Virology Lectures 2020 #1: What is a Virus?

[Music] good afternoon welcome to viral adji I'm Vincent rockin yellow and I am going to be your professor for this entire course I am a professor up at the Medical School I have had a lab there for 38 years working on viruses and I think they are the coolest things on the planet cooler than anything else that exists and part of my goal is to convince you that they're really amazing I absolutely love viruses I have a passion for them that few people have and I want to impart some of that to you now as a professor out of medical school I have zero teaching obligations I don't have to teach this course I've been doing this for 10 years because I want you down here on this campus to know about viruses when I started doing this 10 years ago there was no virology course at Morningside and I thought you guys are paying 60 grand a year and you're not learning about viruses this is completely unacceptable so that's my motivation and I guarantee it you're gonna really like this course you're going to like what you learn it's not easy but in the end you're going to know more about viruses than most people on earth and this is a great time to be taking this course because as you know we have a brand new virus emerging from China and circulating around the globe and everything you have heard about it on Twitter and Facebook and so forth is probably wrong but here you're going to get the facts by the end of this course you're going to understand exactly what is going on here's what I feel if you want to understand life if you want to understand human health and human disease you need to know about viruses we live and prosper in a literal cloud of viruses viruses infect every living thing on the planet everything nothing escapes a virus infection we regularly eat and breathe in billions of virus particles probably on a daily basis and viral genomes are part of our genome as well they're truly per most pervasive they're everywhere and what is really remarkable is the extent of viruses on the planet and here's one example in the waters of the planet just the oceans saltwater there are over 10 to the 30th bacteria phages these are viruses that infect bacteria 10 to the 30th that is too big for you to really comprehend so here let me put it two ways for you first of all and a teaspoon of sea water there are a couple of million virus particles so next time you go swimming in the ocean and you spit water at your friend you're aerosolizing virus it's completely harmless but their virus is in there a bacteriophage particle weighs about a femp 2 gram so if we multiply that times 10 to the 30th we get more biomass by a thousandfold of old elephants on earth so now you're starting to see how many particles there are and then if we put them end to end each of those 10 to the 30th particles they reach a hundred million light years into space that's farther than the nearest galaxy way beyond our solar system of course incredibly flowing distance and these are things you can't even see that's the amazing part there's so many of them and this is just in the oceans and in this course we're gonna talk a bit about the impact of those viruses on the oceans and on globo global biogeochemistry they have enormous roles to play so the numbers is part of the way viruses are successful whales for example are infected with members of a family of viruses called calluses these are members these are related to the viruses that can give you gastroenteritis we'll be talking about that later in the course gas our itis is vomiting and diarrhea we've all had it these are some viruses that commonly cause that they can also infect whales they can cause rashes and blisters and also gastroenteritis not just in whales but other marine mammals some of these whale viruses we think may infect humans spillover from animals into humans that's a word I will use a lot in this course and these whales excrete 10 to the 13th virus particles a day in their feces that's a lot of virus particles going into the ocean there are lots of whales out there and whales aren't the only ones in fact this is just another example of the viral numbers game if you will and that's a Khaleesi virus particle in its glorious color of course these viruses are not colored at all we color them because it looks good at its informative but as you'll see later we know lots of very detailed structures of virus particles that we can use to understand how they work it's a little bit more about the oceans here's a set of pie charts showing you the amount of virus is relative to protists and prokaryotes so on the Left we have by biomass and you can see the yellow is the prokaryotes the bacteria largely they constitute most of the biomass in the ocean there's lots of microbial activity in the ocean in fact it accounts for most of the oxygen that we're breathing the photosynthetic bacteria in the oceans and viruses in blue just a very small part of the biomass however we if we now look at particle number that's on the right or abundance viruses constitute 94 percent of the particles in the ocean if you just count a bacterium and a virus as one each now viruses win the race they are more abundant in particles than anything else and these viruses are not just bad news someone famously said years ago a virus is a bit of bad news wrapped in a protein I think that's completely wrong sometimes it can be but as we'll see later in the oceans these viruses are responsible for recycling of a great deal of the organic matter to make it available so they have great roles to play and I just want to again point out in a leader of coastal water there's more virus particles than people on earth and as you'll see they have the greatest genetic diversity on the planet nothing comes close to having the number of genes in toto that viruses have another sobering number at this point in time today there are about ten to the sixteenth genomes of HIV human immunodeficiency virus on the planet it's also a huge number and we know this because we know how many people are infected about 37 million currently we know how many genomes they typically have so we can do the math for it very easily but what does the number actually mean it means that for all the drugs we have to treat HIV we have over 40 and they're very effective and now if you are infected with the virus you can live a life without getting disease because of these drugs yet within these ten to the sixteenth genomes there exists resistance to all of them already because as you'll see mutations arise randomly and so no matter how many drugs we make against this particular virus there will always be resistance out there and that's a problem which we'll talk about when we talk about AIDS how many of you right now have a virus infection raise your hand I guess you don't want to identify right I understand that but you all do you're all infected I don't mean to single anyone out I am infected in fact we all have right now about a dozen different herpes viruses in us including herpes simplex one in two varicella-zoster virus chickenpox virus although if you're vaccinated you might have avoided that one cytomegalovirus epstein-barr virus and then other herpes viruses six seven and eight serological studies have shown the u.s. over 90% of the population has these viruses and then once you get them you can't get rid of them I like to say unlike love herpes is forever it's true and we will talk about why they stick with you and why you can't ever get rid of them I have to say I have an Instagram account where I put pictures of viruses and so forth and I regularly get notices from people who say my herpes was cured from doctor so-and-so let me give you his or her number it's it's wrong you cannot cure herpes and you'll learn why in the herpes lecture so we each have at least a dozen herpes viruses but we have many many more as well let me tell you you know that we have a microbiome right every part of you has certain bacteria associated with it your skin your eyes our respiratory gastrointestinal tract everywhere there's a different collection of bacteria that are good they're beneficial we're just starting to learn why but there's also viruses in every part of your body we have a viral and on the Left our pie chart showing RNA and DNA viruses and different organ systems nervous system respiratory you're a genital tract etc even in health we have viruses in all these places all of us if I did a survey of all of you I would find viruses like this and over you yet you're fine and that's the interesting part we think these are beneficial we have some evidence for this which we'll touch on in this course we are currently looking everywhere for viruses and I want to play you this movie on the left there we can now access any anything on the planet to look for viruses and there I'm going to show you how to access the viral of whale breath what they've done here is they've made a drone which is piloted by the people on the ship and as it passes over the whales a little dish opens up and it collects whale breath I don't know if you could catch that it's pretty quick that little dish coming up is like a petri dish it opens up the whale breath goes in one more time and they can collect it they can bring it back to the lab sequence it and find out how many viruses are in whale breath isn't that something you wanted to know you could you could use that at a party you said you know how many viruses there are in whale breath there are a lot so we can sample any part of the planet and we are we'd like to know what's there just a few weeks ago I saw a paper where they went up to a glacier in the western part of China and they dug very deep and pull that ice cores brought them back to the lab and thawed them and they find viruses and these ice cores are 15,000 years old so we can really understand what's on the planet by doing this kind of sampling it's quite remarkable I mentioned at the beginning that we have viral genomes as part of our DNA and that's illustrated here on this pie chart as you know our genome is 3.2 billion bases in length the sequence many years ago and many genomes are being sequenced right now because the cost has dropped substantially the coding genes are very small as you can see here only one and a half percent and there many other sequences that do other things but I want to point you to this 8.3 percent which is labeled LTR retro transposons I'm going to talk about exactly what they are what these are in a lecture later on but essentially a good fraction of these are remnants of retrovirus infections that happened long before we were Homo sapiens they happened to our ancestors and they were passed on down to us and in fact some of the genes from those retro viruses have been co-opted over evolution to now have uses in us some of these protein coding genes came from retrovirus infections in fact there are sequences of viruses littered throughout our genome that are not shown here and we are wondering what effects they have are they useful and if so what are they doing and people are starting to get interesting results about that now over the years as you will see most work on viruses and most virus discovery is driven by disease and that's illustrated in this graph which shows the causes of 2017 global deaths and you can see the biggest killer cardiovascular diseases almost 18 million deaths globally in one year and I've put arrows next to some of the places where viruses are participating in here the clearest one is HIV the causative agent of AIDS of course almost a million deaths in 2017 but there are other viruses that may not be obvious to you for example a lot of hepatitis is viral so that's up there in the top list a lot of diarrheal diseases are viral respiratory diseases as well and so because of all this this drives a lot of research on viruses but more and more we are understanding the role that viruses play in ecosystems and in beneficial roles on the planet and so the research is expanding beyond just a cause of disease but amazingly despite having all these viruses around us you have so many in you and around you the air is full of them right now you're fine you rarely get sick you get a cold now and then maybe you get gastroenteritis if you're healthy you don't get sick so why is this let's explore why we don't get infected by all these viruses and the first reason is that most of them just pass through us and here is a result of a study from supermarkets in Washington DC where they bought cabbage and brought it back to the lab and looked for viruses and they found that each serving of cabbage would have about ten to the eighth particles of this particular virus it's an insect virus that infects this caterpillar called the cabbage looper so if you ever eat coleslaw this virus is on it if you eat cabbage and even if you cook it the virus will still be on it probably be inactive but you will still be ingesting it but these can't infect us so they pass right through us so the lot of the viruses we encounter can't reproduce in our cells so they pass through it the same with viruses that we inhale that land on our skin on the bottom is a different study where they looked at viral RNA sequences in human feces can easily do this you can collect feces in sequence it the most common RNA virus is called pepper mild model virus it's in ninety percent of specimens so most people apparently eat peppers I didn't know this this is a pepper that's infected with the virus of course if you saw that in a supermarket you probably wouldn't buy it but they can also be infected without showing symptoms and you'll eat them and these viruses passed through you they don't infect you and I get emails pretty regularly because now you can have your fecal viral analyzed did you know who's a company that will do that for you and I get email say oh my god I have this pepper virus what am I going to do so I see a doctor said no you don't have to see anyone because these viruses don't replicate it nothing that I ever see is really pathogenic so that one reason is that they don't replicate on this many viruses are good I call them beneficial viruses and I have three examples for you on the left is a grass that lives around the hot springs in places like Yellowstone National Park if you've been to any of those you see hot water spewing up from where it's heated deep from the earth and around it there are grasses that are growing they are thermo tolerant grasses here's one of them the I can't helium lannigan OSEM can grow up to 55 degrees Celsius you can bring this grass in the laboratory and grow it at 55 degrees and a number of years ago people found that this grass is infected with a fungus this fungus here that's all the little squiggly lines Kerrville area if you take the fungus out then the plants can't grow it high temperatures anymore so somehow the fungus is conferring thermo tolerance but it's even more complicated inside the fungus is a virus that infects the fungus and if you have just the fungus without the virus in the planet doesn't confer thermal tolerance so the virus helps is a 3-way mutualism plant fungus virus that allows the plant to grow and the others of course get a place to live another very cool one on the right I don't know if you've heard of parasitoid wasps these are wasps that lay their eggs in caterpillars and then the eggs hatch and the new wasps eat the caterpillar and burst out it's like alien right basically but this is real life and what these wasps do when they put their eggs in they they inject the virus along with the egg it's called a paladin of virus and that virus is coded for in the wasp genome the wasp you know man codes the viral genes that make up the protein shell of the virus and then this virus doesn't replicate in the caterpillar all it does is produce proteins that immunosuppressed the caterpillar so it will not reject the eggs and the larvae of the wasp so that's why the virus is put in along with the wasp eggs so of course this virus is good for the wasp it's not good for the caterpillar obviously but neither is the wasp but another example of a beneficial arrangement and these are just two tons of them throughout the living world examples where we can see viruses engaged in these kinds of interactions and they're beneficial in some way to at least one of the hosts now you may ask does this happen in mammals because it happened in us we don't know if it happens in us if our viruses are beneficial or not because we can't experiment on us right weakly cannot do experiments but one day there will be broadly acting antivirals like broadly acting antimicrobials for bacteria and we will give them to people under certain conditions and it will get rid of most of their viral and we'll be able to see if it's bad or not but in the meantime we don't know but we do know in mice this the answer seems to be yes so here's an experiment where mice were grown free of bacteria germ-free mice that's gf and here are conventional I swear their gut tracks are full of bacteria the normal microbiome so on the right is a section of the small intestine you can see the villi here conventional mice so they grew up with with a normal gut microbiome nice villi and then on the bottom they have stained for protein C d3 which is a marker of lymphocytes T lymphocytes and you can see there are some lymphocytes here now if you do the same with the mice grown without bacteria the villi are messed up you can see their morphologically wrong and they're not many lymphocytes in these areas anymore okay so you need a microbiome to for proper development and for proper development of the immune system the mouse in the middle was infected with a mouse norovirus that is mouse norovirus mnv and you can see that some of the abnormality has been restored not entirely but it's a little better than the germ-free but some of the lymphocytes have come back as well so apparently this virus is restoring whatever function it is that the microbiome provided so these are very tantalizing experiments there's a lot to do but they suggest that viruses at least in a mammal can have a beneficial role the other reason most of you are well is that you have a really good immune system that works most of the time and most of these viruses that you inhale if they happen to be able to grow in you they won't because your immune system will take care of it now if you happen to if your immune system is down let's say you are immunosuppressed if you have an organ transplant if you have AIDS you will be immunosuppressed even measles will immuno suppress you then the simplest virus infection can be lethal so that points out the importance of the immune system and keeping viruses from growing in us so that's what those are the some of the reasons why you can be healthy with all these viruses around you here's another cool example that I want to give you it's again a that infects just about everyone on the planet it's a polyomavirus shown there in the middle and this is interesting it infects us pretty early in life we usually get it from our family members spread via respiratory secretions saliva aerosols made by talking and so forth and you get infected then you're infected for life and if you're healthy you usually have no symptoms if you are immunosuppressed at some point in your life you can develop serious disease but these viruses can be shed routinely in respiratory secretions and in urine as well and some people are secreting hundred thousand particles per ml in urine and so I always like to remind you that when you go into a public restroom you know every time a toilet flushes it creates an aerosol I don't want to get you paranoid but that aerosol is likely to have the viral of the person who was just before you and maybe by the end of this course someone told me this a couple of years ago they no longer went outside or ate anything because they were paranoid I hope you don't end up the same way anyway these polyomavirus is because they spread within families they can be used to to study human migration and that's what this map is so the dotted line is the progress of Homo sapiens Out of Africa into Europe and Asia and the Americas determined by genome sequence the black lines are the migration of Homo sapiens based on infections with this virus we can tell different lineages because they each have a unique polyomavirus as I said it tends to be spread in families so you can track movement of families by looking at what they've been infected with and you can see it mimics the movement Out of Africa and even provides more detail on the migration of humans than the genome does so again that's a harmless virus turns out to be useful to track where people have moved so that's just a little hint of what's to come we're going to dive into all of these topics in great detail in this course the viruses are amazing it really is a remarkable subject once one year a student wrote after the course ended that every lecture she had something to tell her roommate about that she didn't know and I think you'll find the same thing this year as well it's a remarkable subject and I want to emphasize that it's an integrative science what do I mean it I mean to understand biology you need to understand not just viruses but chemistry biochemistry cell biology physiology if you want to understand how viruses spread you have to know a little sociology certainly epidemiology you have to know a lot of subjects and in the course of learning about viruses here you're going to learn a lot of that ancillary stuff several students in the past have told me that studying viruses made biology makes sense and that's because it's integrative it really brings a lot of things together and this these are my goals for the course I want to give you a big picture the way this course is arranged is not by virus if you go to a lot of colleges and universities throughout the US you will find virology courses some of them mimic this one but others teach by virus you'll have it influenza lecture herpes lecture a retrovirus lecture that is the wrong way to teach an introductory biology course you're not going to learn any principles that way all you're going to know is a collection of facts about different viruses that's great for a more advanced course but for an introductory course you need to know the principles and that's what I'm going to teach you if you notice the syllabus every lectures is for the first 13 lectures or so it's a step in the replication cycle of a virus we're going to go through it slowly and then in the second half of the course explores how viruses cause disease and we have a cast of viruses that we're going to come back to all the time so you don't have to learn every virus but in the end you're going to have a great overview of how viruses work so that's what I mean what I I want to teach it to you as an integrative discipline not a collection of viruses diseases or genes and as I said earlier you're gonna learn things that amaze the uninformed and the informed and and frighten the uninformed right now there's a lot of fright out there about this new coronaviruses because of lack of information now I'm going to show you how to get that information in the end and I guarantee you that in two or three years when another outbreak occurs you're going to remember this course and say now I understand what's going on because of what you taught us and as I said we're in a perfect moment now because we have a new virus circulating and just this morning I pulled these headlines down to show you what I'm going to teach you to be able to do so here on the top you know they don't go to Wuhan don't leave Wuhan desirous of course originated at a fish market in Wuhan and the virus could mutate and spread further okay and here's another article China warns virus could mutate and spread where did all this come from came from the National Health Commission Vice Minister there is the possibility of viral mutation what you are going to learn in this course is that this is wrong there is no possibility of virus mutation it's already happening viruses mutate with every reproduction cycle that corona virus has already mutated extensively as it goes from one person to another what they mean of course is that it will eventually have a mutation that does something like make it spread more okay but the distinction is subtle and the Health Minister doesn't know it and then the press just picks it up and amplifies it and that's what you see and so every outbreak I see their headlines like this the virus may mutate and from year to year they do not seem to learn the fundamentals but you're going to learn it in this course you're going to understand why this this statement is incorrect and what kind of consequences mutation might have for viruses in a human population I guarantee when you see these headlines in five years you're going to understand why they're not correct now one of the things I'm going to do in this course is to have quizzes as we talk here to give you a break so you can do this on a laptop cell phone a tablet whatever you have that's internet connected you have to go to Socrative and that's the link there be socrative.com slash login student and you'll be asked to log in the room name is virus what else could it be right and here is our first quiz just to make sure it works this is which statement is true hey all viruses make us sick and can be lethal be our immune system can manage most viral infections see humans are usually infected with one virus at a time D the press is usually correct in their virology reporting and E our immune system cannot handle most infections which one is true this is not recorded in any way it doesn't count for your grade it's just to make sure you're getting it some of them are straightforward and you will get others you won't and then I'll explain it to you it's a good way to teach the material to you and at one point in the near future you will get a hundred percent but it will take a few lectures before that happens at least that's been my experience how'd we do yes we go holy you already got a hundred percent that never happened you must be exceptional yes our museum can manage most infections that's the answer that's a good sign for the rest of the course right so I'll do that periodically at 3 or 3 or 4 per lecture just to make sure that you're doing well so let's now define a virus we're going to need this definition for the rest of the course what is a virus I have to tell you that every year I change this I struggle to include what we have learned and the first definition from 10 years ago that I gave is different from this one and this year's definition is an infectious obligate intracellular parasite comprising genetic material can be DNA or RNA often surrounded by a protein coat and sometimes a membrane it's kind of a wishy washy definition there are a lot of qualifications in there but that's the way it is let's let's take it apart so infectious I actually debated dropping that from this year's definition but I think it's the important concept it infectious means the virus can go from host to host and cell to cell and get in it because an obligate intracellular parasite means viruses have to get into cells in order to reproduce they will not reproduce in the air or on your skin they have to get inside of a cell so infectious they move from cell to cell host or host obligate they have to get in the cell now parasite is something that takes something from another organism and damages it so taking nutrients is considered damaging because otherwise you would have those nutrients and you'll see many ways that viruses damage their hosts and you may be confused at some point we're going to talk about viruses that infect us without harming us how can that happen but they're still taking something because in order for them to make more virus particles they have to take something from the host so it may not be serious or overt damage DNA or RNA viruses are unique and that they their genome can be either it's always the same for a particular kind of virus so influenza virus has always have RNA genomes and herpes viruses always have DNA genomes but no else nowhere else in the biological world do we see RNA is genome and that's very interesting and we're going to talk about that when we talk about where viruses came from then often surrounded by a protein coat well it turns out that the vast majority of viruses do have a protein coat I added this this year because I want to include as viruses some naked nucleic acid molecules like this one right here it's a piece of RNA that's called the viroid and it infects plants has to get inside the plant cells it reproduces and moves within the plant and can cause plant disease and it was called a viroid because people didn't think they were viruses because I didn't have a capsid the protein shell I don't think that should be the defining character of a virus I want to include viroids in viruses so that's why I have often surrounded in fact you can see from from the diagrams here most of these viruses do have a protein coat and so here on the lower left this icosahedron particle that's poliovirus next to it is adenovirus these are made of pure protein shells with the nucleic acid inside we'll learn more about this as we move on other viruses sometimes have a membrane so here's a corona virus right down here it has a lipid membrane around it which add no and polio viruses do not so not every virus has a membrane and many of them here do so that's an option but most of them will have some kind of protein code around the nucleic acid except for these fibroids and we'll talk about viroids and other naked nucleic acid virus particles later on now viruses have to infect cells in order to reproduce if they don't they disappear and I'm sure that many virus lineages have disappeared over billions of years that they've been around they can't find a host and that's the end of them but when we study viruses we have to also study the host cell so every solution of the virus reproductive cycle reveal something about the host many of the great discoveries about host cells were found by using virus infected cells and I'll point those out to you as we go along and these are some of course various hosts for viruses as I said they infect everything on the planet do you think there's only one organism well there's so many species out there you can't possibly hope to find a virus for each one because nobody studies them all right I always learned that there are more insects in certain areas than we've ever catalogued but the only organism for which I'm not aware of a virus is tetrahymena but I'll bet there is one and they just haven't found it for many years C elegans there were no viruses of C elegans and then they were found so you just have to look hard enough so you can study the virus of any organism and you learn about the organism as well so mosquitoes can be infected us of course this is a very interesting protist that lives in the ocean it is one of the most numerous protists in the ocean and there's a virus that infects it which we will talk about and these are tulips these are very prized tulips in Holland they have stripes and the stripes are caused by a virus infection and people used to breed these tulips to make the stripes and they were unknowingly including the virus because the virus is what interrupts the pigmentation it makes them strike so the other question is our virus is alive and I have a poll on my blog here which I just looked at the other day that about 7,000 people have taken that you can see it's pretty evenly split between yes and no and something in between I don't know what that would be you're either living or not and so I've actually thought about this a lot and I have an answer to this question and it's not a simple answer it's embodied on this slide so when pee most people think about virus they think about a particle like that one on the left at polyomavirus and that is in no way shape or form the living it's a protein show with some nucleic acid in it if it's here on the table it will sit there forever and not do anything you can't reproduce on its own so it can't be alive it has the capacity to become living when it gets inside of a cell kind of like a Spore when you pour water on it but a spore has many different energy making systems and so forth that viruses don't have so I don't think that's a good analogy so the virus particle which I call a virion the infectious virus particle is not living it can't be but when the virus infects a cell the infected cell is taken over by the virus it's now devoted to making virus particles it's no longer just a cell it's a virus infected cell and it's alive so I look at it this way a virus is an organism with two phases one that's not living which is the particle and one that is which is the infected cell I think that solves the problem but people usually don't like to part solutions like this and so it's not really taken hold but this is has to be it because they're infected cells certainly is living in the particle cannot be the problem is us as I say when people think of virus they always think of the particle and not the infected cell so that's my answer to that the other thing I want to warn you here at the onset of this course is please do not anthropomorphize viruses it's very easy to do because it makes it easier to talk about them and if you read any article in the popular press about viruses they will have viruses doing things the virus wants to do this or the goal of the virus is to do this they have no goals whatsoever they do not think they do not employ they do not insure exhibit display you know do anything are entirely passive agents and you may think well so what I understand that why can't I say it anyway it's because if you anthropomorphize then you're going to misinterpret things that happen you're going to be given viruses goals when in fact they do not and it's very important to look at all the things we're going to look at in terms of virology here with a neutral attitude understanding that these things happen randomly mutations happen to random lis in a genome and they may lead to something but the viruses doesn't have a goal of infecting people in making them sick the only selective force for a virus is to find a new host that is the major selective force it's an entirely passive force and whatever happens during evolution to make that effective that is selected for so try not to do this I try not to anthropomorphize as well it's very difficult with science writers often do because it's very easy and the alternative is sometimes convoluted but it's really a warning to not think that way don't think that viruses can actively do things they're passive now the other part of the definition of a virus that I used to use was that they were very small in fact I gave them a limit I said they will pass through a point to micron filter there's no more size in the virus definition because now we have viruses that are way bigger than 0.2 microns we have one-and-a-half micron viruses and everything in between so size is no longer part of the definition but I do want to give you a sense for the virus size here they are very small here's an e coli at a hundred thousand X and there is a bacteriophage virus attached to it so you can see it's much smaller than the e coli but you know it's not hugely smaller here on the in panel D is HIV particle and that see the rod-like virus is tobacco mosaic virus of plant virus which we will talk about momentarily so they are relatively large compared to e.coli and then that little panel has a variety of objects which are magnified to a million fold here and here we have carbon atom we have tRNA and antibody molecule there's a ribosome and some other cellular components actin and myosin and so forth and here's a poliovirus particle so it's about the size of a ribosome and so on this panel it's quite small compared to e coli and that's not the smallest particle so 30 nanometers is getting there but there are viruses between 20 and 30 nanometers in diameter those are the smallest ones we know of and so here's the another way of looking at the size range of virus particles first on the bottom there is a cell with its nucleus and various organelles a eukaryotic cell of course and here are some virus particles outside of it and we've magnified them on the right and the bigger one is a herpes virus about 200 nanometers in diameter so one of the larger ones and there's poliovirus again about the size of ribosomes so quite small compared to a cell lots of these virus particles could fit inside of a cell on the top is an interesting scale which goes through from the left plant cells to atoms all the way on the right and how you would visualize each of these entities invite you can see viruses fall somewhere in the middle between bacteria and some of the smaller components and you you typically cannot see viruses by the light microscope a few can be seen I'm going to show you one in a moment but mostly you need to use electron microscopy to see viruses and of course everything's smaller than that you need to use these sorts of techniques as well this is answers the question how many viruses could you put on a pinhead in case you were interested there's a pinhead which has a dust mite there that little pink thing is a dust mite and in the square here are a variety of very small objects including some red blood cells one of these is a lymphocyte one of these is a yeast and here we have a few bacteria then you can barely faintly see this long ish structure there that is a virus that's Ebola virus it happens to be very long so you can see it here so it's very small with respect to the pin itself pin is about 2,000 microns in diameter so you could put 500 million rhinoviruses on a pinhead those are the viruses that cause a common cold and if you have a common cold every time you speak you're making a aerosol and those little droplets are full of rhinoviruses enough to infect many people and that's part of the strategy for viruses to transmit make lots of progeny and go from one host to another now we used to think that viruses were smaller than point two microns I'm going to tell you why in a moment and some of the smaller viruses we knew about Rhino virus says it's about the same size as polio it's about 30 nanometers HIV slightly larger and herpes virus is about slightly larger than HIV as I showed you but about 15 years ago a group of viruses were discovered which we could now call giant viruses because they were bigger than anything we'd ever seen and one of them is Mimi virus shown here made the cover of American scientist and you can see it's quite larger than any virus that we knew here's a electron micrograph of an infected cell with - Mimi virus particles in it we'll talk a little bit about giant viruses and what they mean but they have expanded the size range and we have even bigger viruses now this one is the biggest I know of on the left that is a light micrograph of this virus Pandora virus just put it under scope in the lab they're too much there one and a half microns long so you can see these in the light scope to quote Pandora virus that's the biggest virus we know of and the genome is 2 and 1/2 million base pairs of DNA huge mostly encoding genes we have never seen before and the more viruses we discover this is incredible more viruses we find the more genes we find whose functions we have never seen before the proteins don't look anything like the proteins we know about so it's a very exciting time to do virus discovery because you can find all sorts of new things there is also a fundamental difference between viruses and bacteria and the way they reproduce and bacteria shown on the lower right here you take a single bacterium you put it in broth it starts to divide it makes two and four and eight binary fission right if you put a virus in a broth it will do nothing it needs a cell and it will get into the cell but it will not divide it will make parts it will make genomes and capsid parts and assemble them and then you have an infectious particle a fundamentally different way of reproducing make the parts assemble the final product and as a consequence you add viruses to cells you have a period where nothing seems to happen there's no infectious virus being made we call that the Eclipse and then at some point after infection it varies depending on the virus then you see new infectious particles made so a fundamental difference between viruses and bacteria so let's take a moment for a quiz here which of the following is true concerning bacterial versus viral replication viruses must assemble using preformed components bacteria do not replicate via binary fission as viruses do bacteria must assemble using preformed components viruses do not have an eclipse period and viruses replicate by binary fission okay how do we do yes viruses must assemble using preformed components 91% of you got that a few of you got the other ones but that's the key everything else is wrong but bacteria do replicate via binary fission but and so therefore C is wrong as well viruses do have an eclipse period they do not replicate by binary fission how old are they so we now can sequence many many viral genomes and do computational biology experiments to estimate evolutionary rates the oldest genome that I know of so far in the literature is a retrovirus that seems to have existed 450 million years ago in the Ordovician period which would be about right here where the first land plants are emerging and it seemed to originate in the oceans which is kind of interesting because there you've had the first animals fishes growing up or evolving and then coming onto land so maybe the virus has evolved in the ocean and came onto land and this is one of the interesting critters that live then ortho Sarris lived 488 million years ago hard to go beyond that because the genome mutation rates of viruses are so great that the data disintegrates beyond a certain age and we have no fossils of course where we can withdraw nucleic acids from nucleic acids don't last very long in fossils and so it's very hard to get them there are some old fossils but not millions and billions of years old I happen to think that viruses originated before cells which would be many billions of years ago I think the first viruses were actually self-replicating nucleic acids which could replicate outside of cells self polymerizing nucleic acids this is one of the ideas for the origin of life we call those replicas they're replicating nucleic acids they're essentially viruses and from those emerged cells and then later on the viruses said well they didn't say of course virus has entered cells because that was a hospitable place we'll talk more about that when we talk about evolution now if you start to move through recorded history you start to see evidence for viral infection we didn't know what viruses were till about the end of the 1800s but here on the left a 700 BC Vaz where it says rabid Hector referring to rabies virus presumably or rabies the disease and on the right and Egyptian carving from these years 1580 BC where this young man has a foot that looks exactly like what polio myelitis is today we call it a drop foot the muscles are paralyzed so you cannot keep your foot elevated it just drops we don't really know if this is folio but it looks very much like and there are lots of references in history throughout the years that suggest virus infections were around in the 11th century we know that in China the variolation was practiced now at this time smallpox was ravaging human civilizations this was a virus that evolved from probably camels and rodents to infect humans as the populations of humans grew these viruses invaded them and smallpox was particularly devastating killed a lot of people in China they practice a kind of vaccination and this is in the historical record where people with smallpox they would take the pustules grind them up and blow them into the nose of someone to make them not get the disease had no idea this was a virus of course but they just knew that some people who survived smallpox never got it again so they said we will give it to you and about a third of the people died but the other two-thirds not an FDA approval vaccine but they did that and then the wife of the English ambassador to Turkey the practice had reached Turkey by that she noticed this and she brought it back to England and they started practicing variation and then in the 1790s Edward Jenner did experiments to establish vaccination which we'll talk about later in the vaccine lecture but let's talk now about the origin of this virus concept how did it grow from a point where we didn't know anything about any microbe to where we now have this concept of virus so we start with leaven hook in in the 1600s he did he invented the microscope and for the first time we saw that there were things that were living that you couldn't see because people thought what everything I can see that's all there is to the world but he said Oh in water there are little things swimming around the concept of microbes Pasteur of course took it further he showed that microbes can do good things in particular bacteria can make wine and cheese and so forth and so at that point we know there are bacteria there are as microscopic organisms that can do these things and then finally coke towards the end of the 1800s said these bacteria can cause disease so we established the germ theory of microbiology so by the end of the 1800s we know about bacteria we know what they can do and we know they cause disease but we don't know anything about viruses yet a key point here is this that we use the word virus way before this we can find as early as 1728 the use of virus and the literature to describe any agent that causes an infection so in 1728 we don't know about bacteria but we know that people can transmit a sickness to each other and people started to say well this is a virus that's doing this because virus is a Latin name for poison so they thought a poison was spreading from one person to another they thought it was some kind of liquid that could be spread in the air when Pastor came on the scene he decided that every virus is a microbe remember he was studying bacteria and he said these bacteria or viruses they're all the same these things that are making people sick they're viruses so again we don't know what a virus is yet but we're using the name virus to explain infectious diseases caused by bacteria a little confusing but bear with me he discovery this gentleman Chamberland he was working with Pasteur and the water they had in the lab was dirty it was contaminated so he designed a filter to clean it up it's called the Chamberlain filter it has a porcelain insert and you put water in it and you try a suction the water goes through the bacteria are retained on the filter so he can make clean water and he ended up selling this in Paris they could have clean water Chamberlain filter Pasteur use this in the lab and he found that whatever it was that caused rabies who thought it was a bacterium went through the filter that must be a small bacterium then and the pores are about 0.2 microns in size all right towards the end of the 1800s by then people are smoking big-time tobacco and in in Germany and other parts of Europe there's a disease going through that the backhoe crops called tobacco mosaic disease it makes the leaves blotchy like this and it impacts the price of tobacco so people want to know what's causing it so a couple of scientists took the Chamberland filter and they said it must be a bacterium so let's grind up the leaves and filter it but what they found was nothing stuck to the filter the agent of the disease went into the broth okay so one of them said it's just a small bacterium but the other scientist said no this is something different and that's where the concept of virus as a different entity emerged they called these filterable viruses now remember viruses are everything they called them filterable viruses these two individuals discovered the tobacco mosaic disease filterable virus again virus meaning some kind of a liquid for many years people think that viruses are actually liquids in 1898 the first animal virus was discovered foot-and-mouth disease a very important virus of cattle which we deal with to this day and as time went by the key concept was not only are they small they passed through this filter point 2 microns which we now know not all viruses do but they will not replicate in a broth they need a cell in which to grow so if you take the filtrate and put it on a tobacco leaf it will grow but if you just incubate the filtrate by itself the virus will not reproduce but again at this point 1898 we still think viruses are liquids many new viruses come to be discovered yellow fever rabies smallpox polio etc even up to 1933 we're not sure if they're particles are liquids yet we're still calling them filterable viruses and here is a nice chart of the discovery of bacteria and viruses acock introduces efficient methods for working with bacteria you see the bacteria discovered increases and the number of viruses also goes up and up to 1935 we're still calling them filterable viruses but a key experiment they're actually two key experiments that change that the first is the development of the electron microscope by Helmut Ruska and Germany and that's the first e/m there on the left in 1939 takes a picture of a virus infected e.coli and he sees these particulate things on it these are bacteria phages first picture of a bacteria phage for the first time we realize the virus is not a liquid it's a particle our next question is which the key concept first discovered about viruses that distinguish them from other microorganisms too large to pass through a point might two micron filter only replicate in broth make tobacco plants sick small enough to pass through a filter none of the above how do we do it small enough to pass through a filter that's right yeah then at this point they're not too large to pass through a filter today they are but back then the key point was that they didn't they don't replicate in broth of course they need sales in which to replicate making tobacco plants sick is not a key feature another key experiment the same year as the electron micrograph 1939 people are doing growth curves with bacteria and viruses remember you take that back to your room you put it in broth it starts to divide by binary fission if you take a virus and infect cells there's always this lag this Eclipse and they said it can't be a small bacterium because bacteria don't have this lag it has to be something different so between the e/m and this it was clear that a virus was something different than a bacterium so they stopped calling them filterable viruses they were just viruses now so we had viruses and bacteria that were agents of disease so there's a little convoluted history there but I wanted you to know that our current day understanding a virus wasn't always that way and if you happen to look in the literature and see this in the old they were talking about something else nowadays we know lots of information about viruses we take pictures of a variety of them using the electron micrograph here's a bacteriophage a particular type that has a lovely tail and tail fibers tobacco mosaic virus the one that started all of this the one that caused this disease rabies virus and a virus that causes gastroenteritis we know great details about many viruses we can solve their three-dimensional structures we can't know where every atom is in the virus particle this is a two different views of poliovirus one of the viruses I've spent most of my career working on we know the chemical formula for the virus because we know how many atoms it has and on the left is a very high-resolution three-dimensional structure where we can locate every atom in three dimensions and on the right the lower resolution we'll talk about how we get these later and what they mean this is the virus that I carry on my cell phone this is poliovirus with its receptor and I do know other people with viruses on their phone but not that kind we classify viruses to make sense out of them not because there's any natural organization but because humans like to classify things and I often refer to classification throughout this course so I want you to understand what I'm talking about we classify viruses today mainly by the sequence we sequence the genome and we say oh it's this virus that's how the new virus in China was identified from one of the patients the isolated virus they sequence the entire genome about 15,000 bases put it in a computer do a phylogenetic tree and boom it's a corona virus similar to SARS virus because you can see exactly on the tree so that is how we classify viruses and of course we get something new that we've never seen we have nowhere to put it on the tree and it exists on its own until new relatives come in the old days we used to use other criteria like the shell the membrane the dimensions but we really don't use those for classification any longer we use the classical hierarchical system of classification which you've probably encountered in other organisms we start with orders in this course I'll mainly be talking about virus families they all end in viridi so for example the Ebola viruses are part of the filo viridi or the phyllo virus family then we go into general in this case Ebola virus and then virus species so I want you to understand when I say feel a Verity or a corner of your idioms talking about the family level and so forth virus discovery is no longer driven by disease of course when disease occurs we'd like to know if a virus was involved but a great deal of biology now is to know what's out there and how it affects eco systems and here's a great experiment from a few years ago where a number of research groups isolated 220 different invertebrate species these are all collected in China you can see various insects crustaceans worms mollusks and so forth and they just ground them up and asked what viruses we find by sequencing complete sequencing and in each of these organisms each of these species they found new viruses in the RNA viruses are in orange here on the top you could see lots of new RNA viruses in each of these and most of them are new things that we had never seen before and so this drives virus discovery now the ability to sequence very quickly many genomes and know what's there now what you may ask why do we care about all this other stuff out there why don't we just focus on the viruses that cause disease well here are some reasons first of all I said earlier that viruses outnumber cellular life by at least ten to one they have the greatest to biodiversity on the planet and we know that viruses exchange genes not only with each other but with their hosts so that's important and we need to know about that they drive global biogeochemical cycles we're going to have a lecture on ecology this year the first time to see how viruses interact with the broader global ecosystems and we'll see how they're so important for the recycling of many nutrients as I also alluded to they can be beneficial so we want to know what virus is out there are beneficial for example there are some newly discovered viruses that only infect insects that are now being used as a vaccine platform in humans so you'd never know where the good for us is going to come from and finally we do want to know what's out there because the next pathogen could be out there this new corona virus in China is not a surprise people have been sequencing viruses in bats throughout China for many years and find lots of related corona viruses so we knew the opportunity for spillover from what will probably be a bat into humans was there and that's another reason why we do this now you may think that this is all very complicated but in fact in the next two lectures I'm going to tell you that this can be simplified because of these two facts first genomes are obligate molecular parasites they have to get inside of a cell and once they're in the cell they have to be translated by the host translational machinery so we're going to use that to take these billions and billions of viruses and simplify them mechanistically so you can understand how they work so next time we are going to talk about the infectious cycle that is what happens when a virus gets into a cell all the way to reproducing how does that work and how do we study it [Music]

Channel: Vincent Racaniello

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Id: lj3NhPgOoX4

Length: 66min 9sec (3969 seconds)

Published: Sat Jan 25 2020

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