we often want to adopt the latest and greatest. But I urge against offering this to a kid who is gonna do perfectly fine with laser treatment. Just a quick observation. And that's it seems that there seems to be a correlation between the cost of an intervention and how excited we get about the ethics of something. When something is very inexpensive people don't get too excited about it. It's only when things start costing a heck of a lot that a lot of people seem to get very excited about it. So kudos to you to addressing this. Thank you very much. The, I think it's just that anti-veg agents have become so popular within ophthalmology in general and we've had such significant success particularly in the world of macular degeneration with them just being a revolutionary treatment. But our approach to innovating and developing this in kids I don't think has been as well thought out as it could be. For example, the dose we use is half of the dose that you would use for an adult. And I can tell you a 574 gram baby is not half the size of most of our adult patients. So I think it's, again, I think it's something that has a lot of potential and the tide is certainly moving in the direction to embrace it wholeheartedly. But my hope is to add just a little bit of thought and caution to the process before we embrace it wholeheartedly. I should preface this by saying I'm not a physician scientist so I apologize if the answer is obvious. I'm curious first in my nature, I've noticed in the list of items that she'll at first ask about consent, I was curious about the relevance or at least how it got on the list about urine and product products. So that is probably something that is, it's on the list, but it's a fairly low significance for people, but that's where the anti-vegeta is derived from for a vastan. It is around 100%? Most people are. So we asked everybody whether they were mentioning that or not and most people, as you could see, were not. I personally have never mentioned that during any of my consent discussions. Well, I think we wanted to have a somewhat exhaustive list of options for people to tell us what they were doing. My experience with sending out surveys is rather than having people fill in a lot of answers if you give them checkboxes of different options, sometimes they're more likely to respond. Crabbits, thank you. I just have a few concluding remarks. Thank you all for coming to the 27th Annual McLean Conference. I wanna give a special thanks to the 40 or so presenters yesterday and today. Talks were, as always, splendid, magnificent. I know people have come, many of them, from far away and I greatly appreciate that. I wanna thank our moderators, Blaney and Marshall and Monica and Dan. I think I moderated a few and Peter Angelo's for moderating the sessions.  If you're registered for the conference, we will send out an announcement of how you access the YouTube channel in the next two or three weeks. I think Paul takes about two or three weeks to get things pulled together. Let me also tell you the dates of next year's conference. Have I done that yet? Just decided it will be November 11 and 12, again, a Friday and a Saturday of 2016. And the conference, this was supposed to end at 510. I believe we've made our deadline and I wanna thank you all for staying here so late and attending. Thank you.


I'll welcome everybody to this session. It's called the Human Brain Deconstructing Mental Illness. I'm Joe Palca. I work for a radio network in the US called NPR, National Public Radio. Our speakers today are Amit Etkin. He's an assistant professor of psychiatry and behavioral sciences at Stanford University. And the Etkin lab is trying to understand the neural basis of emotional disorders in their treatment and to leverage this knowledge to develop novel treatment interventions. And to my immediate left is Tony Weiss-Corey, professor of neurology at Stanford University. And his lab is trying to study the role of immune injury and response in neurodegenerative Alzheimer's disease and understand the pathways that modulate neurodegeneration during aging and age-related changes to the brain. So deconstructing mental illness. Difficult to, oh, I mentioned before cell phones, please have them off. And there's also a hashtag, hash global health. We'll be taking questions from people watching around the world and from the room, if you prefer. And we'll be taking questions in the room. So you're welcome to chime in when the time comes. But I was thinking about a way to start, which was deconstructing, is there any way, I mean, to if, I mean, radiologists can take a picture of you and say, OK, you've got an enlarged spleen or you've got a broken femur or something like that. Is there any picture that you can take of the brain that will say that person has an emotional illness? So thank you for the question, Joan. Thank you for having us here. So let me answer that simply. No. Let me ask Tony. Yes. So the more elaborate answer is actually to take a little step back and think about what a psychiatric disorder is, right? So a psychiatric disorder is problems in thought, in emotion, in behavior, a whole bunch of things that can go together. And how are they currently defined? Well, at present, they're defined by checklist of symptoms. Those checklist of symptoms are created by committees of people and not necessarily based on an understanding of how the brain works or how we should be carving nature at its joints, so to speak. So the reason, in part, we don't have those images that say you have something wrong with you is because there's a huge overlap in the brains of people who are healthy and who are ill, even with an illness such as schizophrenia. And so part of that is really trying to, instead of having this dimension of symptoms, to move it a little bit, such that we're now talking about dimensions of brain function. And so we can talk about how much you are within or outside the normal range with brain function, just like you'd give a lab test if you're looking at your cholesterol level, right? There's a normal range, and if your level's outside the normal range, then that's a problem and that's dealt with. And that's not how we approach psychiatry right now. We approach psychiatry as something somebody tells us late in the disease that doesn't necessarily reflect all the processes we care about in the brain, and for that reason, we don't yet have that image. We are moving in that direction, and that's been a big area in the past couple of years really, that has refocused the field around an understanding of the brain as the basis of the illness, and therefore our diagnostics should be at that basis. Our treatments should be at that basis as well. So before I get off this question, I like that idea that these diseases are sort of defined by committee. Are there errors? I mean, can you go to a doctor or a psychiatrist who will say, yes, you've got this disease and you go to a different one, and a different doctor will make a different diagnosis, are the disease states sufficiently well captured by the committees to be reliable from one person to another, one therapist to another? Yes, so I wanna be careful not to knock completely our current diagnostic system, it has value, and the value is actually reliability to some degree. That is, the question you asked was, if I make a diagnosis or you make a diagnosis, do we come up with the same diagnosis? So now we have a more reliable system than we had before the diagnostic manual was introduced several decades ago, but not really where we need to go. For most illnesses that affect most people, so these things are like depression, anxiety of various forms, the reliability is actually pretty low. In fact, it is so low and in the almost questionable range of reliability that if you are looking at it blindly, you would argue maybe we should remove that diagnosis because it's not that way we make the diagnosis because it's not reliable. So there's reliability, then there's something called validity and validity just says there's something about this diagnosis having it that says something about the real physical outside world that your brain is different or something is different about you. These diagnoses were not designed to have validity in that way, they were designed to be reliable because as bad as our current system is, it was worse before. So progress is being made, but even in that reliability question, it's not really clear. It's not even checklist of symptoms like you have to have every one, you have to have five of nine for depression. With the way post-traumatic stress disorder, for example, the categories have been changed basically in the new diagnostic manual in the United States, there's 600,000 different ways to have that disorder. Yeah, 600,000. So, and that's up from I think, I don't know, maybe with the previous one was maybe 1,000, 2,000, still a lot, and that engenders lack of reliability and really the patient that I'm seeing and giving a label to may not be the patient that you're seeing and giving a label to in that way. Wow, that's a great number, maybe we'll come back to that. So Tony, I know that you're more on a cellular basis, but if I hand you a tissue sample, can you say I see something in that cell that reliably tells me that there's a neurodegenerative disease in that person that that cell came from? Yes, that is the case for a number of diseases, Alzheimer's is an example, where if I get a piece of tissue from a person who has Alzheimer's disease, I could actually see that. There's certain changes that occur in the brain that lead to degenerative changes, both in neurons that communicate with each other, that some of these connections have been lost, but at the same time, there's also changes that certain proteins start to accumulate, we call those amyloid or tau proteins, and they form sort of sticky materials that the brain puts into a defined space either outside the cell or inside the cell for a reason that we don't quite understood yet, but we know these deposits are not good, so yes, we could see that. What we're trying to do really, what the field is trying to do, and this gets back to what Amit was mentioning earlier, is we're really trying to get chemical molecular signatures of all these diseases that will allow us to measure expression of certain genes, proteins, or other modifications that will tell us this person has a disease or is on the way to develop a disease, and I think there's increasing progress, again to come to the example of Alzheimer's disease, we can take the cerebrospinal fluid, so this is the fluid that is present in our brains and also in the spinal cord, is produced at a high level, it's similar to the blood, it's a different liquid, and it's localized to the central nervous tissue. So in a person with Alzheimer's disease, we can measure these two proteins that I mentioned that accumulate in the brain, we can actually measure changes in these levels. So if I took cerebrospinal fluid from a living patient, I can tell this patient has the disease. Even more interestingly and promising, I think, is that we can tell if a person is on the way to develop disease, because you can already have changes in the levels of these proteins and not yet have cognitive problems. So your brain is still functioning normally to the outside world, you may not even notice it yet, but we can chemically detect that there's something on its way to develop, and this is really the hope that we will be able to hopefully treat these diseases earlier, but the challenge also is that these changes seem to take place up to 20 years before you get dementia. So these diseases develop over very long periods of time. So if I'm 50 and I will have Alzheimer's at age 70, there's something going on in my brain right now that leads me to that disease. Now this is both sort of daunting, but it also provides hope that we will have a long time to interfere with that disease process. So again, I wanna be clear.  That is absolutely the case. But looking, but having that advantage over me in terms of being able to see something altered in a physical property, does it work the other way? Are you sometimes diagnosing people with Alzheimer's, not you, but are people being diagnosed with Alzheimer's only to find out later it wasn't Alzheimer's at all because we can now do the biopsy after they die and say, no, that's not showing. I mean, how reliably can you tell whether Alzheimer's is what's causing the symptoms that you're looking at? So I will try to answer this from a molecular perspective and maybe Amit can answer it from a clinical perspective. So these tests that we can do now with the spinal fluid, they're not that old yet, but we have probably data from five up to 10 years and they're extremely precise in predicting that you will get the disease. Not exactly when you get it. So there's still sort of an uncertainty how fast that disease will progress. But we can almost definitely say, you will get this disease. You may also get Parkinson parallel to it. So it's not going to be that this is the only disease you will have. This sounds terrible, but we can definitely say you will get Alzheimer's disease pathology because there's something wrong in the metabolism in your brain. But from the clinical perspective, and I think I want to give this to Amit, there is a diagnosis unfortunately for Alzheimer's disease and you will not have Alzheimer's disease. Maybe you can elaborate this a bit more. Yeah, and actually let me kind of generalize it a little bit as well that the diagnosis we make almost for all of the behavioral disorders. So whether you're talking about psychiatry or neurology. So things like certain types of dementias in neurology can actually present like psychiatric disorders and like other types of dementias. They're all basically presumptive diagnoses. So clinical diagnosis based on experience and certain patterns, which of course become more reliable as the person gets more ill and is more terminal, right? Which is not so helpful in terms of you'd like to have more certainty earlier on. So these are presumptive, as Tony was saying. You really only know when you look at their brains what happens. So you do make misdiagnoses in that way. Something like traumatic brain injury, TBI, which we see for example is very prominent now from NFL issues in terms of chronic traumatic encephalopathy. Warfighters in Iraq and Afghanistan getting a lot of improvised explosive devices driven TBI's. The kinds of changes induced by those injuries look like changes you see in Alzheimer's and in fact put you at greater risk. Psychiatric diagnoses themselves change the structure of certain brain areas and put you at risk for dementias. So you have to actually start now thinking about these things as more of a continuum across these different pathologies and different brain regions and systems. And so there is a lot of misdiagnoses for if you will good reason, right? Because there's a confluence of mechanisms around things like the hippocampus which underlies your ability to form memory and is impacted in dementia but also in a lot of other disorders. So that's just one example. But before we leave this point, I'm just, I'm struck by the possibility, again, at least at this juncture, maybe you can tell me that there are more things you can do. But if you find out, or if I should find out that in 20 years I will have Alzheimer's disease, that's a kind of a burdensome thing to me as an individual because I'm not sure what things I can do about that with that knowledge. Is that a, are we in that funny stage now where we can diagnose better than we can treat? Or funny isn't maybe the right word. Yeah, right. Not sure that we can diagnose better than we can treat. We know there's a lot of things that can be done for a range of these conditions. Well, that we should all be doing now, like your diet, your exercise, all these things that are modifiable risk factors. So smoking is a risk factor for a lot of stuff that can go wrong with the brain. So you don't have to actually know that you're gonna have a disease to be able to do those things so people don't do them anyway, even though we know we should, including doctors. I think our problem is actually in many ways the opposite, that we only get certainty about diagnosis far too late. So if you think about psychiatric diagnoses and Alzheimer's being kind of the extreme, right, where we can really only diagnose once it's really gone too far, and a psychiatric diagnosis, typically the person's been ill for a long time before they ever come into your office to get diagnosed. If it's something like autism or schizophrenia, it's affected their brains and them throughout their development. And so you kind of miss the window to really have the biggest impact. So I think our problem is too late diagnoses where symptoms are obvious instead of getting to the point which is what we'll get through through the science of early diagnosis, risk factors, and so forth. And then we'll worry about is that a burden? Can we modify it? We're nowhere near there yet, I think. But it does occur to me that to change behavior, we could just tell everyone that they're gonna get Alzheimer's and see if that doesn't change. Sorry. Tony, I'm sitting here also wondering, do you think, I mean, we talked about this that, I mean, it said we need to look at the brain because that's gotta be, do you think that every, even Alzheimer's, but any other kind of neurodegenerative disease will show some sort of modification in cells or could it just be that the connections between cells are altered and you won't see it in an individual cell? I think if we use the right tools, we will see changes always at the cell or the level because the cells respond to their environment. There's different types of cells in the brain and one of the most sensitive cells in the brain, it's called a microglia. This is an immune cell and these cells basically survey sort of the state of the brain, as soon as anything goes wrong, they get activated, they get alerted like the police, they will go in and try to fix things. Sometimes they do the wrong thing, I'm stopping making analogies. But they're clearly very sensitive to anything that changes. So if connections between nerve cells start changing, these cells will react to it. But even in the neurons, if we have good enough tools and we can measure the expression of genes in these neurons, we will be able to see that there's something wrong in how they fire, how they're responding to their environment. Actually, it's interesting that you talked about glia. Maybe you could tell people, it used to be that people thought that neurons where all the action was in the brain, but the brain has got a lot of different kinds of cells and maybe you could tell us a little bit about what people have learned about what the brain is made up of. Yeah, that's a great point. I'm glad you're bringing that up. This is sort of my pet peeve. I'm actually an immunologist by training, so I studied initially the immune system and then got into neuroscience. So there was really a time where people studied only neurons. That was what the brain is about. And maybe 10, 20 years ago, really people started to say there are other cells in the brain. They were actually termed glue from the Greek word glia, means glue, and they were just thought to stick the neurons together. But we now know that these cells are equally important. They're not as electrically active, at least not. There's some that also have electrical activity, but they're not the main sort of the computer network, but they're the maintenance system. And I mentioned one type that is actually an immune cell, these microglia. So there's cells in the brain that have very important function, like isolating the wires, the axons, and that neurons are used to communicate with each other. That's also fulfilled by these other cells, the glue cells. But even beyond that, if we look outside the brains, certainly we have a vasculature in the brain. The brain consumes 20% of the blood supply, the energy supply in our body. This is facilitated by a very elaborate vascular network. So if anything goes wrong with the blood vessels in your brain, you might get a stroke, or you don't get enough energy to the brain, that will have an effect. And then beyond that, we know now that the rest of the body communicates with the brain. So there is a much more intricate system of how the brain responds to what is going on in our body. So it's really a multi-level system. And we start to explore this interaction at all levels now. So when you hear, I mean, this kind of complicated multi-level structure that you're dealing with on the inside, but you've got somebody sitting in your office, I mean, how does that make you feel? And how do you tackle that? Are you the psychiatrist? Oh, sorry. I'll just, I'll just. So I guess you can answer that question in a couple of different ways, which is in part, how do people want to hear about what is going on, right? And how do I as a psychiatrist in the clinical interaction, which is limited by the tools I have, versus I as a neuroscientist, perhaps less limited by the tools I have, kind of make sense of that. My sense is that the patients I interact with tend to appreciate understanding more about their illness, as well as they should, right? We're trying to create more of a consumer understanding from patients in general. And so it's good to be able to understand that your disease is biological. There's nothing at fault. Often there's a lot of stigma associated with mental illness. So being able to even explain that biology, if it's not their biology, at least it's the general biology that we're understanding about psychiatric disorders. That helps de-stigmatize. Putting it in the context of the body, as Tony was saying, helps explain why it's not just mental content. It's how your physical brain health, your general cardiovascular health, what you're doing in terms of exposure to light, the amount of sleep you get. All of these things are not your mental content that you might feel like you're wrestling with all the time, but the way that you then influence the organ that is the basis of the disorder. So that actually, it's helpful. I've not really had too much of an issue with people feeling like it's biological and not my fault you fix it if you educate them sufficiently. There's a tweet that came in from someone named Zebulon Carlander who asks what would be the most effective single measure possibly taken to combat mental illness? Would you offer one? Or would you say it's a constellation? Because you did mention exercise, diet. This is a, but is there something beyond that? Yeah. So among those, it's the most important. So I'd actually say awareness, awareness of yourself and your emotions and know that there is a problem and that it can be fixed to some degree in some people. So our treatments are not perfect, a lot of trial and error for sure, but our biggest problem globally is actually that people don't know that they have a psychiatric disorder, don't know that there's something wrong that can be helped. And then because of stigma and all the other things that happened throughout the world, they never actually get treatment. So even in places where there's a horrendous ratio of psychiatrists to population even asking for help in the community level to a priest or somebody who isn't even trained that itself is the barrier. So, you know, I would stack that is the biggest global impact. And then in places where there are care, it's an entirely different nation in terms of developing new interventions, but most of the depression in the world is untreated. Here's another question, which I may modify slightly, but it comes from Eileen Nora Vitarelli, who says it's important for understanding how the normal brain works to support cognition and motion sensory function. And I guess the twist on that was yes, you can see when things are abnormal, but what is normal, essentially? Is there a good understanding of what that is to compare what abnormal is when you're doing on a molecular or cellular level? That's a great point. I think for certain conditions, and again, looking sort of at this continuum from healthy and then aging and then getting a degenerative disease. So I'm talking about age-related neurodegenerative diseases specifically. I think there's clearly signs where the brain is degenerated and there are clear changes that are very different from a healthy brain. But as I said, there's a continuum. So for a lot of these conditions, especially psychiatric conditions also, people are starting to look now at hundreds or thousands of individuals who have a certain disease and compare that to people who don't have the disease and try to see what are the exact differences? And can we find patterns? Not just one gene, not just one protein, but looking at a hundred or a thousand together and see there's actually a whole network that is being changed. And if that is changed, that will tell you something. Either this disease is developing or it's already has manifested. So I think there are ways to clearly delineate these changes and we're developing this as we speak, I think. All right. Oh, you knew what I was gonna say. That was quick. Yes, why don't we take a question? And I think we have microphones, but if we don't, I'll tell you what, I'll repeat the question and we'll get the microphone next. Are human beings that are stronger or different kind of environment and different situations? Different environment, different situation and cultural element, like from Asia, obviously. And but it's matter of how you perceive it, how you deal with that. This mental attitude also determine how eventually your brain cell could be trained. So let's say how we can train our brain cell mental muscle to deal with that. And that's another thing is an even higher level of spiritual muscle. You mentioned about priest. Because often we see some very weak human being physically, health-wise, but they are so resilient of a certain extreme cases, they survive. So how we can train our brain cell for that because I come from a very strong Christian family. So I often explain myself for that.  Yeah. It's an interesting question actually from a couple of perspectives, one of which is just in general health. The other is there are certain things where you know that a stress will happen or somebody will go into combat or something bad will happen. So it'd be great to inoculate somebody in that way. And I think your question also speaks to the issue of how you interface the psychological with the biological. So how do we kind of understand our experience, which is critical to having a brain with our understanding of the brain itself. And so I trained as a basic neuroscientist, I now work primarily with people doing a range of translational basic to very applied. And so what I like to do in trying to think about that question and the way Joe has sort of expanded upon that is try to operationalize it, try to break it down to what it really is. So actually there's been a lot of talk about mindfulness, for example, at this meeting. So and that's been linked to certain spiritual practices. So what does it really mean? What is a person doing? There's nothing magical, I don't think. There's something the person is doing that you can start to bottle and you can start to operationalize it to the point where you can maybe do it on a computer. So mindfulness just being one example. You're training attention, right? You're focusing your attention and trying to shift it around to different topics. We're now doing the same kind of approach using computerized training methods where through rote practice that gets harder and harder, we can train those same brain circuits. So the message then is really trying to take these things that seem like they're different, right? The brain and the mind and all these other kind of greater things and putting them in the same language so that we can operationalize it. We can study it with science. And then the really exciting thing is you can start putting things together because now if I know how a medication works and how a brain training approach works, then they come back together because they're now speaking the same language.  But I wonder, and so that's on a macro brain. I'm measuring all the electrical activity of these billions of cells. And then you can also stick an electrode into an individual cell and measure that. But I wonder if there is gonna come a day when there will be a physiological change in an individual neuron or would it have to be a group of neurons or a group of neurons in glia that would say, yes, you have affected the change in the brain that you're looking for. And here we can measure it with this thing. Do you think that'll ever happen? Oh, it happened already. Really? Yes, yeah. No, I mean, it's amazing the progress that has been made. So for many decades, neuroscientists have been able to use what you said electrodes and sort of listen to the electrical activity, measure the electrical activity of neurons. Then they could do this in living animals, for example, and do the same thing. The animal responds to something and you can detect that electrical activity. But now we have tools that allow us to put sensors inside these cells in a living animal and they start producing light, for example. They start glowing or they become fluorescent and we can detect them. So we can actually measure the activation of a gene. We were able to do that in cell culture for a while, but we can do this now in living behaving animals. So we can train an animal to do a certain task and to respond, for example, to a circle that we show it. And if it sees this circle, a certain type of neuron will get activated and we see that a gene gets expressed in this specific neuron. So this is all still very sort of isolated and very defined settings. But what neuroscientists hope to do is that they can put this together in larger and larger ensembles that then actually relate to cognitive aspects that a psychiatrist can relate to. So by working together, we can start to put the outside world together with the molecular microscopic world. It's fascinating. Yeah, there's a lot. Can I just ask one question? Does everybody understand why there's electrical activity in the brain? Is that like, oh, yeah, I get that. You just raise your hand if you have a question about that, even a little question about that. All right, everybody gets it. No, electrical activity, it's like your heart, right? When these cells are active, they're changing electrical potentials and you can actually measure that. So that's what they mean when they're, but I'm sorry, I just got stuck on that question. Yes, we have a question.  Is age regression for real? Like in a standard world, we talk about age regression and you can go into your previous life or some of your pains can be cured through hypnosis. So what's the scientific theory behind that? So again, I think it pays to operationalize what's going on, right? So to be at the risk of being somewhat controversial, we as humans tend to scribe a lot of kind of greater causes for things and explanations for things, but ultimately we're still people and organisms and we have biology, right? So that's got to ground what we're doing in a certain way. Hypnosis has been used for a long time in different contexts and there's some thoughts that are really just research that's really starting with brain imaging to understand how different brain circuits that are especially important in attention and focus on yourself versus focus on the world are affected by these. But for pain, for example, it can definitely help. By operationalizing it and demystifying it, I think we can get more at the mechanism. Right now it's more hypotheses than anything else, but if you look actually at a phenomenon considered in that same related sphere, which is placebo, we're actually starting to understand how placebo works in very interesting ways. And placebo, by the way, for anybody who's wondering, is not nothing, right? It is actually the most powerful treatment we have for everything. And I say that without the least bit of tongue in cheek because we compare medication to placebo for everything, right? Talking about cancer treatment, HIV, psychiatric disorders, anything, we have to have a placebo, right? And oftentimes we see a little bit of a difference between our placebo and our medication. But that placebo effect is big. And that placebo effect is you're getting attention, you believe you're going to get better, and all of these things that are very biological and have a huge effect. For pain, placebo changes transmission in the brain in a way much like other drugs that you might give to relieve pain. In fact, you can quantify how much morphine equivalence a placebo intervention has. So did you show them the needle before you injected? Did you wear a white coat? Did you do all these other manipulations? You can say, well, that was eight milligrams of morphine. And this one was 12 or whatever it is and actually understand it with imaging, with all these other tools, what it's really doing. So demystifying, getting back to biology puts things in that same language, which is exciting. Someone mentioned earlier 20% of the blood supply goes to the brain. And if it goes down, let's say to 15 or 10%, then the brain faculties diminish. I guess it begs the question of what if it goes up? If it is 25 or 30%, is there a mechanism to improve the brain by improving the blood supply or the quality of the blood to the brain? Oh, that's obviously for Tony. Yeah, I think this is very tightly regulated. So you could not quickly increase the blood flow to the brain without causing a stroke or something like that. I think this is a very tight control. Now you could deliver more nutrients to the brain, more glucose maybe. The rate at which this exchange happened is dependent on how good the blood vessels, for example, are able to exchange the nutrients that are in the blood to the tissue. With age, we think that decreases, and so there may be a lack of active transport. So this is a way one could potentially manipulate that system. Let's take a question over here and then a question over there. I have too many questions, and I just recently read something about the positivity of gene mutation to spot family members who perhaps all of whom have Alzheimer's except one, and that one person has this gene mutation, which we've always associated with a very negative thing, but it now looks like it's gonna be a positive breakthrough and all that. But that's a different thing, sorry, to go back to, can I just say, without at the risk of getting a bit woo-woo here, I don't wanna do that. But somebody described mental diseases glibly, maybe, as life-intensified. And are there individuals who have traits that are intensified, that is part of their personality, that then doesn't go on to develop in a damaging way? And can that be spotted? One, two, sorry. We all inherit genes. Do you believe, I don't think there's evidence, but do you believe that we can inherit memories of trauma through generations before us? Yeah, so two great questions. So, let me just take the second question. So the second question is actually a really interesting phenomenon called transgenerational transmission of trauma, which actually does happen. It's been demonstrated in people and demonstrated in animals. So you can actually, and with people that it's a bit confounding because you have genetics, but you also have a common environment that you rear the child in, right? But actually with an animal, you can separate the animal. And so you can, this is work, for example, recently by Kerry Restler at Emory, who's shown that across multiple generations you can transmit kind of the risk that goes with having had that trauma exposure. So that's something just starting to understand that, but it's through what's called epigenetic modifications of genes, so not the code of the gene, but the accessibility of that genetic code to be read out. So things that happen to the DNA that either allow it to be read out more or less, which gate the code itself. And the issue about life accentuated, I think that it's a really fundamental kind of distinction I wanna make between what a mental illness is and what life is. So a mental illness being a physician is something that's impairing the person's function, right? Having a trait in a very strong way could be a huge advantage. In fact, most likely if you look around this room, the traits of conscientiousness and obsessiveness and some anxiety and fear and all these things are gonna be very different from the general population just because everybody here has been driven to succeed. Now among scientists I can tell you if you're not an obsessive scientist, you're not gonna get your job done. So those are traits that vary in the population and if you have a lot of one or the other, it may actually be quite beneficial to the point where it's impairing and you can't get your life lived in the way you would want to or you should reasonably live it. That's where the mental illness boundary kicks in. So we're not aiming to pathologize normal behavior. In fact, celebrate normal behavior. But it's when somebody comes and says, look, I need help because I can't get out of bed. I'm gonna be fired. I've been not promoted a bunch of times because I'm just not able to focus on my work. Sometimes, sometimes some traits are there through childhood and into adulthood and are fine and some traits put you at risk. Yeah, that's right. We have a question over here and then a question over here. Francis Collins from NIH. I wanna ask about schizophrenia. Here's an enormously debilitating and fairly common disorder affecting perhaps 1% of populations and across the world. And yet, we haven't had a new therapy for schizophrenia really in 50 years. And that seems so ironic given the way in which research on schizophrenia is moving forward at a pretty impressive pace, whether it's by imaging approaches, by genetic analysis, a recent study, 108 regions of the genome where there's variations that contribute to risk, whether it's understanding the cell biology by using stem cells and being able to take a skin biopsy from somebody with schizophrenia and make neurons out of that and see whether they're the same or different than somebody who doesn't have this. And yet the drug industry is pretty much runaway from any investments in this particular area for some time and there's not much going on there. Seems like such a great opportunity. What are we missing? How do we move that agenda forward more quickly? Given the enormous burden that people with this disorder and their families and friends sustain because it can be so debilitating and our treatments are really ineffective. So maybe we can answer this on kind of two levels. Again, I want to separate a bit of the sort of first world and non-first world or developing world. The developing world doesn't even have access to the treatments that we have in the first world. So that's where we start in the developing world. Let's take that just for a second off the table because I think you're asking really about, on a bigger picture, why aren't we making progress? If you look historically at all of psychiatry and schizophrenia is emblematic of this, we've discovered all of our interventions by chance, all of them, right? And then we've developed animal models to try to develop more drugs like that that basically are sensitive to the effects of the drugs that we found by chance. So drugs that block dopamine, for example, which is what we give as an anti-psychotic medication, if you give an animal amphetamine and it runs around the cage and acts like a mouse on speed, and you can block that with an anti-psychotic, that becomes an assay for an anti-psychotic, which means that you only are gonna find things that act in exactly the same way. You never understood the biology of the process to begin with. I think the change we're seeing now, and I actually have a lot of hope that in the next couple of years we'll start to see a lot of progress in this regard, is that by understanding things at the level of brain circuits, we can now say, look, cognition, ability to think is really important for schizophrenia. In fact, some people have suggested psychosis is not that important. It's the ability to think that is a thing that is there early, predicts outcome the best, and is very poorly targeted by current treatments. So people are developing computerized approaches at training cognition. Drug companies are developing molecules that target those functions more specifically, and the FDA has even accepted cognition as an indication, as opposed to schizophrenia per se, which is really assessed with the psychosis symptoms. So that's progress, and I think that just has to be kind of played through. The genetics has really only exploded in the past couple of years around schizophrenia, I mean really since 2011, and so that is just too early to know where that's going, but I think that for me, the moral of the story is, you take a complex disease which is probably many, many diseases, reduce it down to discrete brain systems that underlie discrete behaviors, and then there's a hope of targeting with, say, non-invasive brain stimulation, TMS, or transcradial magnetic stimulation, giving brain training, giving medications, and then best of all, combining these things because we understand what we're doing, as opposed to give one and then the other and hope for the best. Tony. Yeah, maybe if I can just add to what you alluded to, that there has been this tremendous progress in understanding genetic bases. We see changes in how neurons work in these individuals, and I think I have great hope that this will show us what is actually wrong at the molecular basis in these conditions, and as Amit mentioned, we start seeing in a number of different diseases that it's not just one type of disease, but there's variations, and that they might have different drug targets, and I think there's actually hope that pharma will see, this is a specific entity that is not the same as this other one that we used to target in the past, and so by personalizing the medicines for these individuals, you can actually start new programs which will then address diseases sort of in an individual way, and not as a big lump together where people really have not exactly the same biological disease. So let me actually present one other almost counterpoint to that, which is that there turns out to be some commonalities that are quite interesting across disorders which themselves have not been known. So we are simultaneously moving in the direction of personalizing, and I would argue asking some basic questions about what it is that that category even is. So we have a paper, for example, it's gonna come out in the next two weeks, where we just simply ask the question that nobody to my sense has thought to just ask before because the data was already there to answer it, which is, is there a common biological basis using brain imaging to all the major psychiatric disorders in adults? And so we looked at schizophrenia, depression, bipolar, obsessive-compulsive disorder, drug dependence and anxiety, and it turns out there was, and it was a single well-understood brain circuit that is important for emotion, important for cognition, and starts to identify things that exist across disorders, and then simultaneously we're taking the personalized approach to go within a disorder in a very fine way. And genetics has actually revealed the very same thing, that there's been mutations or polymorphisms that carry risk for five disorders, right? So I think we have to break our concepts to begin with of what is a disorder going back down to the individual patient, but also asking the question of the nosology to begin with, and through both of those, I think we're making tremendous progress. Well, we reached the end of the session and I'm sitting here thinking, okay, how can I sum this up? I think it's a time of actually some hope. I feel quite positive listening to both of you that this globby thing that sits inside our skulls is coming under some, even if it's not being thoroughly understood, it's being understood in enough detail to make some rather precise changes that can be helpful. So I feel pretty positive. Anyway, thank you all for coming and we'll do this again next year and see how far they've gotten. Thank you.


The dictionary of chimpanzee language Cinderella did not wear a glass slipper across of gold brings disaster to many men Can you imagine that yes ladies and gentlemen? This is Lindsay McCurry speaking I'm back with my charts and another collection of odd and sensational facts with which to regale you for a while in just one Minute and a half. We'll all be back with the proof the statements made a moment ago. So wait for us. Will you please? That's a strange noise isn't it but don't be alarmed No one here has suddenly gone to chasing imaginary dinosaur is around the studio what you heard was Charles Fuller saying he's glad to see us And who is Charles Fuller? Well, according to a newspaper of March 6, 1915 Charles Fuller was a chimpanzee who could talk so that his owner E. W. Nolton of Pasadena, California could understand him Can you imagine that said mr. Nolton when interviewed I have lately been making a dictionary of the words I found fuller uses is so far I have found six distinct words and no doubt there are others but these six I have identified Positively each one is said on precisely the same sort of occasion I think this proves that monkeys of the higher orders can converse among themselves That they can think is already proved Listen for yourself Mm-hmm That means he's hungry. He wants something to eat and that wasn't all Charles Fuller would say here are a couple more of the phrases in his vocabulary That according to mr. Nolton meant I am afraid and then In chimpanzees that is go away and don't bother me We have mr. Nolton's word that Charles Fuller could so untie knots and untwist a swing when the rope got tangled up But other chimps have done that before what made Charles Fuller unique was the fact that his vocabulary could be understood by his owner Can you imagine that? Well now comes the time for our fairy tale class today's story is that of Cinderella and the fur slipper pardon teacher glass slipper Huh fur slipper glass it's still fur and I'll prove it for you glass So I'd sit in the corner and I'll explain you see the story of Cinderella is of French origin When the translator took the story and began his work of translation He made a very odd but still a natural mistake for anyone not working in his native language in the original French version The slipper is referred to as pantouflon ver meaning a slipper made of fur VA IR is the French word for fur The translator was more familiar with the actual sound of the word there than he was with its meaning He wrote the word down as VEE double RE meaning glass So we today because of a translator's odd mistake know the pretty little fairy tale as Cinderella and the glass slipper instead of Cinderella and the fur slipper. Can you imagine that? Well, there are countless stories about the evil that follows famous jewels about the bad luck They bring to each successive owner the hope diamond for instance Well that has a history crowded with deaths of tragic episodes in the lives of its owners along that line I dug up a story that has all the character of melodramatic fiction with the added punch of being true From a newspaper dated July 8 1929 comes an item saying that the curse of the cross has been set at rest The cross is really the Mount of the Holy Cross that nestles in the heart of the Rocky Mountains of Colorado and the curse Well, listen to this in 1873 members of the Hayden Geological Survey Party were exploring in that particular region of the Rockies as they went on They became more and more odd by the grim grandeur of the scene before them and then suddenly wait wait down there Look Look at that just look at why a mountain must be over 10,000 feet easily But that isn't what I mean. Look at the side of it that cross. Yes I see it why it runs the entire length of the mountain The stem must be a crevice and across piece up near the top is another crevice just imagine a gigantic cross over 10,000 feet high why wait look here is the foot of the cross What does this look like? look like Why it's Gold this is this is literally a cross of gold The geologists stood at the foot of the great cross odd by its mighty size Perhaps they felt something of the intangible majesty of the unknown as they gazed at this masterpiece of nature They reported the discovery of the mountain and also of the gold to be found there then in 1879 two prospectors named Farley and Smith take out a claim at the foot of the cross Say this place has got enough gold in it to set us up for life and then some look at it I've been a wondering about the stories we hear about this place some folks say it's Sacred or something like that. Sure. I hear them too, but gold ain't sacred and there's play of it here for the takin Oh, come on now pitch in give me a hand. We'll clear the rubble away and then start digging in earnest Why this whole cross is filled with gold come on But did they get a chance to get the gold out? Suddenly Smith and Farley fail ill of a mysterious melody which the doctor could not diagnose Unable to work their claim the prospectors hired two men Johnson and Olson to dig the claim for them Then one day the two hired men were out on a little lake rowing Both men were drowned in the sudden squall that overturned their tiny boat Farley and Smith went back to working their claim back to the business of taking the precious ore from the cross of gold on the mountain side Then one day while they were at their cabin. How much we get out today Farley What are you watching out the window? I don't know thought I saw something moving in the brush over there Farley was killed Smith escaped and went to Australia Even going to another country didn't save him from the weird curse of doom that hung over him Or he was killed in a mine explosion in succeeding years the cross brought tragedy disaster or death to every man who scarred his sides in Search of gold then on July 8 1929 the Mount of the Holy Cross in Colorado was made a national monument of the United States The glittering yellow metal lies in the cross protected from men or perhaps men are protected from it. Who knows? And now for the musical portion of this can you imagine that I wonder how many of you remember that famous old song under the bamboo tree? Of course you do it's an exceedingly hard song to forget once you hear its catchy tune the lively sparkling lyrics and the Toe tingling swing of its rhythm, but if you remember the song I wonder if you remember the story of how it was written just in case you don't here it is It was written you may recall by two gifted Negroes Bob Cole and Rosamond Johnson, but how well it seems that Cole and Johnson We're walking uptown one evening in New York Johnson was humming as Bob Cole turned to him and spoke Rosamond, you know, that's the song we need for our new act Nobody knows the trouble I see. Oh, no, you don't Bob We're not gonna desecrate a sacred song that way. We simply can't use it now I reacted it's more than just a song to me Bob somehow it typifies our whole rage Oh, I know that but listen to me you went to the Boston Conservatory didn't you? Well, what's that got to do with a new song for a whole lot? Well, you should be able to take that song and change the melody a little and set the rhythm up a little and Have a new song I'll try it. Yep. I'll try it good Inspired by the grand old spiritual Rosamond Johnson set to work on the melody for a new song Finally finished it. Its first title was a few lack of me But when Cole and Johnson presented it to a music publisher It was suggested that the title be changed to under the bamboo tree Then the two sang it for Miss Marie Cahill who liked it instantly But when she insisted that it be incorporated into the show Nancy Brown Another snag was hit for said the composer of Nancy Brown. What put that in my show never never Let have my score ruined by that that well I refused to call it a song but the lively Miss Cahill who knew a hit when she heard it Calmly put her dainty foot down and said the song went in or she went out The song went in and so out of the past out of a race in whom music and love of it Is born came under the bamboo tree In the jungles lived a maid of royal blood though dusky shade A marked impression once she made Apollo Zulu from Matta Bulu And every morning in what he had and gently squeezed Time to turn you back to your own announcer and until we get together again for another session of can you imagine that? This is Lindsay McCurry saying goodbye now


Alright, so today I'm going to walk you through my photo sales from February. I'm going to talk about some changes to the channel, and I'm also going to talk about my new NFT project. Now, if you're new to the channel, I'm James, and I do these revenue reports every single month, so I go through and take a look at how much money I made selling my photos and videos online. If that's something that interests you, go ahead and click the subscribe button and make sure you click the light button for the YouTube algorithm. So my top site for February was Deposit Photos. Only $28, so not a great top site. Deposit Photos has been doing much better recently, so it's not surprising. It is surprising, though, that I didn't get a lot of sales on the free sites last month, so they typically are in the top set, but they weren't this past month. Next is Fine Art America. I did make two sales on Fine Art America that I averaged out to $20, so that was my second best site. Now, the third site was Pexels. So this is a bit lower than it has been in previous months. Now, I didn't upload any photos to Pexels last month, so that could be why. Although, I still, you know, typically do make higher donations on Pexels or from Pexels, even when I don't upload photos. So that was a bit lower, but again, if being a donation site, it kind of goes up and down, so not totally surprising. Now, next is Shutterstock. Bad month for Shutterstock, again. I did move up a level in their, you know, their tiered system. So for those of you that don't know selling on Shutterstock, your tier gets reset in every January. So I went back to the initial tier. I've now moved up to tier two and, you know, probably by, you know, depending on how sales go, by June, I might be up to tier three or tier four, which will start making a bit more money that I was making last year. So a really low month in February, typically February is a bit lower month from my stock sales. So not totally surprising, but this is pretty low for Shutterstock. It's been going down quite a bit recently. Next is Adobe Stock, again, a bit disappointing there, too, but still $12. This time last year, Adobe Stock was doing much better. It just seems to have been going down for me recently. Maybe I need to upload more photos there, but that is another one that hasn't been doing well for me recently. Next is Pickfair. This is pretty rare. I don't get a lot of sales on Pickfair, maybe a couple of year, but one of them did come in February and Pickfair, they give you a much higher percentage of your photo sales. So I get $8 for just one photo sale as opposed to, if you look at Shutterstock, I, you know, get $12 for 48 photo sales. So that is one of the good things about Pickfair. Though they're less frequent, you can get a higher revenue from them. Next is Smokemunk. I made one download off my Smokemunk site. Again, being my own site, I get a higher revenue, so I got that for $7. And then, you know, you can go through the lower ones as well, too. You know, pretty average here. Dreamstime had a lower month. And if you get down to the bottom, I made a revenue of about $120, which again is on the low side for me, and this is the time of year when it is typically lower February. Typically for me, things start to pick up a little bit around April, May, June timeframe because a lot of my photos are landscape photos from the summer, and they're used by companies that want to, you know, sell travel services. So with things opening up for travel, with the vaccines rolling out, I do expect that my sales will hopefully pick up a bit more in the spring because I expect that this is going to be a big season for travel companies and, you know, travel magazines, travel blogs. Everybody wants to get out and travel after being inside for so long. So as people get vaccinated and are able to travel more, I think there will be more advertising going on, which I think will be good for me from a revenue point of view. Now, for those of you that watch the channel regularly, one of the things I'll notice is the format of these has changed, right? Right now, what I'm doing is I'm, you know, doing this kind of PowerPoint presentation thing with myself in it, and typically what I would do is I have the camera in a different position and, you know, I have the revenue go down the side. I've decided to go ahead and change things. And the reason is, is because I have to spend a lot of time on editing when I do it in that format. And what I want to start doing on this channel is being able to post more videos. You know, if I look at last year, I post revenue report every year and I post another four or five videos. I really wasn't posting very often. And the main reason for that is because of time. It's not because I don't have ideas or nothing because I don't have things that I want to share. It's just because I don't have time to, you know, shoot and edit and upload the videos. And, you know, I don't really like that. And what I want to be able to do is to be able to post more regularly, maybe a couple of videos a month or even maybe one a week that might be a bit ambitious for me, given all the other responsibilities I have, but just be able to post more in general. So what I've decided to do is kind of come up with a new YouTube setup that will allow me to be able to post videos more frequently, because I'll allow me to be able to edit them much more quickly and to spend less time on them. So what you're going to notice going forward on this channel is that they will be a bit more raw, a bit less scripted, and hopefully there'll be more of them, right? So I really do want to start being able to share more of my ideas, and this is the way that I plan on doing it. Now, one of the reasons that I do want to start posting more videos is that I want to start posting more about NFTs. Now, let me just kind of talk about how I got to this place for a minute. Last year, if you watched my year in review video, you'll notice that, you know, my stock sales have been just going down year over year for a number of years now. And last year, my highest site was Fine Art America. So, you know, one of the things I looked at this year is, I'm like, you know, maybe I should be selling my photos more on the art on demand sites as opposed to on the stock sites and spend a bit less time focusing on stock, a bit more time focusing on art on demand sites. So I did a lot of investigation into that.  So I started going that round and thinking, well, maybe this should be a good idea for me to sell my photos as, you know, t-shirts and merch. So I started looking into that. I signed up for an Amazon merch account and set up for the accounts. I was doing research and investigating there. I've also looked into videos and I was really looking for ways to supplement the fact that my stock sales have been going down and just look at other avenues or other sites that I could sell my photos on and also, you know, post on these on this channel, right? So the idea was as I would go and try a bunch of these sites, see which ones were successful and I'd be able to share that with you. Now, as I was doing that, one of the things, you know, that got very popular recently was NFTs and, you know, so I started looking into those as well and looking into the NFTs, they really just excite me so much more than, you know, selling my photos as art as well as selling my photos as merch. I just think there's like a huge potential upside for NFTs. I think they are the future and so I'm going to talk about that a bit more, but one of the things that I've really noticed is that it's not easy to learn about NFTs, you know, it's such a new technology. It's such, you know, a lot of the websites are new. It's been really difficult for me to learn. I'm a pretty technical person, right? Like, you know, I'm a software developer. I can go and write code, read code. I'm pretty technical, but understanding exactly how these NFTs works was very difficult and I have figured out a lot of things over the past couple of weeks and what I'd like to be able to do is share them. So as I kind of figure out some of these things with NFTs, I'd like to be able to set it up and quickly share those items. So, you know, just to know what to expect is that on this channel, I do plan on posting more videos about NFTs as I learn more as I try to make my own NFTs sales. I'm going to be posting videos about those here on the for the channel. So on that note, in this particular video, I want to talk about why NFTs are valuable. Now, there's a lot of things you can talk about. NFTs have been really, you know, I've been in comments. I've been on Reddit talking to people about this and I haven't seen the same things come up over and over again. So I'm going to try to address them on this channel. There are things like, you know, are NFTs bad for the environment? You know, should we be supporting them because they are potentially bad for the environment? Things like the high gas fees and I'm going to do videos about those in the future for sure. But in this video, I want to talk about is do NFTs have value or is there any value in NFTs? Right now, this may seem like a silly thing to talk about considering one of them just sold for $69 million. But what a lot of people are saying is that this is a bubble and this is a fad and these NFTs are going to go away and I don't think that's true and I want to explain why. Now, I do think there is a bit of a bubble in NFTs right now, but I don't think they're a fad. I can definitely see like I've been really looking into the technology, how these work and I do think that there is going to be a huge future for NFTs in the art world as well as in the photography world. There's one of the things to note is that I was aware of NFTs and I was aware of all these sites a couple of years ago. I went back and looked at my notes. I went and looked at wearable and looked a lot of these sites and I saw all these pixelated images there and I thought, you know, this is never going to be, you know, mainstream for photographers. This isn't something I want to focus on right now. But I have changed my mind about that and I do think that photographers, videographers in general are going to be using NFTs in five years in some way or another. Now, one of the reasons around that is just because all the popularity of the NFTs in the art world and because of that, these NFTs are going to become valuable for the general public eventually and I think they probably are valuable for myself and even maybe you and let me just kind of explain that one of the arguments you'll see is that NFTs have no value because you can just download the JPEG. Okay. So, you know, why would anybody buy an NFT? If you could just get the JPEG. Now, one of the things that you need to understand though, is that value is all in the eyes of the beholder. Okay. Even money is based on the fact that it has value, even though money really doesn't have any value. You know, if you think about the currency in whatever country you're in, you can get a million dollars or a million pounds or whatever of that currency, a million euros of that currency. If you go to some spot in Asia in the Himalayans where they don't know what that currency is, it has no value. The only reason that money has value is because everybody agrees that it has value and that you can take that money and you know, you can get by food with it or you can buy, you know, a hotel room to stay. If you have a million American dollars up in the Himalayans and nobody knows what that million American dollars is, all of that million dollars is worth for is, you know, starting a fire to cook food and to heat yourself. You can't do anything with that because people aren't going to accept it as tender. Okay. So that's one of the things you really need to kind of think about is that, you know, money is only valuable because people make it valuable. Right. And NFTs are exactly the same way. They're only valuable because people make them valuable and they obviously are valuable. Now, you know, people sold at NFT for 69 million dollars. Okay. Now that was probably way too much. It was a bit of a marketing stunt. You know, there's a number of different ways you can kind of look at that, but the reality of it is, is that that NFT is now worth something. Okay. It's worth something to general society. It's probably worth something to me and it would probably worth something to you. Right. Just the fact that it sold for 69 million dollars. If someone had come up to you or people had come up to you six months ago, if you didn't weren't familiar with NFTs at that time and said, you know, I'll sell you this digital token that represents, you know, my artwork that I post regularly on Instagram and I'll sell it to you for $100. Nobody would have done that or the vast majority of people wouldn't do that. You might like his art and maybe do it at a charity, but there wasn't you. Most people didn't see value in that NFT six months ago. Okay. Now let's go to today. Let's say the say you found a way or somebody can say, you know what? I get that NFT that somebody purchased for 69 million dollars. I can tell you that one and only unique NFT. This is not a scam for $1000. I'd buy it. You'd probably buy it too. The reason is because you know that it had 69 million dollars for the value to someone else and for $1000. You can probably put it on auction and solve for $10,000. Maybe a million dollars. Okay. So something that had no value to me six months ago now has a value to me. I would value that NFT at six at $1000. Even if the only reason that I would value it is that I could, you know, sell it again later. It does have value for me. So you can already start, start to see the shift that people's perceptions and these things do have value and you can't go back now, right? Once people see something as having value, it will just have more and more value, especially when it's something that is in limited quantity. All right. This is the exact same thing with Bitcoin. Bitcoin doesn't really have any value, but millions of people have agreed that it has value. So it will continue to have value. It will not go away, right? Same thing, you know, and this is not new. This new that is happening in the digital world. It's not new that it's happening. The same thing goes with, you know, gold, right? The gold standard. If you have a block of gold, what am I going to do with a block of gold? A block of gold. I can't pay my mortgage with a block of gold.  And that's where NFTs are going to be. That's where Bitcoin is pretty much already going. You always already know that people are going to be able to sell Bitcoin for something. So that's why I think NFTs do have value. Why I think they will continue to have value and I don't think that it is going to fall away. So although there may be a bubble right now and we're probably not going to see, you know, multi-million dollar NFT sales, you know, every month in the future, I do think you're going to see NFT sales in the future. I do think they're going to become more mainstream as the technology matures and I'll talk about that in future videos. Anyways, you found this useful. Make sure you hit the like button and if you're new to the channel, make sure you subscribe and best luck selling your photos online.