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BIO270 Lecture 1.doc

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David Lovejoy

Wednesday, October 21, 2009 BIO270 Lecture 1 - This is the second half of 270 – the professor is David Lovejoy & he will be teaching us until the end. He is also the course coordinator for this course. He has been involved in the behind the scenes stuff – we haven’t seen him but the subtle hand of activity has been involved. - Just before he starts the class, we are getting an overview of the next 6 weeks & there are a few things he wants to get through. - He’s asking about the midterm. The class average (unofficial) was 67% which statistically is where the cohort should be. Every once in a while there is an anomaly where we have really high marks or years with low marks but this is exactly where it has been – the worst year was around 50%. He doesn’t have anything to do with that midterm so we talk to Dr. Forder if we have problems unless there is a really serious problem, but if there are no serious problems then she looks after it. - The final exam which this year is interesting because it will only be on the second half of the course, on Lovejoy’s lectures. He was going to offer to put in other questions if we thought his stuff was boring. The class average for his section is consistently higher than 67, but it’s not 95 so however he tries to make this as painless as possible & hopefully we learn something, to get us excited about the next section. - He’s joking about how hormones can affect pethonality change when some guy in the audience made gorilla sounds. He has a course in the 4 year called endocrinology of transformation & it’s about how hormones can change an individual. - A couple of other housekeeping issues. We had our lab reports & they’re going to be handed back in the next week or so & there was a bit of an issue he wants to bring up – about 10% of the lab reports received has material on them from previous lab reports. This happens in every university but it’s considered a form of fraud. Those lab reports are going to be scrutinized much closer so please don’t do that. We are free to get info from wherever we want but rules & regulations of this course say that this is considered an unauthorized teaching aid. We shouldn’t do that & it makes everyone’s lives easier & the last thing they want to do is to grill us in a backroom which they had to do occasionally. - There were only 200 when he started the course years ago – we’re proliferating. He is asking why we’re taking this course so how many are interested in graduate work, how many want to pursue a career in medicine, business & law, etc. - His day job is a professor; his night job is operating a biotech company. Apparently he got “picked up” by a prof & stuck into a graduate program. - The number is for an absolute emergency. The person we’re dealing with on a regular basis are the TAs – we go to them first, the second person is Peggy Salmon who handles logistics for this course & he is the coordinator but Salmon does all the real work. If the problem is so big of an issue then we can see him – he has office hours but he will be holding them posted on blackboard. - Somebody asked him if the lectures will go up – the lectures should be up, the entire set should be up. This is the first year they got them all up before the class began. - His office hours will be from 11 to 1 on Wednesdays so we can come & talk about issues – they are usually referred to I’m having difficulty with the subject material, other issues can be talked about so select issues wisely. There were 500 students last year & only 7 students showed up for these office hours over the 6 week period, but everyone did well so everyone probably understood the subject material at least he assumes. - This brings us to the subject material. He wants to ask another question, & it’s about Professor Forder. He’s asking how many thought she did a good job, he is now making excuses for her, & we haven’t seen the exam yet. - What he will be talking about is endocrinology in the big scheme so a little bit about his background – he is an endocrinologist, he started off as a comparative endocrinologist & his laboratory & research over the last 20 or 30 years encompasses everything from genes to behaviour to even some ecosystem work. He worked with a variety of species: flies, worms, Tunicates, starfish, & just about every vertebrate class so he wants to think that he is reasonably comfortable with it. Now he’s doing clinical work as well so things have expanded. He is looking at it in terms of pure discovery & in terms of applications as well, so it has been a very fun ride, a lot of fun. Now one of the things that really struck him with endocrinology. - He is telling us a story – he has a friend who is a punk rocker, this guy is older – we imagine the geezer on stage & he is also a university professor as well which is scary. He met him a number of years ago after a long period when they didn’t talk. He told him he was doing endocrine research & he looked at our prof & said GLANDS, GLANDS. But that reflected the historical understanding of what endocrinology was – there was no concept of endocrinology really until the first glands were discovered & what a gland was. There were these ductless secretions that came out of glands & that was called endo-for internal secretions & so that is where the word came from. - So we’re going to use the word endocrinology in a couple of different contexts. On one hand, we will talk about it really as an internal secretion so something from the pancreas that is released to the blood. Insulin comes to mind – we can’t possibly go through U of T without learning about insulin but it is a good example of a hormone. - Endocrinology, because that was the first thing that was discovered, those ductless secretions, those internal secretions, because they were the first things that were ever discovered. It has gone on to mean a whole gamut (series/range) of different secretions. So we also talk about autocrine, paracrine, intercrine type secretions & juxtacrine which is the newest -crine that has been added. But each of those has different meanings, very discreet meanings. We think of endocrinology as a very discreet thing but also encompassing the entire field as well. - One of the things that is really interesting about endocrinology he thinks is the communication system. First & foremost it is a communication system – these hormones exist because they have to convey information from one cell to another cell. So we know a little bit about the brain – the brain sends out all these various nerves to certain areas but it is impossible for the brain to send a nerve to every single cluster of cells, it just can’t happen. The brain uses not only nervous connections but it also uses what are called neuroendocrine secretions which we will talk about. But how do all of those other tissues in the body communicate back to the brain? The brain says okay look, muscle do this, look pancreas I want more insulin or whatever. But those tissues then have to feed back to the brain but not just the brain, it has to tell everything what is going on. - Imagine you’re in a community & you have a bunch of nosy neighbours & they’re all looking through your window & asking so what is going on, did you know this person got gout? Cells need to do the same thing – they need to know what their neighbours are doing, they need to know what the head honcho, the brain, is doing & so the only way they can communicate is by releasing these chemical messengers. There are hundreds if not thousands of these things, tens of thousands of these things from many, many different classes & every cell in your body is bathed in these things. - Some of these hormones are more potent than others. His field of research which is involved in designing new hormones is all about tricking cells into thinking that they’re supposed to be doing something else. They’re not doing what they’re doing so we’re going to trick them into doing something else. Just by manipulating these chemical factors can have a profound effect on the organism – it can change the developmental profile allowing them to develop into something very different. In humans, can change personality entirely – it is very profound & the secret is presumably to keep these things balanced. - Having said all that, this is what we’re going to be covering. Now these lectures have been laid out as 8 lectures. Some of us may be panicking, & doesn’t he know there are only 6 classes left? Yes, he does know that. Lectures are based around subjects & not around time constraints so some of the lectures are a little short, some are a little bit long so there won’t be a day-to-day correspondence of each lecture. Lecture 2 will follow lecture 1 & so on & so forth. - However we will get through all of the material – if we don’t get through all the material then we won’t be responsible for material he didn’t cover since we won’t be punished for his inabilities. - He will just tell us that upfront because around December, people panic & say Dr. Lovejoy, you haven’t covered this or that topic – if it’s not covered then it is not on the test; if the test is already made up, he will tell us to ignore those questions. There is a certain reason for how this is laid out. - The other thing he wants to say is that these lectures correspond exactly to what is in the text, & he added extra material to help us understand what is in the text. The exam, the questions will be based on his lectures which follow the text & the text material. Now we’re starting to get a little bit of sophistication in knowledge. Some professors love to discuss conceptual things, some professors love to go into the nitty gritty detail so students are trying to figure out whether to focus on concepts or details – he is in the middle, & his details are related directly to the questions. One of the things he will not be asking are small niggly details we wouldn’t even learn as a scientist, for example which version of the alpha receptor is responsible for communicating with cyclic AMP in glucagon, when the animals are in the dark phase or something like that. He won’t ask questions like that but questions he may ask are: what are the 3 subunits of a G protein coupled receptor? Those are basic things we should know. It will seem more obvious as we go on. - This is laid out in what he thinks is a logical way of going about it. Today we will be talking about hormones & just what are they, some of the structural classes & how they work, so basic things. Then we explore what they look like & how they act, how they do their thing. How do they turn on cells, how do cells get excited about it? Once we have that basic concept, we will talk about different circuits; there are a number of different circuits that are out there. He wants to think of the first 3 lectures as structural elements of endocrinology & they’re applicable to any field, any physiology this will be practical for. After that, once we’ve got that we dive into reproductive endocrinology – why do we do that? Well because we have a reproductive endocrinology lab so we try to do it earlier as opposed to later. - Now he’s asking when the lab is. We’re going to talk about steroids today. Then from there we start looking at energy metabolism – this if anything reproductive endocrinology & if we look at the textbook reproductive endocrinology tend to go at the end of books since they’re complex but we won’t go into that kind of complexity – there are plenty of courses that are offered if we’re interested. - He used to teach a third year course called endocrinology (endocrine physiology) – it is still on the books, it’s going on as we speak & some people may be taking it. It’s a very different course, he doesn’t lecture anymore & then he does a fourth year course which does have a fair amount of reproductive endocrinology. Our third year course, we used to cover a number of things in detail about reproductive endocrinology & particularly about sex change. Sex change is neat because it is just so complex & it’s neat because we can bring both male & female reproductive systems together in one organism & say this is how it all works together, so that has been moved to fourth year, that’s done in detail amongst other things – metamorphosis was moved from 3 to 4 year. th - Then stress endocrinology – this is his favourite & his laboratory focuses on stress & endocrinology so this is one of the things he thinks is really cool. Why you get stressed out, why you have issues concentrating, that sort of thing. But that is tied into energy metabolism so that is logical, then from there it’s digestion, water & ion regulation so when you’re stressed out, how come you can’t digest things, that sort of thing. - Now we can start. Chapter 3: Introduction to hormones & chemical signals. Are we all ready? - This is specifically the sections we will be covering – he won’t be lecturing outside this area. This is what our test is going to be based on so he always recommends that we read the intro to every chapter – it provides a very nice overview, putting it in a nice contextual framework, the introduction is good & there is an overview as well. - The biochemical basis of cell signalling which is going to be a bit of a component because we are really talking about molecule-molecular interactions & we’re talking about biomolecules so this is really the biochemical aspect of it. We're looking at it in a physiological sense, so we’re not going to be discussing the real nitty gritty of biochemistry but we do need to know something about that. - You’ll find that he will be lecturing about a number of things – the key points will be listed in the slides. He is not writing everything down on the PowerPoint slides – these are meant to accompany the book so if you see everything an animal does involves communication among cells for example, the moving, digesting foods – this is an example of it. - In fact Gordon Sheppard who is a wonderful neurobiologist out of Oxford he said that no matter how complex the behaviour or the actions of an organism is, just think of yourself, think of all the things you did today, your body can only do 2 things. Everything that you do can come down to 2 things – anybody want to guess what those 2 things are? Survive & reproduce? Okay, in order to survive & reproduce you can only do 2 things. So if I want to survive & somebody is coming at me with a big stick, I might run away; if I want to reproduce, well we know all about that. Those are obviously very important things, but we can get more basic than that. Anyone else want to guess? There are 2 things a cell can do, only 2 things, you can contract a muscle & you can squirt a juice. That’s all you can do, & all of the talking, all of the brain activity he has, eating, surviving & reproducing, comes down to a lot of muscle contraction & a lot of juice being squeezed. & so that is what we’re going to be talking about, are those two things. - There are 2 things to endocrinology we have to think about as the students pointed out – we can send a message & we can receive a message, & endocrinology is involved with both. We think of the hormones that are playing a role with communicating, however, if there are no receptors, if there is nothing to receive on the other end then the hormone is useless. - There is an interesting case, it is called the androgen insensitivity syndrome – these are genetic males who do not have functional testosterone receptors – lots of testosterone there, but they develop as females because there are no testosterone receptors – the hormone is there but the receptor is not. There are lots of examples of this & this is just one of the more spectacular ones. - Your book likes to refer to direct & indirect signalling. For the sake of this course & for the sake of the course, he is comfortable with that & it’s a fine way to introduce the two things & divide it up. When you start to look at different signalling systems, you find it’s actually a gradient & it’s a bit difficult to do this. - The way your book talks about it is really with the idea that there is a direct cell to cell communication & they use gap junctions here where you have 2 proteins that are aligned in the cells & ions flow from one to the other. It is just a matter of how far the cells are from each other – this is what we’re getting at, but they call that direct so the signal goes from one to another. - For something like an organism like sponges, the poriferas, they don’t have a nervous system – what they communicate with is through their epithelial cells & through gap junctions & ion flow. & they still have a number of behaviours actually, & particularly the larva, they don’t need a nervous system for that. - We’re not going to be spending much time talking about that at all – what we want to focus on is what the book calls indirect signalling & this involves a chemical messenger – well you know if you really wanted to get knickity about this, you could say yeah calcium though it kind of acts like a hormone, so does magnesium, couldn’t we call that a chemical messenger? Well maybe & chemical messenger is carried in the extracellular fluid so it’s moving out of the cell & into another cell & some might be secreted into the environment. These are the exocrine – we’ll talk about exocrine & endocrine in a moment – pheromones. So pheromones & there is a very interesting study – they have found that if they take male & female pheromones, & you secrete a huge number of pheromones, we’re just not aware of it most of the time, if you put a male pheromone secretion, gland secretions, underarm secretions is what it comes down to – can you imagine the people who do these studies? Hey Bob, need your underarm for a minute, doing some experiments. What they found actually & very interestingly is that when males were on the seat, other males would not sit in that seat even though they couldn’t perceive it, they had no conscious perception of it, but some women would. If they put female secretions on the seat, oh dear female secretions doesn’t sound right does it? Pheromones let’s say, pheromones. When they did that, it was mostly occupied by men & women. Well what else would there be? The point was that it was attractive to both men & women whereas male secretions were very unattractive to other males. So pheromones are very powerful. In fact even a mouse, a mouse secretes hundreds of pheromones, we think of these things as insects (? Incense?), chemoattractants & things like that, but the more complex the organism, the more complex the pheromone, we just try to ignore them more & rationalize them more. Okay so those are pheromones, we’ll talk about those in more detail later on. - A chemical messenger binds to a receptor on a cell, as he mentioned, you need the receptor, no receptor then there is no communication. It is like having a sort of a telephone & you turn your telephone off or you throw it against a wall & it doesn't work or your son steps on it in the case of my telephone. - The activation of the signal transduction pathway – so once the receptor is bound, we’ll talk about all these things in a moment, then the receptor has to do something – it says okay, yeah this is great, I've got a hormone wow. & then it has to tell the cell, look we have this hormone, we have to act on this & so it sets up a whole cascade of signal transduction & this is why these things are italicized because these are fairly important words & then we get a response in the target cell. This is a career response in a target cell. - A number of years ago, his lab discovered a new family of hormones which are really cool & they’re pretty exciting things – we’ve been working on them for 8 years now & we still don't know what they do in the cell, & he is probably going to be keep doing that until he retires & other labs are starting to work on it now, but it can be extremely complex. The one thing to think about is it’s not one hormone, one receptor, one response, he’ll talk more about that in detail – it is like an ecosystem of hormones that are related & another family of receptors that are related & another several families of signal transduction proteins that are related & they all cross-talk & a number of them can be very promiscuous & start talking to each other & binding whoever comes their way so it can be really quite complex, & it looks nice in a textbook but the reality is when you’re doing these experiments, it can be really quite frustrating, particularly to graduate students & PIs who don’t understand what their graduate students are trying to tell them. - Let’s talk about the first -crines here. He believes he added juxtacrine to this – it is not in your book. What he finds is that physiology textbooks are rarely written by endocrinologists so he added a couple of details here, but they’re all related. - Paracrine is the short distance – it is the secretion of a hormone, of a chemical factor, comes from one cell, goes out & it diffuses & communicates with the cells around it. Paracrine – that is all it is – it releases it & it just goes that way. - Autocrine on the other hand is virtually the same thing, but with an autocrine reaction & he’ll show us a picture in a second – it is released by a cell & a certain amount of it diffuses back & binds to the cell that released it. There is a reason of this – it is like having, it’s like when he talks as if he couldn’t hear himself, then he’d either be very soft or very loud & the students would be getting very frustrated one or the other. It’s the same with the cell – any cell that secretes a chemical messenger needs to know how much it’s secreting so it can either increase it or decrease it. So an autocrine secretion is a feedback mechanism to say okay we've released this much, how much is coming back? Okay, we’ve got to add more or that’s too much. - Juxtacrine is something that has just been really found in the last few years, & that is where you have 2 cells that are together & they are attached physically. So the molecule that is sitting in the membrane attaches to a receptor on a cell that is right beside it, & if that is broken, or if the cell is shaken, it can disturb that. So all cells in your body have juxtacrine mechanisms, but one of the things is they can tell mechanical stresses – so if you get a knock on the noggin, it causes enough of a mechanical reverberation in the brain cells that displaces those cells, just a small amount & it changes how those juxtacrine signals interact with each other & that can form a signal transduction response – so that is juxtacrine. - The endocrine system is what he alluded to already – these are the molecules that are secreted into a vascular system. Now juxtacrine, paracrine & autocrine don’t go into a vascular system – they just go into extracellular space & diffuse, but what makes an endocrine molecule an endocrine molecule is that it actually goes into the vascular system – this is blood obviously in mammals or it could be hemolymph in insects, any kind of vascular system, doesn't matter what it is, as long as it enters the vascular system & it is carried away at a distance. - The nervous system here is also a form of communication. If you go way back in time as he mentioned with Poriferas, with sponges, there are no nervous systems but they can still communicate. If you take a look at the next group of organisms that presumably evolved, the niderians & cylinterates & tinafora, they have a neuroendocrine system so they have nerve cells but they aren’t exactly like nerve cells, they’re kind of like a combination between an endocrine cell & a nerve cell. These are neurosecretory cells so those neurosecretory cells went on. We can differentiate between neurosecretory, & nervous signalling – we’ll talk a tiny amount about nervous signalling because we’ll get a lot of it out of 271 in the second half of this course after Christmas & that is simply neuron to neuron communication, with neuron to neuron communication – it is a nervous signal & this can be neurotransmitters or neuromodulators. - And neuroendocrine is where you have got a nerve cell that puts its axon & its secretory area onto a capillary or part of the vascular system & secretes its contents into the bloodstream. It is carried at a distance but it comes from a nerve cell so that is why it’s called a neuroendocrine & that is also one of his areas so he focuses on the neuroendocrinology of stress & reproduction. & then every once in a while he gets a grad student in the lab that wants to do something different so you go “okay let’s do that okay, that’s cool too”. - Alright here we go. - Here we have autocrine & here is our chemical transmitter (red dots) being released through exocytosis – it goes into the extracellular matrix & some of it will diffuse back & bind to a receptor. - Paracrine action is where the same thing, we can think of this as exactly the same thing, but beside it returning to its own cell, it’s also diffusing out & affecting these cells on the sides. It will only affect those cells that have receptors obviously – if there is a number of other cells here that do not have the receptors, then it is not a paracrine target – it has to have the receptor. - With an endocrine action, here we have our cells on the left, now these are ductless cells. This makes it sort of sound like they’re missing something like oh they're just ductless cells, they’re not a real cell. In the gland here, they will secrete a number of their components into the bloodstream & the bloodstream carries it god knows where, not everywhere in the body, it depends on the structure but it will carry it a certain ways & then it will diffuse out through various openings & facilitated transport, we’ll talk about that as well, into various target cells. Again the target cell is the cell that is carrying the receptor, the specific receptor, for that hormone. - He’s probably going to use a couple of different words here. There is another term called ligand & because we do a lot of receptor hormone binding, anything that binds a receptor is called a ligand – sometimes he might slip in the word ligand since they tend to use it around the lab a fair amount. Don’t panic so if he says ligand, just exchange it for chemical messenger or hormone. - Neuroendocrine action: Here we have our neuron in yellow, & it’s secreting our hormones (green) into the bloodstream & it can go to all the same places & there are the target cells. Once it goes into the bloodstream, they can all kind of act. - Now we’ll talk about this in just a moment. - A lot of hormones can act as paracrine factors, autocrine factors, endocrine factors & neuroendocrine factors – it isn’t a specific discrete group for each one of those things but he’ll give us lots of examples. - Okay here we go. Here is our direct signalling – here it is directly out of your textbook on the left & these ones are to help us to understand, this is your textbook version of it. There is a gap junction so small chemical messengers, small ions, maybe some larger ions as well, just pass very quickly through it & this is usually for very small things, inorganic ions but there may be some amino acids too. It is probably changing on a regular basis as well in terms of where our knowledge is, we’re always finding out there are more & more of these molecules passing through these gap junctions but for the sake of our argument, we’re just going to be focusing really just on the small ions. - Okay autocrine & paracrine – here is our chemical messenger, it goes out, he likes this diagram because it is a bit more integrative than the previous ones – it has different information & it diffuses, hits the receptor, causes a signal transduction response, signal transduction leading to cellular response which basically says stop secreting hormone or secrete more of it among other things. & then in the target cell, then it will still have some sort of signal transduction response. - And the response in endocrine signalling from the cell into the bloodstream, receptor & the response. - And neural signalling the same way – so we can think of a nerve cell as just a really highly specialized secretory cell that is just very, very efficient. - Pheromones, these are exocrine signalling molecules – endocrine is inside the body, exocrine is outside the body. Any organism that secretes it outside the body is considered exocrine. It gets a little bit complex when you start dealing with single celled animals like paramecium or amoeba – there are a number of those things that produce a number of chemical messengers but because they’re released into the environment they are called pheromones & therefore exocrine signalling molecules. - & this just shows fish. This has been worked out really well in goldfish & it shows a female is releasing hormones & the male is picking that up. - It is really amazing & it’s a really simple diagram, but you have no idea how complex this is, & these guys are fighting back & forth. There are all kinds of these hormones that the female produces that say AH HAH MALE I WANT YOU HERE NOW IN THIS SPOT & uh, release your thing. & some of this is really tough – when those pheromones go out there & males go wow this is the best thing! On the other hand, males can also kind of spy on the female & learn what she’s doing: ooh she’s getting ready is she? Oh well I know where I’m going to be on Saturday. & there are all kinds of gradients in between – there are some male pheromones that will tell females to spawn: DO IT RIGHT NOW. Aren’t you glad human society isn’t like this? This is just a behaviour point of view isn’t it? This isn’t a psychology classroom – we’re not going to cover that. - Okay gap junctions. As he showed in the figure, they are specialized protein complexes & there is a pore, it is an aqueous pore because the cytoplasm is aqueous & things, ions, move in between there & this usually causes a change in the membrane potential – when there is a change in the membrane potential, this changes the rate at which things move across & changes direction in which they can move. - & so cyclic AMP is an example of something that is fairly small which can move across. There are a number of really cool organisms that use cAMP to signal. This is an animal physiology course but there is this thing called a slime mould that starts off as an amoeba & secretes cAMP – they all come together & create this fruiting body, they’re really neat, there is some guy in Mississauga working on these things. - The opening & closing of gap junctions can be regulated by the number of proteins that are there so if you upregulate the number of these proteins, then more of them can come together. - After Break: some of the questions he got during the break indicate that there is a bit of confusion between autocrine & paracrine out there. Autocrine & paracrine are really the same things – it is a question of who receives it. When molecules or chemical messengers, hormones, are released, those three molecules have 3 possibilities. Statistically, some of them will diffuse back & bind to the cell that released them – if they do that, that is autocrine. Again statistically a certain proportion of those hormones will diffuse
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