It's very nice to be here. It's my first real visit to Quebec and to the city, and I've really enjoyed it. So I'll tell you a little bit about our work on multi-scale modeling and how we try to fold in different kinds of data, so neural recordings being used in the very broad sense of any kind of data that pertains to neuronal function. So let me just start with a glimpse of how I think about models. Now we have models which can be word models. So here's a very influential word model that coincidentally originated around here, Donald Hebb's model that has driven a lot of investigation into plasticity. But this is a word model. This explains what will happen. It doesn't do so in a mathematical sense. It does not do so in a mechanistic sense, though it gives some indications about where to look for these things. Here's a different kind of model. This is actually quite a powerful kind of model. This model has actually very accurate predictions about things, but clearly it has nothing at all in common with the mechanisms that the real system obeys. Here's a kind of model that we've seen at different points in this meeting, different levels of abstraction of neuronal function. So here's a very simple rate model for how neuronal computation might take place, and this is commonly used in large neural network simulations. It's used a lot in the AI machine learning kind of domain, but we're not going to go there. And then we're starting to come a little bit closer to home. There's different kinds of models which use various abstractions of the biophysics. So here's an integrated fire model. Now the way I like to broach the topic to my students is to say that there's a whole range of basic biophysical biochemical principles on which you can account for a huge swathe of neuronal function. And this relatively small set of equations, ranging from chemistry diffusion, non-spotential cable equation, Hodgkin-Oxley stuff, synaptic stuff. This relatively small set of equations actually is an excellent foundation for a huge range of models and is in fact the basis for some of the work I'll be telling you about. And you've heard about, many of the kinds of models you've heard about fall within the ambit of this set of equations. Now this is the sort of the recurring question that modelers have to address, which is how much detail do you put in and why does it matter? And since I'm going to be delving somewhat deeper into the cellular detail of what goes on, maybe I'll spend a couple of moments giving you my perspective on why the detail matters and why I think that actually worrying about things as fine-grained as molecular function is important. So let's just start with just the computational side of things. If you want to think about how a neuron performs its computation, one aspect of it is something that Yota already brought up, which is that the neuron is not simply a ball that gets inputs from different places and sums up the respective inputs. It's doing a huge amount of computation along the way. The dendrites are in fact a very effective parallel computation mechanism and you can abstract it as like a multilayer neural network as she has done or you can abstract it as I will be telling you about is different domains doing actually quite sophisticated computations ranging from information storage to pattern selectivity. So that's the P here, the parallelism. Next one, which I think is to me one of the most exciting bits is that when you start to look more closely at what's going on in a detail neuron, in a detail neuronal model, you get to see phenomena whose properties are very, very different from just the sum of the parts. This is the interesting nonlinearities that come out, properties of multistability and so on. These are emergent properties if you like, it's a much abused term, but these are properties which make the neuron do much more interesting things than simply add up a whole lot of inputs. Another thing which I've sort of grown to appreciate as I've done these models over the years is that remarkably often when you look at the details that underline neuronal function, when you look at the various channels that are there, when you look at the signaling pathways, it seems to be that nature has put in a lot of perhaps redundancy, a lot of ways of ensuring that the system works even if the conditions are not quite right. And this sort of appears, this sort of just happens when you put in more detail. To put it in other terms, you can make abstract models that will do what you want, perhaps, but will only do so in a very narrow range of parameters. And I've found more often than not that going into a very detailed model means that the system behaves correctly, in other words it exhibits the properties that you're interested in over a much wider range of conditions. And this, I think, is interesting and perhaps a natural outcome of the fact that neurons, biological systems in general have to work over a very wide range. And so when you go into the biological details, you're likely to see some of those properties emerge. Another thing which is important is that very frequently when you look at an abstract model or any model, you do so in a very, very specific context. So in other words, it will work for one set of conditions, but you change the conditions, you change the problem a little bit, and it might not do what you hoped it would do. To put it in other terms, a real cell and real neuron has to worry about not just integrating, say, synaptic input, it has to worry about neuromodulators. It has to worry about the fact that it may be affected by pathogens, it might undergo some kind of damage, and yet it has to continue to perform a function which may be somewhat modified by these additional inputs, but it still has to give a reasonable output. So real neurons are operating in a more complicated context than simple abstract models. And finally, there's the much neglected and I think much underappreciated aspect of homeostasis or housekeeping, which is just keeping the shop going, keeping the neuron alive, keeping the ATP, the channels alive, keeping the iron gradients, there is non-trivial, it's non-trivial in the extreme, and I think there's a lot of very interesting essential stuff going on at this level of computation. And this is just, so this set of things, PER perch, these five points are purely from the computational viewpoint, and if one wants to look at other kinds of domains such as disease or damage to the brain or to development, looking at these additional details, especially the molecular level ones becomes very, very important. So this is why I'm so interested in what's going on in great detail, as I'll be telling you about. Okay, so this is my flame-bait slide. This is my back of the envelope calculation, which says that actually what most people observe through electrical recordings is a small, a very small error term on what the neuron is actually doing by way of computation. And the argument goes like this, that electrical computations in the brain happen fast, they operate say on the time scale of one millisecond, but electricity propagates actually quite a long distance. The length constant is quite long, say about half a millimeter. Chemical computations on the other hand are relatively slow, though of course bear in mind that synaptic transmission is primarily chemical. But even leaving that outside our present discussion, chemical stuff is slow, but the length scale is so short because diffusion is limited that you compensate for the slow chemical calculations by having a lot of calculations going on in parallel. So you could basically say that every spine is performing its own computations in parallel. So now, in addition to all of this, or to multiply all of this, there's the fact that when it comes to electricity, there's one signal. It's the potential or the current, you know, which are, which are flip sides of the same coin, whereas in chemical signaling, you have hundreds of different pathways. And so you put all of these things together. And so in principle, the amount of computation you can do chemically is far more than you can do electrically speaking. Now anyway, so this is, this is a bit of flame bit and we can have some fun discussions on it later on. But again, it motivates some of, some of the analyses and approaches that I'll be telling you about. Okay, so what I'll do is I'll start out talking about the modeling framework that we use. I'll discuss some of the data framework and Sharon give a very nice overview of the importance of such frameworks. And then I'll just give you some glimpses of what we're planning to do with this, with these capabilities. So our modeling framework is Moose, which stands, I think I actually forgot to put in the acronym. It stands for multi-scale object-oriented simulation environment for those of you who are wondering. Here it is. Oh, I've actually got it up there. And it's open source, GPL, all the rest of it. You can download it. You can play with it. You can make your computer overheat very, very nicely with all of this. And the key point of Moose is that it was designed from the outset to be able to do multi-scale computations, that is, calculations ranging from literally molecular single molecule level events all the way up to large networks. There are two particular domains that we've been playing with in recent years. One is the multi-scale domain ranging from few molecules doing chemical computations embedded in their natural setting, that is, in the neuron in a single cell. So these calculations, which I'll tell you about a bit more, use a framework called RDesigner. And this basically is aimed at describing what single neurons can do computationally, including all of the chemical events. And then we also have a bunch of network computations that we can do, which are, and you've seen a lot of those kinds of multi-scale computations. For example, Ivan gave this marvelous talk about using really, really detailed models, even at the single cell level and then embedding them in a large network. So these are all things that one can do with Moose. So just to remind you the kinds of calculations one does, you can use your standard electrical ingredients, which are cell morphology, a bunch of ion channels. You can define these things using neuro-ML. You can define them using some legacy formats like the genesis.p format. You can define the morphology using the SWC format from neuromorpho. These are all things that the system can take in.  And this is solved using one of our numerical engines, which we call the H-solve in honor of Mike Heinz, H4 Heinz. And this can do partitioning of course from in a very wide range of levels of detail. The chemical side is actually very reminiscent of the electrical side of things. We can import a bunch of definition formats for chemical systems. What we define is a set of reaction diffusion system. And much like compartmental modeling in the electrical domain, the way you do these calculations is you subdivide the cell. You have to subdivide it more finely because the length constant, as I said, for diffusion is quite small. And so you may have to do far more subdivisions of the cell in order to accurately describe the chemical reactions, diffusion going back and forth. And then you have some set of reactions which are solved using differential equations. And you can partition this in various ways. And we have two numerical engines for doing this, which work in tandem. One is for doing the chemical kinetics, that's the K-solve. And the other one is for doing diffusion stuff, that's called D-solve. And these can do fairly large reaction diffusion systems, subdividing the cell into 30,000 or so little pieces. Each one of those pieces may, just so that you're aware of what it takes, may have a lot of reactions in it. And this is a small subset of the kinds of reactions that one worries about in synaptic functioning, for example.  And of course, things have gotten worse, if you like, since then. There's a lot more reactions that are now known and that are realized to be important for synaptic function. So we put a little bit of extra effort on the spines for a number of reasons. This is something for which, to my knowledge, there is no standard to define what spines do and how they should compute. But we have a specification within the R-designer framework, which I'll tell you about in a moment. But spines do a lot of very interesting things. I mean, for one, they house a lot of reactions, of course, and they, of course, house the synapses, they house the NMD receptors, and so on. But spines are not static structures. I mean, for that matter, nor neuronal morphologies. But spines are really very dynamic. And when you have spines changing their size and shape, that does a lot of strange things to the possible physiology, to the possible computations. For example, a spine gets bigger. Assuming that the receptor density is the same, the total receptor conductance is going to become larger. Assuming that the number of molecules in there is the same, those are going to get diluted out. Assuming that the cell membrane properties are the same, the passive properties are going to change all over the place. And something else happens, which is also actually quite a complication, which is that when the spine geometry changes, the diffusive access that the spine has to the dendrite, that changes dramatically. And all of these are the outcome. All of these changes are the outcome of some chemical event that caused a spine change in the first place. So you have all these interesting loops of scales of events happening from the chemical, electrical, and morphology. And you have to fold these all together when, especially in the case of modeling spines. There's some interesting side notes here. For example, it may be a bit surprising, it was non-intuitive to me, that it's actually faster to do the stochastic calculations for chemistry when you're doing it in the volume of a spine than it is to do standard deterministic calculations. So your ODEs take longer to run than your stochastic Gillespie algorithm kind of calculations, which is kind of nice, because when you're talking about volumes of a spine, you need to worry about chemical noise. And that's what the stochastic methods give you. And so again, you have to deal with tens of thousands of spines in some very detailed models. OK, so and this is the kind of stuff that lives in every single one of those spines and that we need to crunch through.  So we've devised something called R-Designer, and I should really have broken up that acronym. It stands for Reaction Diffusion and Electrical Signaling in Neurons. That's what the R-Designer is. And what it can do is listed over here and sort of schematized over here. But basically, you can define the somatic excitability, you can define molecular transport along the dendrites, dendritic excitability, you can insert spines in whatever positioning and spacing you like, you can address matters of spine structural change, you can define protein synthesis and turnover, synaptic input of course, and deal with diffusion and chemical signaling all over the cell. So let me give you a simple example of what you can do with R-Designer. So here's a little system where you have a cell which is excitable. It has a couple of spines on it which have some reactions in it. They have synaptic input coming to glutamate and NMDA receptors. And then there's some reaction diffusion signaling happening in the dendrite. And here's the chemical system, some bits of it are in the dendrite, that's just the calcium diffusing, some bits of it are in the spine, head, and some bits of it are in the postsynaptic density. So this is a neat little system. And what you can do with this is actually kind of cool. This turns out to be bi-stable. It's a fake system, but it's bi-stable which is kind of an interesting property, which by which I mean that it starts, if you're giving it a regular, ticking away of synaptic input at one hertz, the system will settle down to a certain low value of membrane depolarization.  So at 10 seconds what we're doing here is we're giving it a burst of synaptic input. And what that does is it opens the NMD channels, calcine floods in, and it kicks off the reaction system you see over here. And that works its way through to the camkinase 2. And what the camkinase 2 does, it translocates to the postsynaptic density, it phosphorylates, and therefore increases the conductance of your glutamate receptor. That means that every synaptic input causes a greater depolarization, and that means that more calcium will come in even for the low synaptic rate input. And so there's the phosphorylation happening of the receptor. And basically to cut a long story short, this flips it into a state where the baseline synaptic input is enough to keep the thing in a state of high responsiveness. Okay, so this is, it's a toy model in some sense because it's obviously somewhat artificial, but I think it illustrates the levels of complexity that come up when you are dealing with multi-scale events that include the chemical events, the electrical events, and it takes one line to change this to also deal with, for example, morphological change. And just to indicate what our designer can do for you, this is the entire definition file for this model. So there's a few lines here for defining the simulation, specifying the time steps for display and computation. There's a list of prototypes which include the channel prototypes. Basically the channel kinetics are defined in a neuro-ML file somewhere. There's something that defines what the cell geometry is, something that defines what kind of spine we're using, what its dimensions are, what its channels are. Then we have a small section which tells us where the spines are on the neuron, where the channels are on the neuron. And you can put in fairly complicated, here I haven't done it, but you can put in fairly complicated distributions depending on position from soma and so on. So that's the distributions part. And then in just these two lines, we're doing the multi-scale bridging. We're going from the chemical to the electrical, that is the channel phosphorylation to changing the conductance, and we're going from the electrical to the chemical, that is the calcium ion influx into the calcium concentrations. So that just takes a couple of lines. And then we deliver the stimulus which takes all of one line. We have a bunch of lines for displaying it and running it. So this is the entire definition for this rather interesting loop. And that's not all. But let me just spend a couple of moments describing what these adapter things are, because these are the core of mapping between different domains of function. What you have to do when you're mapping from chemical to electrical, for example, is that as I said, the spatial discretization of the chemical system is much finer than it is for the electrical system. So if you want to take, say, a concentration term and use that to modulate a channel conductance term, what you need to do is you need to say, actually, I'm going to take all of the concentration terms in all of the pixels, all of the voxels, that map onto the one voxel, the one segment that was used for the electrical calculation. So it has to do an averaging over a certain length scale. So that's a space averaging. But interestingly, you have to go the other way for doing the averaging in the time domain, which is that you might have some complicated but very fast electrical event, let's say the ion influx. That is happening at a much finer time scale than the chemical events are, than the chemical computations are. And so you need to now do the averaging, the summing over the finer time scale and pass that onto the chemical system. So all of this happens behind the scenes and then there's various scaling factors that one can apply, for example, to map the concentration of the channel to a conductance change. And this is all it takes, really, to map from one physical, to one domain of computation to the other. And that's how we do the multi-scaling. So just to give you an idea of the kinds of complexity we look at, so here's the simple model that you just saw. It has six electrical segments, four ion channels, two kinds of receptors, some 60 chemical voxels, and eight or so reactions. The more complicated version over here, significantly more complicated version, has got a full neuronal morphology, suitably subdivided into lots and lots of spines, lots of ion channels, and much more complicated reaction scheme. And the key point is that to do this, to go from one to the other, you need to change three lines. You need to change one line which says, this is the morphology. You need to change one more line which says this is the chemical system. And you need to change a line which says that this is how you're going to deliver the stimulus. And that means that this short snippet of, this not snippet, this entire program that defines this reaction diffusion, this multi-scale system, can define this simple model here, as well as this complicated model here. And that I think is a very nice way of using the modularity of standards. That is we take some standard definition for morphology, we take some standard definition for chemical systems, and it's up to now the software to package all of these and make them work together. Just, I'm sure this is of interest to some of you. That is the speed question. How long does it take to run these things? Well, the simple model runs significantly faster than real time, which is nice because very often chemical type experiments, such as LTP experiments take half an hour to run. Unfortunately, unless you do parallelization, the big thing runs a lot slower than real time. And it's kind of interesting that the rate-limiting thinger is actually the electrical computations because you have to run electrical models at a much finer time step than you have to run chemical ones. So adding the chemistry doesn't actually slow it down that much. You can have a really, really complicated chemistry in a model of this size. Okay, so that's just an indication of what you have there. Okay, so that was the modeling framework. And now I'll tell you a little bit about how we parameterize and get the numbers into such a system. So you've already heard about various data frameworks. The BlueBrain project had a very systematic way of building up their parameters. You also heard about the Allen Institute's framework for defining specific kinds of experiments and having them in their database. And so we've also developed a database and it actually bears some resemblance to something that Sharon talked about. How do you define a set of experiments and map them onto a set of simulations? So the basic idea is that we have our model. For example, it could be defined in SPML or it could be defined using RDesigner. We have a stimulus that was used in an experiment. So they put it in a slice in a dish and they zapped it in some way or they poured some chemicals on it. And then you have the expected outcome. You had what actually came out of the experiment. So we define this in what we call the fine sim format. And this is basically, at this point, it's simply a table format which allows us to unambiguously specify all of the inputs that go into this calculation. And that feeds right into Moose, which does everything that needs to be done and you'll see a little bit more about that. And that gives you a readout and then you can compare that with what the experiment actually got. And that gives you a score and you can do all sorts of things after that. You can optimize it. You can decide whether or not you believe this experiment and so on. So this is the pipeline that we employ for this system. One important design decision that we had to make here was how do you define what is the model on which you will base everything else? So one way of doing it might have been that for each experiment you have a model and you try to find a way subsequently to put them together. We felt that instead we'll have a reference model which has all the pieces in it because the interactions between the pieces are actually also fairly involved. So here's our reference model up here in panel A. And for a given experiment which might only involve a small subset of pathways, it might be in a test tube and only involve a few molecules, what we do is we sort of trim away the excess and just focus on the parts which we are interested in. So this is the rough pathway that we're interested in for this experiment and just zooming in over here. So we trim away all of the other bits, all the bits there and there, focus on that. And even within that there's some bits that we drop out and then the system cleans up all the loose ends and it runs the simulation just for that bit, just for that experiment. And then you can specify all the necessary aspects of the experiment. It turns out that it's actually quite, there's a common subset that seems to account for many, many things. You define what kinds of readouts you want, these would be the results, so you could have a dose response curve, some kind of bar chart, you could have an action potential coming out of a current clamp experiment and so on. And then you run the simulation, get a score out of it, you can do different kinds of fitting, you can use this for optimizing it. And in the end though, it comes down to scientific judgment to decide how much you trust this experiment, how much weight you want to give it. We have over the past few months built up a database of experiments and this is something that we keep expanding. I think there's some, at this point there's some 70 different experiments with each of which can constrain the model in different ways, looking at different pathways. The model at this point, version 0.9 something has got roughly 300 molecules and 200 reactions in it and it draws on data from many, many sources. So that's the framework in which we are working to get decent models. So let me just end then with what we're hoping to do with all of this. So let me get back to my perch acronym here. So P, we've been analyzing parallel computation over the cell. And so here's the, here's our sort of a monster model which has got all sorts of horrible things in it. It was morphology from neuromorpho, some 5,000 spines, a huge reaction set in each spine, background synaptic input, the works. And this is just a picture of it. All the little blinky lights which you may or may not be able to see are synaptic input coming in randomly at background except it's not totally random. Somewhere embedded in all these blinky lights are certain sequences of input. And the parallelism comes in because the cell is, this is our interpretation, is in parallel able to monitor whether or not there is a sequence of input, a sequence of activation coming in in any particular end right. You could also argue that the cell is in parallel at every single one of those synapses assessing whether the pattern of inputs is such that it should engage in synaptic plasticity. So that's parallelism. Here's an example of emergence. So this is a very old study that we looked at where the emergent property was that of bistability. So you have a feedback loop, a chemical feedback loop in this case, and that is interesting as a switching function. Here's another kind of emergence. We were looking at sequence selectivity and basically what we find is that with the right chemical system in place, if you follow a synaptic input that comes in successive locations along at end right, you get a strong response, but if it comes in a scrambled order, as in this case, so it sort of jumps from there to there, the net result is very small. So here are examples of emergent behavior that is happening at the biochemical and electrical interface and is able to do an interesting computation. We're also using this for some disease models. We're making reference models to the extent that we can get the data for healthy neurons and we're comparing them with experiments done in fragile X models, mouse models of mutation. And this is a consortium effort and we're actually very keen to bring in other people who are interested in such efforts. So these are models which look very closely at the chemical signaling events that underlie these diseases. Okay, so to summarize, there are very many important problems in neuroscience which require models that actually pay a lot of attention to biological detail. And these typically span many scales, electrical and optical, and you can get data from them from interesting new recording techniques that you heard about in the morning. You can look at chemical reporters and you can look at morphological change. These are all inputs that you can give to these analyses. And we've developed tools to run these and parameterize these and analyze them and we're hoping to build up collaborations to work on these. So there we are. This was the framework for modeling, for the data handling and analysis and what we're planning to do with it. And these are some of the crew who have worked on the project. Thank you. Thank you, Upi. Any questions? Please use the microphones.  Like incorporating temporal and spatial scales, I think that's in there and chemistry as well. So why would I use moves instead of neuron? Neuron can, in principle, do some of the chemical stuff, but it would be painful in the extreme. And I don't think it at present can do the stochastic calculations, though that may have changed recently. I think it can. Yeah, but it would not be fun. Very nice. Yeah, so some of the, you kept emphasizing the chemical aspect was very slow, but obviously there are some very fast chemical reactions. And so I was wondering whether things like calcium binding to synaptotechement, for example, whether you can run your chemical reactions at different rates to take into account the spectrum of kinetics of the chemical reactions. So that happens sort of automatically if you're using the Gillespie algorithm. So if this is happening in the spine, then the different rates are partitioned without you having to do any further effort. So are you using mostly the stochastic approach? In the spines, that's what we're doing. For the dendrites, the volume is large and so the Gillespie method really gets bogged down. So there you have to use a deterministic method and there one needs to deal with stiffness of the kind that you're describing. We are currently using a Runge-Kutta method to get very technical, but there are some nice implicit methods that would address the point that you bring up where the fast things can be handled cleanly even though there's a lot of most of this happening slowly. Okay, just one related question, which is if you have a low copy number in the spines of the proteins that are interacting, does that cause any problems with the adapter approach? Because doesn't that depend on sort of averaging and well-mixed? I mean, we can get you the technical details, but what we do is when we're dealing with any interface between the spine and the dendrite where you're doing stochastic versus deterministic calculations, then you need to do actually probability-based judgment about whether the real value should give you plus one or minus one on the stochastic side and vice versa. So we have worried about that and we've taken it into account. So this may be a slightly naive question, but can your modeling framework sort of deal with gene transcription sort of level things? So it's easy to implement gene transcription in our molecular framework. It's not very efficient. There's other more efficient ways of doing it, which we haven't yet done, partly because we've not really had the use case to do so. But of course, there's an enormous amount of transcriptomic data coming out now, which might be very relevant. So I think, I mean, for now it's easily possible to do it in the chemical framework. It's just not the optimal way of doing it. So I have a question. So the title of the session is standardization in multi-scale modeling. So I understand that our designer is based on runs on moose as the backend, but it looks in principle, it could also be available on Neuron, for example. How much work would be to implement our designer for Neuron? I suspect it would be a lot. It was a lot of work for moose, and moose was designed to do this sort of thing. In Neuron, the chemical stuff has been added on by Tom Morse and others as a subsequent effort. But it could be done. I mean, it's a technical exercise. I think that what we got from our designer exercise was an appreciation of actually how simple it could be to define a really complicated model. That is, we've been able to do it in just a few lines, and there's no real reason why it should be why you need more information to do so. And this is something which you can probably also define this set of things in Neuron, too. There, that does have a fair degree of flexibility. But in all these things, my experience is you first have to have an implementation that shows that it can be done, and then you can figure out how to do it in a clean way. This is not, this is Python, right? So this is not perhaps the optimal way for defining a model. But it shows you what is needed. Any more questions? No, I just have a question about the spine granularity. So we know that many molecules in spines are, for example, either synaptically localized in the membrane or perisynaptically localized like M-glue receptors or lipases. Yeah. Which actually, that organization is really critical for function. Yeah. So can you model that, or do you model that, or do you take right now the spine as one entity? So we can model that. We don't do it yet. Currently our subdivision is we have the postsynaptic density and we have the spine bulk and then we have the dendrite and of course so many other things and so on. But it's not a big step to add additional relevant compartments as the need comes up. Okay, could we have the next speaker please? Jason Sheffey, is it here? And then we'll get to that, any more. Yeah.


Yn y gallu, dyma'n ymlaen, roedd ychydig i mi i ddim i'n gweithio. Rwy'n meddwl oncologist ac rwy'n meddwl i Cambridge, gyda'n y profiad mewn meddwl oncologi, ac rydyn ni'n cydnig i'r cantor ni ac rydyn ni'n cyntaf arill. Rydyn ni'n helpu i'r rhaid i'r gweithio clinical ar y cantor ni'n cydnig i Cambridge. Rydyn ni'n cydnig i'r cantor ni arall, o'r wneud o'r dechydau iawn. I was involved with the initial development, particularly of seraphonib and then some of the other drugs involved. Yes, I'm presenting a summary, if you like, and my view of the data that will affect the choice of first-line treatment recommendations for patients. So, I think there are a number of things that I'd like to cover in this. The first is that we've had a generation of agents—synitonib, seraphonib, pazoponib—which are very similar to each other, they're what we call multi-targeted tyrosine kinase inhibitors. They target angiogenesis, new blood vessel formation, which is very important in kidney cancer, and they do it by hitting a receptor called VEGFR2 and another number of other receptors. So, I think they're more similar than initially we first thought. So, we have very effective ways of controlling the kidney cancer with these agents for between 9 and 12 months nowadays with the existing first-line agents. The data that I'm reviewing at this conference is comparing two of those agents—synitonib and pazoponib. The bottom line is that in effectiveness terms, they are pretty similar. We couldn't see any statistically significant difference between them in a large study. Those data are presented by Bob Mox's data originally, presented by Camilo Porter at this conference. The other data I'm thinking about are what I would call the second generation agents. These are agents which are also similar to synitonib, seraphonib, but they are more potent at hitting the key target, and they are much less potent at hitting the targets we don't want to hit. So, this is trying to give the idea that we have on-target things that we do want to do and off-target things that we don't want to do, because they cause side effects without benefit. So, the second generation of agents like tyvosynib and axitonib do cause side effects, but they cause on-target side effects—things like high blood pressure, things like dysfonia, so you can get a hoarseness of the voice. Why that's on-target? We're not sure, actually, but we do recognise it with all these agents, and it correlates with how potent the agent is. Another thing sticking with the neck is that it can tone down the thyroid glands and hypothyroidism. We would consider all of those to be on-target effects. Examples of off-target effects are things like the skin rash, the hand-foot syndrome that one gets, the diarrhea. We think those are off-target effects, and another one, which is important, our liver function test abnormality. So, it's a question of balance between the side effects on the one hand and the effects on the other hand. Now, when we're comparing data from the COMPAR study, which compares sunatonib, which is our existing standard of care with posoponib, which is a very similar drug, but used in a slightly different way, we find that in effectiveness terms, there's really nothing between them. There's no statistical difference between them, but what there is is that patients seem to prefer the posoponib. So, these are from a separate study called the Pisci study, where patients were given first one drug, then the other, and asked, which did you prefer? And neither the patient nor the doctor or the nurse knew what treatment the patient was getting. And 70% of the patients actually said they preferred posoponib compared to 20% saying they preferred sunatonib. So, it's not 100-0. Not everyone could choose between them, most people could, but most people who could choose chose posoponib. We didn't see such a clear distinction in this COMPAR study. The purpose of the COMPAR study really was to check that you weren't swapping slightly more convenience and slightly fewer side effects for much less effectiveness, because I think that's a very difficult thing to square then. So, I would say that the bottom line of those data of importance today is that for most patients who have no liver problems, most patients would probably tolerate posoponib a bit better, it would be a bit more convenient, it would be a bit easier just to include it in your normal day. But I think that sunatonib is still a good drug and will still be better for several patients. Now, in certain parts of the world, you'll be able to get both drugs. In the part of the world I come from, you'll probably have to choose one or the other. So, it may be more important data in one respect for me in that it helps me if I've got one shot, which shot do I offer the patient. So, those are the data for today. There are also data for tomorrow, if you like, which I don't think are quite ready for prime time yet. The most advanced data are with a drug called tyvosanib. That's one of these second generation drugs, highly potent, highly specific. And that was compared with seraphonib, which was, I suppose, meant to be a drug which is easy to beat. Interestingly, we are much better at using seraphonib now. We recognise how to use it better. And so, the results we're getting with seraphonib are really in exactly the same ballpark as the ones we're getting with sunatonib and posoponib. Interesting. I wouldn't say that's really established it as a first line of care at all. But in this study, tyvosanib was found to have a longer period of controlling the disease just over a year. It's the first time we've gone over the year mark for patients who've not had treatment before. And apart from these on target effects, tyvosanib was otherwise pretty well tolerated. So, we are getting hypertension. We are getting dysfonia, the changing of the voice, and we are getting toning down of the thyroid gland, all of which can be coped with, particularly the blood pressure, hypertension and the thyroid gland. The dysfonia is trickier, actually. Although it sounds least serious, you can do less about it. And so, for some patients, this is irritating. From my experience, it's not terribly irritating, because it does happen with the other drugs as well. It tends to happen a bit more with these highly potent agents. So, I think tyvosanib, you could say, well, it's a good drug, it should be available immediately. And in fact, the company has applied in the US to use it. And I think that would be a reasonable thing to do. So, for somebody where quality of life is the number one consideration, and that's certainly in my practice in the United Kingdom quite a lot of patients, I would say tyvosanib is quite an attractive option. Other patients would feel efficacy and long-term survival at best, and we don't have those data reliably. In fact, interestingly, this study was mainly done in Eastern Europe. About 80% of patients came from Eastern European countries, where the situation is very different from the US. Often no effective treatment is available outside a clinical trial. So, in this trial, patients who got tyvosanib were able to go on to tyvosanib after that drug failed, after tyvosanib failed. But the same was not true, or the opposite was not true of patients who were allocated to tyvosanib. So, after tyvosanib, most patients didn't get any other treatment. And that is one plausible explanation for why patients in the tyvosanib arm going on to tyvosanib survived longer. So, there is a significant difference there, but the data are early. And I think although the explanation I've given is plausible, just because it's plausible doesn't mean it's the right one. And I think we have to say that that is a caveat. My own feeling is that we can get a little bit bound up in detail in oncology, but I think this is quite an important distinction. I don't think we need another phase 3 trial to show that tyvosanib causes the same, or helps the patient to live for as long as, shall we say, pysopanib or sunitanib, because I think that's going to take another three or four years. So, I don't think we need another phase 3 study to compare survival, but I do think we need some data to show that the results we're getting for patients with tyvosanib are very, very similar to those we're getting with sunitanib. So, I think those are data for tomorrow. And the other data for tomorrow will, I think, be available sometime at GUASCO next year, are with acsitanib. So, there is a first line study comparing acsitanib and other second generation with syrhaffanib, the drug that everyone wants to beat, because it's meant to be the weakest of the available options. So, I am expecting that we will have data for that drug as well. And I think those could be very persuasive data, and the importance of those would be that acsitanib could then be brought forward as a first line option. And I think that depending on how good those data are, that may well establish acsitanib as the agent of choice in the US, where it will be available first. In Western Europe, that would be much slower. So, if you like, in my view, pyzopanib has a period of time in the sun, but then there are new agents coming down the line. And the very last comment I want to make is that this is not the end of the story. I think we're very close to achieving all we're going to do with single agent tyrosine kinase inhibitors. But at this conference and other conferences, about new immunotherapies, new targets for drugs, we're going to get adjuvant therapy data, all of which may cause major benefits for patients in the years to come. And I think this is a really exciting prospect where hopefully we will be controlling disease for much longer. And of course, the golden chalice, if you like, is to get rid of it all together. I think there are two questions that everybody should ask their doctor when they get this sort of news. And the first is, can you tell me exactly what's wrong with me in my kidney and elsewhere in my body? Because that's going to determine what some of the treatment choices are. And I think that you do need to know these things if... And I say if, not because I'm a particularly patronising person, but because not everybody wants to make their own decisions. Other people want to listen to what the doctor, the nurse, their primary care physician suggests and do that. Other people want to be very involved in the decision. If you want to be very involved in the decision, then there are some basic things you need to know. The first one is, where is my disease? What is my disease? And what other problems do I have? Those are all important because they will tell you, or they will tell your advisers, if you like, what treatment options you theoretically have. So, for example, if the disease is limited to the kidney, surgery is going to be your best option. What kind of surgery? If you have disease in different parts of your body, is surgery really an option? No, probably not. It might be in a few cases, but usually not. So what treatments are available? Am I fit enough for them? What are the pros and cons of each of those options? So, I think the second thing to ask is, what are my treatment options, given what you just told me about what's wrong with me, and tell me the pros and cons of each of them, please? And the last thing I would say is, there are very few decisions in kidney cancer which need to be made on the spur of the moment. Much, much better to take your time to reach a decision not necessarily that you're happy with, it may not be a happy situation, but the important thing is to make the best decision for you. You must be satisfied with the decision and the reasons you've reached that decision. And if you're in two minds and you want to be guided, then ask for that guidance. And there are people who can guide you. The nurse specialists who are helping you are often extremely helpful at putting it in the right language rather than the medical jargon that I and others often use. You need to understand the issues if you want to make the decisions. And most doctors and I think most nurses would like most patients to have a part in the decision even if it's not the whole part but a significant part. It just makes life much easier. You will do better in my view if you feel that the decision is something you can live with. Yes, the importance of asking questions is it's important at the time that you understand what you're told. If you don't understand what you're told, that doesn't mean you're thick. It means that you just don't understand what's been told. So we all break into jargon at times. Do please clarify things which are not clear. You are not wasting our time. It's one of the most important parts of medicine to make sure that you are communicating properly with the patient. And actually for me it's much easier for somebody to say, hang on a second, I didn't understand that. Then for me to whitter on at length and then ten minutes later work out that actually stage A wasn't understood so everything else that I've been going on about hasn't been understood either. So please, please, don't feel embarrassed. We are there for you. You're not wasting our time. Much better to interrupt us.


Amen. Keep your place there in 1 Samuel chapter 16. We're going to be there throughout the sermon in that area of the Bible talking about this story of King Saul. So what are we talking about this morning? So we're in our emotional series and what have we been talking about? We've been talking about different emotions that we go through in our lives and how to handle these emotions. We talked about anger in the first sermon. We talked about how there is a time to be angry. A lot of times the Bible says that there's a righteous anger. Jesus himself got angry. But we're not to be quick to anger. The key with anger is having that righteous anger for the right reasons and also not being quick to get angry. Then we talked about fear. We talked about anxiety last week. We talked about how there is a time to be fearful and what we should be fearful of. And it's pretty simple with fear. We're only supposed to fear the Lord. That's it. We're not supposed to fear man. We're not supposed to fear what's going on in this world. We're to fear the Lord. That's it. It's pretty simple. So there's a time for some of the emotions that we're talking about the last couple of weeks. But the emotion that we're going to talk about this morning is not really a time that you can say that this is a good thing. So we're going to talk about depression this morning. We're going to talk about depression. Depression? I was actually pretty surprised when I started looking up numbers on things, especially now. Depression in the country has gotten way worse than it was in previous years. Imagine that. Most of you probably are thinking that that's not a surprise. But depression is a huge problem today amongst Americans. It's about between the age of 12 and 30, there's about 12, one in 12 people suffer with major depression. And what major depression is, look, first of all, let me just give a disclaimer. I'm not a doctor. I just play one on YouTube. So I'm not a doctor, but here's the thing. Depression, major depression, we're going to talk about this morning, is defined as someone that goes through a two week period where they are just so down that it affects their actions, it affects how they can live their normal everyday life. So 80% of these people that go through this depression of this one in 12 people have difficulties performing everyday tasks because of the depression. So it's not just the point I'm trying to get, is this depression, this thing that we're going to talk about this morning, it's not just a feeling. It's not just you're down. It actually affects the way people are living their lives and prosecuting their everyday lives. And I can guarantee you that with coronavirus, because with the whole thing that's been going on this year, that with the numbers that you've seen from like substance abuse and all these types of things that you will find that this one in 12 has gone is skyrocketed. I guarantee it. So look, it's a big deal today. That's what I'm trying to say. And I want to give you this morning, I want to give you some troubleshooting tips from the Bible on how you can handle depression in your life. You say troubleshoot. I'm going to give you a methodology this morning on handling depression. You say, what do you mean by troubleshooting? I mean, we're going to isolate problems and we're going to eliminate possibilities is what we're going to do this morning. That's what troubleshooting is. You're isolating things, you're eliminating possibilities and you're looking for what? You're looking for the root cause of a problem. You're not looking for all the effects of the problem. You're looking for what's actually causing the problem. So I'm going to give you some tips, a methodology this morning on how you could narrow down, if you're depressed or suffering from depression, how you could narrow down the root cause of your depression. I mean, wouldn't you want to know what was causing the actual problem if you had a problem like depression? So what we're going to do is we're going to first study this story about King Saul. We're going to first study this story and see what we can learn from this story, turn back to first Samuel chapter 10. And let's kind of begin with King Saul. Let's look at when King Saul was chosen as king. So of course you remember the book of the judges in the Bible, you know, it was about how God sent judges to free the Israelites, to judge the Israelites, to lead the Israelites, you know, out of captivity, you know, to get them right. And then the people they just saw too many of the heathen nations around them everybody's got a king. It's like we want a king too. So they wanted a king and God gave them a king. God chose a king for them. And this king was King Saul, the very first king of Israel. So Saul is anointed king. Look down at first Samuel chapter 10. Saul is anointed king. And then he's told to go and meet with these prophets. And the Bible says in first Samuel chapter 10 in verse number five. And the Bible says after that thou shalt come to the hill of God. This is Samuel. Whereas the garrison of the Philistines and it shall come to pass when thou art come thither to the city. He's giving Saul direction here. And thou shalt meet a company of prophets coming down from the high place with sultry and a tabaret and a pipe, musical instruments and a heart before them. And they shall prophesy. And the spirit of the Lord will come upon thee and thou shall prophesy with them and that and shall be turned into another man. And then look down at verse number nine. So Saul's been anointed king and then he's being told by Samuel to go and do this thing. And then it comes to pass in verse number nine. And the Bible says and it was so these things happened that when he turned his back to go from Samuel, God gave him another heart and those signs came to pass that day. And when they so now he's been given another heart kind of sounds like he was born again here. Right. So this is where Saul King Saul he's been anointed. He goes. He gets saved. Look salvation is the same throughout the entire Bible. It's not some mystical thing. It's always been the same. Okay. Saul gets changed. God gives him another heart and those things that came to pass that day. When they came thither to the hill behold a company of prophets met him and the spirit of God came upon him and he prophesied among them. Turn to Acts chapter 19. So what's this all about where the spirit of God he's he's gotten saved. Now the spirit of God has come upon him. Look at Acts chapter 19 and verse number six. Acts chapter 19 and verse number six. So we're going to look at a New Testament equivalent of what has happened to Saul where the spirit of God came upon him. And if you look at Acts chapter 19 and verse number six the Bible says and when Paul had laid his hands upon them, the Holy Ghost came on them and they spake with tongues and prophesied. So this is also like you know the day of Pentecost where you know the spirit of the Lord came upon them and they spoke in all these different languages and were able to preach the gospel. So the spirit you know the Holy Ghost coming upon them in Acts chapter 19 and many other parts of the books of Acts is the same thing that happened to Saul when King Saul when the spirit of God came upon him and it's interesting because the same thing happened right. The spirit of God came upon him and he prophesied right. That's why you know you can be you know we're all sealed by the Holy Ghost right. When you get saved you are sealed you know Ephesians one says you are sealed by the Holy Ghost. You are sealed by the Holy Spirit.  You know you say great things for God. You're filled and you prophesy right. You prophesy right. You know I pray that I'm filled with the Holy Ghost when I'm preaching. I pray that the Holy Ghost would fill me and then I would able to say the right things and not say the wrong things you know and I pray that that happens before every sermon. You know I would pray that the Holy Ghost would you know fill me so I could say I could prophesy great things. So this is the New Testament equivalent. I want you to see what the Spirit of God coming upon Saul and then he prophesies what that's all about. All right. Now turn back to 1st Samuel chapter 15. So of course now Saul's become he's he's saved. He's the king. Here we go. He's the first king of Israel. You know it doesn't take long for king Saul to get filled with pride and he gets rejected from being king. Okay. He gets fired from the job. So he doesn't obey. He was supposed to go destroy the amicolites and he doesn't do it. He also you know one time he doesn't wait for for Samuel and he sacrifices himself. He's just doing these things that are just disobeying God and then when Samuel calls him out on not following what God told him to do with amicolites he does not admit fault. Look at 1st Samuel 15 in verse number 26 and the Bible says and Samuel said unto Saul I will not return with thee for thou hast rejected the word of the Lord and the Lord hath rejected thee from being king over Israel. So this is after you know Samuel points out you know he's like why did you not destroy all the the animals and why did you not destroy everything? He kept the king. He didn't kill everything like he was supposed to.  He said the people wanted to do all this. He doesn't take responsibility and then in verse 26 Saul basically tells him that the Lord has rejected you from being king. Okay so look look at 1st Samuel chapter 16 the chapter that we read. So now we've been brought up to the chapter that we just read and you know David has just been anointed king. So God you know replaces Saul. Saul is still the king but he's been replaced by God. As far as God is concerned Saul is done and David is now the king. So now we have a little bit of a political conflict of interest.  So this is an issue right. So God is is basically he's removing his favor from King Saul and he's he's moving David into the position. Look at 1st Samuel 16 in verse number 14. God wants Saul out at this point. Because why? Because he's been rejected from being king. All right so he's chosen David and he's trying to or he wants King Saul out of the position. Look at 1st Samuel chapter 16 in verse 14. But the Spirit of the Lord departed from Saul. So this is you know an interesting statement right here the Spirit of the Lord departed from Saul and an evil spirit from the Lord troubled him. Now this used to confuse me right here when I first started you know reading the Bible and studying the Bible. I mean an evil spirit from God. What is that all about? All right turn to Judges chapter 9. Let's look at this idea of this evil spirit from God. So we see that the Spirit of the Lord Paul or Saul is no longer filled with the Spirit of God at this point. It's been removed from him. He didn't lose his salvation. He's just no longer filled with the Holy Ghost. God has removed his spirit from him in that sense and then he's replaced it with an evil spirit from the Lord. Now remember first of all when the Bible says an evil you know God was going to do evil or God repented from the evil that he was going to do to Nineveh. When that word evil is used in that sense it's talking about hurt. It's talking about trouble. It's talking about judgment. Okay so it's talking about you know God you know wanting to judge a situation. He was going to do judgment to Nineveh. He was going to do judgment to Saul here. All right turn to Judges chapter 9. Look at verse number 23. We see here you know a bimilech. You know we've studied a bimilech. We see a bimilech. He did an evil thing. He killed all of Gideon's sons and then the Bible says in verse 23 then God sent an evil spirit between a bimilech and the men of Session and the men of Session dealt treacherously with a bimilech. So here this is another evil spirit from God. Okay look at go turn to 1 Kings chapter 22. Let's look at another another example of an evil spirit from God or a bad spirit from God. So in 1 Kings chapter 22 we see the story of Ahab and Jehoshaphat. Ahab is trying to convince Jehoshaphat to go to war with him. Ahab of course is a wicked king and Jehoshaphat is a good king of the you know the lower kingdom of Judah and he's trying to get you know Jehoshaphat to join forces with him and go to war and this is when Micai you know Jehoshaphat you know says hey don't you have all these prophets came and said to Ahab you know you're going to do great and you're going to win the battle and they're just lying to his face right. They're the yes man and Jehoshaphat sees right through it. He says do you have a real prophet here? Is there a real prophet around here?  So but the point is look at 1 Kings chapter 22 and verse number 21. The point is that God wanted Ahab to go to battle. God wanted Ahab to go to this battle and die okay and look at verse number first Kings chapter 22 and verse number 21. Or look at verse number 20 where the Bible says in the Lord said who shall persuade Ahab that he may go up and fall at Ramoth Gilead and that one sent in this manner and another one said in that manner. So God wants him to go.  He wanted to remove Ahab and then there came forth the spirit and stood before the Lord and said I will persuade him. And the Lord said unto him where with? So the Lord said unto him you know how and he said I will go forth and I will be a lying spirit in the mouth of all his prophets and he said thou shall persuade him and prevail also go forth and do so. So all these prophets that told Ahab that he was going to you know win the battle and you remember you know the prophet that made the horns of iron he's like you're going to be like these horns of iron you know and you're going to just win the battle and all this. They were influenced by this lying spirit from where? From the Lord. Okay because the Lord wanted to pronounce judgment on Ahab. Now look Jehoshaphat when God's judging somebody you don't want to be standing next to him.  The prophet said to Jehoshaphat so look if this is just another sermon in itself if you got somebody who's a wicked person and doing all these things first of all you're not supposed to fellowship we're supposed to be separated from all that but look the thing is God's judgment is coming down on somebody you don't want to be standing next to him. I mean Jehoshaphat he almost died. You know there was a saying right close only counts and horseshoes and hand grenades you don't want to be standing next to somebody who's being judged by God when the hand grenade goes off. Okay when the tactical strike comes down on that person from the Lord you don't want to be standing there. Jehoshaphat almost died. All right turn back to 1st Samuel 16. So we see that this is I mean this is a method that God uses to judge people by sending so basically this evil spirit from the Lord is one of God's angels that goes to perform judgment on somebody for the Lord. Okay it's not a it's not a demon it's not something like that it's someone doing a task that the Lord wants done in that case. Okay look at 1st Samuel 16 in verse number 23. And it came to pass when the evil spirit from God was upon Saul that David took in harp and played with his hand so Saul was refreshed and it was well and the evil spirit departed from him. So I mean David was a musician and this is just another really interesting point and one of the guys actually preached about this on Friday night but Saul was troubled. God removed his favor he removed his filling spirit from Saul this is what happened. Saul rebelled against the Lord God rejected him from being king he removed his spirit from it didn't mean he wasn't saved anymore he's under the chastisement of God now and God sends a troubling an evil troubling spirit on him and it just makes him this I mean you see if you read the story of King Saul it makes him this just depressed this this angry person all the time I mean he's trying to kill people he's he threw a javelin at David he tried to kill his own son I mean he just became you know this troubled individual and but it's interesting because he was troubled by this spirit and what helped him what helped him turn to Ephesians chapter 5 and this isn't what the sermon is about but it's also helpful okay look at Ephesians chapter 5 and verse number 18 Ephesians chapter 5 and verse number 18 this will just show you this this verse in 1 Samuel 16 23 it shows us the importance of the right type of music of the right type of music look at Ephesians chapter 5 and verse number 18 and the Bible says and be not drunk with wine wear in his excess but be filled with the spirit so we can be look we can be filled with the spirit it's over and over and over again in the Bible right and it says if you're drunk with wine if you're in sin you're not going to be filled with the spirit Saul was not filled with the spirit anymore okay so you're if you're saved you have that earnest that down payment of the Holy Spirit that seals you but you can also be filled with the spirit okay but then the Bible says in verse 19 speaking to yourselves that means speaking amongst ourselves in Psalms and hymns and spiritual songs singing and making melody in your what in your heart to the Lord so this I mean music goes to your heart the Bible says and while in first Samuel 16 23 it talks about how that music that David played it it calmed Saul it made him it made that troubling spirit that evil spirit depart from him it made his heart better those spiritual songs those Psalms those hymns that David played it made you know but look it works the opposite way too it works the opposite way too I mean there's a reason that all these violent you know you know kids they go and like murder a bunch of people are listening to like all this death metal satanic music I mean there's a reason for it because it affects your mood it affects your heart it affects the way that you think it affects the way that you feel just the way David's music affected Saul in a good way music of the world that's out there can and can and will affect you in a bad way and I mean it can depress you it can depress you so go back to first Samuel chapter 16 we see that Saul is he's troubled he's depressed at this point so he hires you know David to he has David play this music for him to so he can feel better okay so what but what were the causes of this evil spirit what were the causes of Saul's problem because look the the music is just a it's just a fix for that but it's not the I mean it's not fixing the cause of the problem go back to first Samuel chapter 16 first Samuel chapter 16 first say I'm going to turn there myself first Samuel chapter 16 so let's look at the root cause here because the bible says that I think I've got the wrong verse listed here I think I'm in 15 yes go back to 15 there you go I had a mistake and I caught it during the sermon I'm getting better at this okay first Samuel chapter 15 and verse number 23 this is after you know Samuel is is currently rebuking Saul he's currently rebuking for not destroying the amicoites and he's telling them he's telling him look it's a big deal he's saying you know it's not that you just you know just missed a command from the Lord by him you not admitting that you you literally I mean because he said you know you didn't listen to what God said and he said instead you know you basically said you still you did what God said and you didn't and then in verse number 23 he says for rebellion is as the sin of witchcraft he said you have rebelled against the Lord and stubbornness is as iniquity and idolatry because thou hast rejected the word of the Lord you have also rejected thee from being king so look he said because you know you haven't admitted your fault you haven't admitted that you haven't followed God he's like you're in rebellion right now so you think about that you think about that you know with your parents kids when you're not going to admit fault and you're not going to follow what your parents say you don't want to be in rebellion rebellion I mean you say oh it's just I just didn't listen to my parents that one time no rebellion is as the sin of witchcraft you see why we're a family integrated church now because kids need to hear this too so even the smallest thing if you're not admitting I mean what did Saul do he left a few cattle you could say oh that's not the point the point is he didn't listen and he didn't admit that he didn't listen he was in literal rebellion to the Lord you don't want to be in that place because it's as the sin of witchcraft as the sin of witchcraft very serious so first of all he rebelled against the statutes of the Lord he rebelled against God so that's the first reason the first reason the second reason is this turn to first Samuel chapter 18 so we see rebellion just sin is the first reason the second reason is this vanity vanity was the second reason look at first Samuel chapter 18 look he was envious of David from the beginning he was insecure in his own position he wanted all the attention for himself look at verse number six of first Samuel chapter 18 and it came to pass as they came when David was returned from the slaughter of the philistine that the women came out all of all the cities of israel singing and dancing to meet king Saul with tablets with joy and with instruments of music and the women answered one another as they played and said Saul had slain his thousands and David his ten thousands uh-oh and Saul and then look at the next verse do you think now Saul was like you know what i'm glad i've got a good general i'm glad i've got a guy that can just that can just do what he's supposed to do and he's overachieving no Saul was very raw the bible says he did not like that David was doing better than him and that people were seeing that and the saying displeased him and he said they have ascribed unto David ten thousands and to me they've ascribed but thousands and what can he have more but the kingdom he's insecure he's he's focused only on himself saw he's focused only on retaining power he's focused only on retaining his reputation his image his vanity he's focused on vanity so we see the main problems with Saul and the reason that you you'll see throughout the rest of the story in first Samuel with him and David it's all because of his rebellion against the Lord and his vanity those two reasons okay so you say what does that have to do with us well let's let's do some depression troubleshooting this morning okay let's look at depression troubleshooting let's apply these two things to us today and see if it matches all right so the first one is what sin just sin in general I mean let's just talk about you know the unsaved the the world let's talk about a sinful lifestyle what will that lead you to in this world and this is the most ironic thing ever because nobody except probably people in this room seems have this figured out okay most people out there think oh you know the christian life you know most people probably talk to me and they realize that you know i'm not going to go out with them after work and i'm not going to do all the stupid things that they do and all these kind of things and they probably think i'm boring but i'm telling you i don't have a boring life at all i'm telling you if you are living the christian life and you think it's boring you're doing it wrong you're doing it wrong i mean this is not a boring life and it should be filled with joy but you know what you know what they're misunderstanding they're misunderstanding because this world out here for the unsaved for everybody what they're after they're after this immediate gratification they're after this you know this life of of the drunk is they're looking for this immediate instant gratification this you know this quick you know but look this is this is normal today i mean this is normal i mean just think about just drinking i mean alcohol itself it's people do it because it's fun do you know that it actually depresses you you know they do it because it's they're looking for this short term short term high but do you know that it actually i mean even science and the medical profession will tell you that alcohol is a depressant it depresses you it brings you down let me just read you a quote when broken down scientifically alcohol is in fact a depressant the more alcohol you drink the more it depresses the functions of your body i mean it'll actually slow your heart rate and all these different things it says it says many people feel a little extra pep when they first drink alcohol however this effect is short lived it does not take long for the depressant effects to begin to take over do you know that if you drink a lot you will become depressed alcohol is a depressant you know the side one of the side effects of being in what they call an alcoholic is depression suicide people drink to become happy but it actually brings them depression it's crazy the world tells you here's another one the world tells you that fornication is normal the world tells you that you know fornication is normal and if you're not doing it you know i mean what you know everyone's doing it everyone's just living with their girlfriends nobody gets married anymore i mean it's a generational problem at this point it's a generational problem everybody's just out doing it and you're like oh no you know i'd like to wait till i get married people are like what what are you crazy but do you know that fornication will depress you do you know that that fornication leads to disease leads to like unwanted pregnancies it leads to like murder i mean that sounds fun look this isn't fun this is short term high everybody's chasing a short term high and and they're ultimately just gonna lead themselves i mean they're leading i mean these young girls and women today are being sold the biggest lie called feminism hey you don't have to get married you don't have to get married and have children that's just the the man trying to keep you down you need to go out and just live in fornication and just live with all these different people and just you know basically become a whore but you know what that will lead women today too depression depression turn the first great thing is chapter six and you wonder i mean look i was involved like my mom has been involved in like the pro-life cause since i was i can't even remember since and i remember there's so many statistics on women that you know they they get abortions and it just leads them into severe depression later in life because guess what they may have done something wicked and evil when they didn't know what it was you know someone was lying to them oh this isn't a child this isn't you know a human being and they go and they make some decision when they're 16 years old 17 years old 18 years old and then you know what they grow up and they get married maybe it maybe they got maybe they get saved hopefully and then they have children and they're like oh what have i done and they realize they've murdered their own child 10 years ago 15 years ago i mean that's why like pro-life you know people that are against abortion i mean they're for women they're for women not ruining their lives they're for women i mean this is all a lie it's all wicked evil lie i mean that that's fornication though oh but it's fun i mean forget the marriage stuff how to ruin your relationship with your future husband or your future wife and it could even cause you to not even be able to get married to certain people i mean forget all that it'll just wreck you it'll ruin you first Corinthians 16 18 flee fornication every sin that a man doeth is without the body but not this one it's different the bible says that this sin is different because it says all these sins that you do are without the body you go out and you steal in your you know whatever else it's all without the body but he that committed fornication sinned against his own body say look you're destroying yourself i mean it should be pretty easy to convince people not to go into fornication because all you have to do is convince somebody hey could you not destroy yourself please the bible says you shouldn't destroy yourself don't destroy yourself i mean it just leads into all these terrible things and look if you get into all these things and it leads you into all these serious serious sins as fornication is one of them look you're going to be depressed that's why people are depressed that's why many people are depressed they're chasing the short term high that the that the world tells them is what they should chase and they end up destroying long-term things that can't be undone and they're depressed look it's just this life is this world is just one pursuit of sinful pleasure after another and it will all lead you to pain and suffering all i mean today the world the world by the way they'll explain this away the feminists will explain this away they'll say oh no it's all these it's all the restrictions that that the bible and god has put on people and there's guilt on them that that's causing the depression really that's the dumbest thing i've ever heard in my life yeah it is a disease made up in your mind no that's real physical that's real physical consequences is ending an unborn child's life is that is that made up in my mind these people are morons and they're wicked as hell and they're liars and they're destroying women is what they're doing they're destroying women it's a nice counter punch from satan but it's not even really a good one right that oh it's it's the religious restrictions that are just depressing people it's like when you're an idiot all these consequences are real they're physical they're medical they're they're real they're real so what's the next one and by the way all these things that we talked about as far as the unsaved they apply to the save too if you get into all these things get into all these things because i mean is it a possible for a saved person to become a drunk is it possible for a saved person to fall into sin to fall out of church to just backslide in the christian life is that possible happens all the time it happens all the time i mean the worst thing is watching it happen to people that's the worst because you're just watching this happen and you're like hey this is happening hey you know and you just watch it get worse and worse and worse it's it applies to save people as well it's even worse with saved people because you're going to be under the chastisement of god right god's going to make sure you get away with nothing in this life if you're saved so what's the second thing we saw that saw was in sin what's the second thing that caused his depression caused him to be down caused him to be troubled the second thing is vanity the second thing is vanity turned to ecclesiastes chapter one you want to learn about vanity read ecclesiastes ecclesiastes was written by the wisest man who ever lived aside from jesus he was given everything by god he was given all this knowledge by god he was given all this wealth by god he was given everything and he wasted it all he wasted it all but he didn't really waste it all because he gave us the book of ecclesiastes so we can read it so we don't do the same thing look at ecclesiastes chapter one what is vanity let's talk about vanity i mean the bible i mean even the front of your bulletin says vain glory what does that mean let's talk about that look at ecclesiastes chapter one in verse number three the bible says the words of the preacher this is king salomon king salomon is the preacher here the son of david king and jerusalem vanity of vanity say at the preacher vanity of vanities all is vanity sounds like this guy's in a good mood what prophet have a man of all his labor which he had taken under the sun he's like he's like he's an old man at this point he's saying he's like what was the point of all of this i mean imagine does anyone want to be where he's at right now this guy is depressed he's saying it's all vanity but what does that mean look at ecclesiastes chapter two just one chapter down he's saying here he's saying by vanity he's saying everything that i have done has been out of personal pursuit or pleasure that's what he's saying look at ecclesiastes chapter two in verse number nine now you've heard of keeping up with the joneses right i mean everybody you know you see it all the time around here everybody's got to have the nicest car everybody's got to have that you want to find out who the most broke people are look at the people driving the newest cars that's a general rule it works right i mean people just strapped with so much debt but that's not the point of the sermon anyway here here's the bottom line king solemn won the race you can't win the keeping up with the joneses what that will do is that will just make it to where you're not happy with anything that you have ever if you move into a nice house and you're constantly looking at the nicer house then you move into the nicer house you're constantly looking at the guy that has the nicer house than you there's always somebody with a nicer house it'll just make it so you never appreciate anything that you've been given you'll never appreciate any of your blessings but solemn won he won this he won this competition he's the only person i've ever heard of that actually won the the competition look at verse nine he says so i was great and increased more than all that were before me in jerusalem all my wisdom remained with me he's like i was the smartest and i had more than everybody ever he's like i i no one could keep up with me is what he says look at verse 10 he says whatsoever my eyes desired i kept not from them i withheld not my heart from any joy from my heart from my heart rejoiced in all my labor and this was my portion of all my labor then i looked on all the works that my hand had wrought and on the labor that i had labor to do and behold all was vanity and vexation of spirit and there was no profit under the sun he's like hey look down at verse number 17 he's like hey i had it all he's like anything i asked for i got it right there i wanted something right now i mean he had hundreds of wives anything that he wanted he was just his right now he withheld nothing from himself and in verse 17 i hated life he says therefore i hated life you're like what all i need is a million bucks and i'll be happy no you won't he's he had everything and therefore i hated life because why because why because the work that was wrought under the sun is grievous unto me this is why this is why he hated life even though he had everything because he did it all for himself because all was vanity just like sol he was obsessed with himself maybe we look you're depressed do a selfishness check i mean why are you constantly thinking about yourself you're depressed you don't think there's people in worse situations than you turn to philippines chapter two or just look at the front of your bulletin here's what you need to do if you're depressed and you're like you know what i i i i i i i i i here's your problem philippines chapter two verse number three or look at the front of your bulletin the bible says let nothing be done through strife or what vain glory that means just constantly just trying to glorify yourself that's what that means it says you know but in lowliness oh so you know here's another one of those great opposites bible verses right where it says hey don't do it this way instead do it this way just in case you misunderstand right he's going to give you both sides of the coin here but nothing be done through strife or vain glory but in lowliness of mind let each esteem other better themselves hey why don't you start thinking about other people hey why don't you get your your mind off yourself so much and just start thinking about other people look not every man on his own things but every man also on the things of others let this mind be in you which was also in christ jesus maybe just maybe this whole thing isn't just about you you know what the opposite of vanity is selflessness the opposite of caring about nothing but yourself is selfish here you know here's here's another thing there's all kinds of studies out there let's look at some what science let's look at science today because they figured this out last year helping others can relieve anxiety and depression 2017 i mean somebody spent their whole career studying and doing all these different studies and they found out that helping others can relieve depression and i mean in this article in this big it's an abstract okay an abstract as means this person has done a huge study and a white paper in the abstract is the summary here's a summary here's what you should do if you want to not be depressed be supportive of others have compassion for others make a positive difference in someone's life make constructive constructive comments to others avoid doing anything doing anything that would be harmful to others avoid being self-centered brilliant i mean it's brilliant i wish someone would have thought of that sooner i mean i was 2017 there's people been depressed for thousands of years an article from time.com look i could read you articles and i just had to stop because there's so much scientific evidence out there here's a an article from time.com time magazine think about it the secret to happiness is helping others it's amazing here's a quote from the article giving back is as good for you as it is for those you are helping because giving gives you purpose when you have a purpose driven life you're a happier person goldie hon it's brilliant i mean goldie hon figured it out in 2018 many people look first of all i'm so irritated with people repackaging the bible and selling it as their own you know i'm people make an entire career out of repackaging ideas that aren't their own and just you know passing them off but i'm not even going to go off on that one all right study after study shows that the bible is true on this is what i'm trying to get across to you becoming less self-focused and helping others literally brings joy to your life you know try it try it i look i have done this on several different occasions something has gone wrong whether it be at work whether it be things just aren't going the way i want them to go and i'm like you know what i'm gonna go help so-and-so dig up a sewer pipe and every single time it happens it it helps it works and look here's the thing if you're depressed and you do this i mean this is a troubleshooting technique okay if let's let's try a fix right i mean that's what you do if you got a car that's broken and you want to you know it's one of four things all right let's start with the least expensive thing and start fixing those four things and we'll see what happens right if you're depressed and you go out and you help somebody with something you're like you know brother frank needs help building the fence or he's struggling with this thing i'm going to go over there and i'm going to be labor for him i'm going to help him or i'm going to just be a blessing to somebody in some way and it helps your depression you found the problem you found the problem you're too self-focused you're too self-focused look i'm not saying don't pay attention to issues that you need to worry about in your life but i'm saying if you're literally depressed and helping other people helps bring and it will it will trust me that that's part of your problem is your too self-centered you're too focused on yourself so i mean use these two criteria for troubleshooting depression in your life you know look i'm not downplaying you know hormonal problems or changes people go through in their life or or whatever you know or actual medical struggles but here let me just tell you something from my limited medical experience okay when somebody i knew that was going through depression whether they were you know treating it with medication or not there was always a root cause and the problem look the problem with the medical industry today is they're not even interested in the root cause they're just like take this pill i mean people i mean don't get me started on like anti-depressants and all this people are just going and they're just thinking that just pills are going to fix their life and and you people they're crazy crazy i mean these anti-depressants that you read about you know what the side of one of the side effects is suicide depression it's an anti-depressant and its side effect is depression and suicide it's like hey this will make you feel better unless you kill yourself i mean look if the problem is this i mean if you have a car that needs fixing you got to find the problem i mean if you got a car that's leaking oil you i mean you can just keep buying oil and buying oil and buying oil but the leaks going to get worse and worse and worse and pretty soon you're going to destroy the motor you got to find the problem you got to find the problem and the bible says that mainly you know do a sin check on your life am i into stuff that i shouldn't be into and if you're saved you know i mean that could be actual judgment from god on your life like don't go around being like hey brother i think you're depressed because you know don't be jobe's friends this is for you personally to do a check on yourself if you're suffering with depression and then second of all you know are you just living a life of vanity because people that are really selfish they're they get depressed a lot because they're just living a life of vanity so do this do this and then go help somebody with something if that's you start thinking about other people start thinking about others you see i mean haven't you ever felt good buying someone a gift i mean when you actually help something with something serious it's like that times a hundred that's why soul winning is so great that's why soul winning is so great look soul winners you're going to get to a point where maybe there's going to be a day especially if it's 150 degrees outside where you're like you know what this isn't that much fun right now but you know what those are the days where something great happens and you go home and you're just like you know what that was awesome you know what i'm glad i got out of bed and went soul winning today i mean those are the days where you know if you just stop focusing on yourself and start thinking about other people you know and you know from christmas gifts to their very soul you know it's going to help you not be depressed so i mean just look at this look at this listen to the wisdom of Solomon don't be Solomon that's the beauty of the bible is is we can look at somebody else's mistakes and we don't have to fall in all those pits what let's let's listen to this wisdom that the bible gives us and do these checks on your life and i bet you you know what i bet you get some joy back in your life let's bow our heads and have a word of prayer