[Music] foreign [Music] welcome to virology I am Vincent rack and yellow I'm going to be your professor for this entire course there's nobody else that teaches it but me and hopefully I'm good otherwise you're in trouble if you would like to understand life on Earth if you want to understand human health and disease you need to know about viruses and that is what this course is all about to give you everything you know to understand the interaction of viruses with the planet I am a professor at the medical school I have been there for 40 years doing research on viruses and I think 12 years ago I started to teach this class now you have to understand that at a medical school you don't have to teach you have to teach medical students but the clinicians do that the basic scientists such as myself all we have to do is do research we have to raise money to do our research we don't have to teach but I've always loved teaching and I realized there was no virology course down here which is a shame right you're paying a lot of money to go to school here or maybe your parents are paying a lot of money and you don't have a virology course which in my opinion is the most important course on the planet most places don't even have a virology course so I started teaching this 12 years ago it started small 30 students then 40 50 60 100 the most we ever had was 175 one year that was a lot and we have moved around to different classrooms but I love doing this I love viruses more than anything else on the planet and don't tell my family that I think they're amazing and I want to impart to you some of my amazement for viruses they're really incredible entities and notice I use the word entity so what exactly are they well we're going to Define it today we live in a cloud of viruses viruses infect every living thing on the planet I was amazed to hear that people during the pandemic didn't know that everything was infected with viruses they thought there are a few viruses around and now and then they give trouble but for the most part not but in fact every living thing on the planet has many viruses that infect it there are viruses in the air in this room of different sorts you are breathing them out and you are inhaling them toilets are full of viruses did you know that toilets generate aerosols when you flush them and that you inhale those aerosols man you better close the lid with your flush if there is a lid I I often see if there's a lid or not not much you can do if there isn't one so the viruses are everywhere we regularly eat billions of virus particles if you have coleslaw it's full of viruses because the insects that crawl over the Cabbage have viruses in them so we take in and give off billions of virus particles on a regular basis and in fact our genomes have in it integrated nucleic acids of viruses and some of those are actually expressed and we'll talk a little bit about those today and some of the genes of those viruses that are integrated in us or act have actually been repurposed by us to do other things really remarkable so everything is infected the number of viruses on the planet is is simply staggering this is the game of viruses if you want to say that they make a lot of progeny because the likelihood that any one virus particle will find a cell is very low so they just spew out billions and billions of particles and maybe a few make it so here's an example of the numbers in the waters of of the planet earth mostly the oceans there are over 10 to the 30th particles of bacteriophages these are viruses that infect bacteria 10 to the 30th can't comprehend that number right it's just too big so here are some things to tell you what that means so a single particle weighs about a femtogram so if you multiply a femtogram times 10 to the 30 you come up with a biomass that exceeds that of elephants by a thousand fold elephants all the elephants on the planet all the viruses weigh more than those by a thousand fold if you lined those viruses up head to tail they would go 100 million light years into space these are things you can't even see that's how big 10 to the 30th is huge number and that's just in the oceans and you know what's amazing we didn't even know this 15 years ago we thought the oceans mostly had whales and fishes and that sort of thing in it but turns out incredible microbial communities and viruses that infect them whales are infected with viruses they're huge right so they excrete huge numbers of viruses they're commonly infected with viruses called Khaleesi viruses this is a virus which is part of a family of viruses that infect us called noroviruses if you've ever had vomiting and diarrhea for two days a day or two that's a Khaleesi virus it's a neurovirus we'll talk about those later in in Wales they can cause diseases rashes blisters gastroenteritis they can infect humans in fact and infected whales excrete over 10 to the 13 Khaleesi viruses every day so those go into the Waters of course and they may infect other marine mammals as well so the numbers are huge I like to say that viruses are not just messengers of bad news most viruses on the planet are actually not bad if you by bad mean cause disease most of the viruses don't cause any disease now in if you look in the oceans you see that viruses have enormous roles to play in what we call biogeochemical cycling that is the recycling of organic matter to form the elephants which can be reused we didn't realize this 15 years ago but if you took all the viruses away we'd have problems getting carbon and phosphorus and sulfur nitrogen out of organic materials in a leader of seawater there are more virus particles than all the people on Earth just a liter of seawater and in a teaspoon many millions of virus particles so the next time you go to the ocean and you know you take water in your mouth and you spit it out because it's fun to do you're aerosolizing lots and lots of viruses but they're probably harmless for humans now on this chart here on the left we have biomass so the mass of things in the ocean they're prokaryotes rule bacteria right and viruses and protists very small slice of that pie but if you look at abundance particle abundance if you count particles what you will find is that the viruses constitute 94 of all the particles in the ocean so again the numbers game nervous viruses have huge numbers of Offspring and we will talk about this more in our ecology lecture at the end but as I mentioned they're important for biogeochemical cycling they infect say bacteria and the bacteria lice there's something like 10 is it 10 to the 30th I forgot the number but a lot of infections per second in the in the surface of the water phages infecting bacteria huge numbers that liberates particular organic matter which sinks down into the lower depths it's degraded further and it's recycled into the elements so really important constituents of that cycling other viruses are also present in in huge numbers HIV human immunodeficiency virus the only virus by the way which gets its own lecture in this course this is not a virus by virus course but HIV is so important it is a pandemic still right it's there are two pandemics ongoing and depending on how you Define pandemic there may be more pandemic is not really a virological definition it's more of a sociological w-h-o one but HIV AIDS is a pandemic there are 10 to the 16th genomes on the planet today we know how many people are infected we know how many virus particles each of them have so huge numbers we will talk a lot about HIV so how infected are you you have at least a dozen different herpes viruses every one of you I would bet a lot of money that every one of you have at least a few herpes viruses if not more you get infected very young in life from your parents mostly because they're kissing you and most of these viruses are passed through saliva uh and they include herpes simplex viruses varicella zoster cytomegalovirus Epstein Barr and then hhv six seven and eight we'll talk about these separately but once you are infected it is for life you cannot get rid of these viruses they remain in various parts of your body and if in a form we call latent periodically they reactivate a new Shad infectious virus you may have a cold sore in the case of herpes or you may have no symptoms and that's how they spread from person to person but you also have many other viruses in you between besides these these these are the ones that are well studied you know that we each have a microbiome in us right every tissue and organ in US carries a different kind of bacteria as shown here what we also have a vibrom Which is less studied less study because it's hard to study the microbiome is pretty easy because all you need to do is to take samples of each of these tissues and and sequence the ribosomal RNA and that will tell you what kind of bacteria is present ribosomal RNA is quite short so it's easy to sequence there's no ribosomal RNA and viruses of course so you have to sequence most of the viral genome which is harder and then you have to figure out what virus it is but nevertheless we know that in all of these places where there are unique bacteria there are also unique viruses not just bacteriophages there certainly are bacteriophages in each of these compartments that infect the microbiome but they're also cells viruses that infect our cells themselves and this is a picture of that there on the left hand part of the slide is a diagram of a human and the pie charts show you the numbers of DNA and RNA viruses in each compartment nervous system respiratory tract Etc so viruses can have either DNA or RNA as genetic material the only organism on Earth that has RNA everything else is DNA based so we will talk about why that is or how that came about so we have both RNA and DNA viruses look on your skin on your hair and nails you have viruses even in your blood and so all of us have this our blood supply is full of viruses you cannot throw away blood just because it has viruses in it because you wouldn't have no you would have no blood supply and we haven't yet made artificial blood so we can't do that we throw away blood when it has a virus that's known to cause disease but most of the other viruses we leave alone so most of these viruses we think are benign and we suspect that some of them may be helpful actually although that's that's harder to find out now the other picture here on the right illustrates how we can sample the viral of different animals or hosts using different methods and this is a sampling of whales off the coast of Australia and at the bottom is a drone and the Drone has on it a Pete a big petri dish which is going to open up as the whales exhale and of course there's a there's a scientist on a boat nearby and they're controlling the Drone and they're opening the um the lid when the whales blow so let's see if the movie will play there you go that so let's do it again the whales blow he opens here she opens up the petri dish closes now it's got liquid in it they bring it to the lab and they can sequence it and you can find in whale breath lots of different viruses you have to say whale breath because you don't know what's actually in the whale it may not be representative of what's in the ground it might be a subset so harder to get inside the whale right only if the whale washes up dead and then even then it may not be representative so this is the best that we can do we find many many different viruses there lots of viruses in every organism and of course every organism also has a viral nucleic acid in the form of DNA integrated into their genome this is a map of the human genome 3.2 billion bases with all the different elements that are encoded which many of you may have encountered in some of your biology courses but look at the protein coding genes only one and a half percent of our of our DNA I find that amazing every year and there are lots of other unique sequences but the ones I want to point out here are the LTR retro transposons about eight percent of our genome is viral these are from viruses that have infected us and integrated their DNA into our genome and in fact some of these other elements lines and signs have also elements reminiscent of viruses which we're going to talk about so big parts of our genome are are related to viruses now of course not all viruses are benign or beneficial many of them cause disease not just in us but in other animals dogs and cats get sick minks dear all of our all the hosts out there can can get sick and in humans we are we are concerned about human disease of course and that drives a lot of virology and this is a graph of the causes of 2017 Global deaths there's a very nice website our world and data.org has all kinds of data but this year they did not have this same chart which is arranged by disease as you can see the cardiovascular diseases are the biggest killer so this is for one year about 18 million deaths due to cardiovascular diseases and then we have cancers and of course um respiratory disease is 3.91 million in 2017 but covid of course is it has killed at least 6.7 million people globally as of a few days ago I say at least because this is an underestimate we often don't mark on the death certificate cause of death covet could be heart attack or stroke or something else secondary to covid but often covet isn't mentioned so this is an underestimate so that would put it in the number three position here so there's many many respiratory diseases of course are caused by viruses so I have the arrow there to show that then we have diarrheal diseases many are caused by viruses bacteria as well HIV AIDS a million people died in 2017. and that's a pandemic that's been going since 1981. a lot of people still dying and then hepatitis down there at the bottom a number of viruses cause hepatitis so don't underestimate the role of viruses in human disease despite the fact that many of them may be benign so here's a final summary for you of the covid pandemic these are graphs of on the upper left daily new cases this is a seven day running average starting with January 2020 when the pandemic began by the way I was teaching this course in January 2020 on the first day I said anybody here this respiratory outbreak in Wuhan and three people raised their hand that was you know January 17th or 18th and every class after that for the first five minutes I would put up the Johns Hopkins chart and we would see the dots increasing in number and then they started to spread outside China and of course Spring break that was it we all went home and never came back and I'm freaking out because I'm teaching a virology course and it's making me stop teaching that was just the most the weirdest thing I've ever encountered so so far you can see they've been periodic waves of infections for various reasons do variants have Arisen seasonal people getting together we lock down then we come out of lockdown boom you have a lot of cases people go back to school they go on vacation and that's on the upper left the number of cases 671 million cases but again an underestimate because we don't test everyone I don't know how much of an underestimate and then the debts on the bottom right there daily debts you can see again many waves and and lately it's been much lower because of vaccination but it's not zero and we can talk about reasons for that later on so despite this in these diseases I've just shown you most of the viruses that infect us don't really cause disease they seem to not have an impact on our health and well-being so why is that why are we able to handle most virus infections well many viruses we eat and they pass through us they're viruses of insects or plants and they can't infect us and so here's an interesting study where they got cabbage from five different supermarkets in Washington DC and they looked for viruses and they found that each serving about a hundred square centimeters of cabbage had up to 10 to the eighth particles of an insect virus and the insect is the Cabbage Looper shown there on the right and green it looks like a caterpillar right this virus infects them they crawl over the cabbage and they shed virus and you can't wash it off adheres very very tightly so you eat it and it passes through you it's a it's an insect virus that's the virus that long virus particle shown there that's the virus and it will not infect human cells so they pass through us now if you take human feces there's actually a company uh where you can send your feces to and they will sequence it and tell you what viruses you have in your poop I get emails all the time from people freaked out oh my God I have a pepper mild model virus in my poop what's that is that a problem well pepper mild model virus is a virus that infects Peppers it's a RNA virus it's filamentous as you can see at the bottom and the pepper on the right is infected so it gets this modeled surface on the pepper and most of if you sequence your poop 91 of the RNA you find is this virus I guess people like peppers and also ground pepper as well can have this in it so many viruses pass through us and these are just two examples some viruses are beneficial we have lots of examples of viruses that are beneficial for non-humans it's hard to do these experiments in humans so here are two examples on the left that's a grass dicanthelium language genosum it grows near the hot springs if you ever go to Yellowstone and see the pools of hot water there are grasses that grow around it and these are heat resistant grasses and the reason they're heat resistant is because they have in them a fungus that's infected by a virus and you can bring these grasses into the lab and grow them at high temperatures 55 degrees Centigrade you can take out the fungus and the virus and the plants will die if you just put in the fungus without the virus the plant will also die so you need the fungus virus combination to somehow confer thermal tolerance and this is a theme actually in many wild plants if you go into the forest and take a plant they often are thermal tolerant drought tolerant tolerant of many things because they have viruses in them and the crops that we use for our food for corn and wheat and potatoes they're what we call monocultures they're derived from a single seed and they have no viruses in them so they're kind of wimpy and so one thing that people are trying to do is to introduce viruses to make them more robust so that's one example and then on the right is a virus that is good for wasps but not so much for caterpillars so that's a parasitoid wasp and what it does is it injects its eggs into a caterpillar and you see it's got a long injector at its tail and and the eggs are shown in as oval and yellow so the WASP bag goes in and along with the egg goes virus particles those blue particles are called polygena viruses they're encoded in the WASP genome so as the egg is produced the viruses are produced and they both go into the caterpillar together and what those viruses do is they immunosuppress the caterpillar because otherwise without the virus the caterpillar rejects the WASP bag and that's the end of it isn't that amazing the viruses produce G expressed genes that immunosuppress the caterpillar and prevent it from rejecting the waspects or the WASP bag grows it becomes a little wasp and it eats its way out so this is the original alien great it it eats its way out of the caterpillar not the movie but then again anyway the virus is obviously good for the wasp and it has evolved over many years to be part of the WASP genome really interesting doesn't do anything to the wasp now we do have something close to him as a mammal this happens to be a mouse experiment and you can argue whether it's relevant or not to humans but I'll tell you the result this shows us that a virus that affects the enteric tract of mice is beneficial so in mice these are sections of small intestine conventional mice here on the right very nice Villi very nicely formed and there's an immune system in the gut which consists of T cells and so those are staining Brown in the lower two segments those brown cells are T cells if you grow mice under germ-free conditions where they have limited numbers of bacteria that prevents the gut from developing properly so you can see on the left GF is germ free the Villi are malformed and underneath there are no lymphocytes so somehow the bacteria in the mouse got the microbiome facilitates the development of the Villi and of the immune system now if you take these germ-free mices now infect them with a murine Norovirus so neurovirus is a cholecy virus related to that same virus that infected whales that we saw some time ago you partially restore the defect so the Villi look a little better it's not 100 but there are some lymphocytes in the Villi as well so you have a partial restoration the idea being that somehow norovirus which colonizes mice contributes to the formation of the gut and and the gut immune system so you can't do these experiments in people and so it's hard to know if the same would happen in people we're going to have to wait for other experiments and one year in this class someone came up afterwards and said if we had broad spectrum antivirals you could find out right and yes someday we're going to have broad spectrum antivirus we're going to treat people and get rid of all of their viruses because we're trying to get rid of a few and then we'll see if that's a problem we're going to inadvertently see because as you know we treat people with antibiotics and we cause problems because we cause imbalances in the microbiome so it may be that we'll see similar things when we have a broad spectrum antiviral we don't have one yet now the other reason most viruses don't cause any problems in us it's because we have this amazing immune system which blows me away on a daily basis the more I learn about it it's just amazing and it keeps most virus infections in check we will devote two lectures to this which is just a drop in the bucket I know many of you have taken the Immunology course here so you'll you know a little more but we'll talk about how viruses interact with the immune system but the immune system keeps our viral in check and we know this because if your immune system is down why would it be down well if you have an organ transplant and you have to take immunosuppressive drugs then viruses begin to multiply and cause problems a whole field of transplantation virology has arisen to treat patients who are getting liver transplants to make sure the viruses in them don't take over and kill them or you could have a virus infection that immuno suppresses you like HIV is strongly immunosuppressive other viruses will then arise and cause problems and other viruses will immunosuppress as well measles virus immunosuppresses you so we depend on this wonderful balance between the immune system and viruses to keep us healthy now now as you may gather I have said multiple times already not all viruses make you sick and I wanted to give you this wonderful example of a DNA virus called polyoma virus that infects everyone you get infected early in life and you typically get the virus from your family members and so it turns out that this is a wonderful virus to track human migration because you get slightly different viruses of this polyoma virus type depending on where you live and so this map shows you migration of humans Out of Africa where we began as Homo sapiens and the um the dotted purple line is the migration based on the genome sequencing of humans Right Out of Africa into Europe eventually Asia and North America but the black line is the migration based on polyoma virus we can take blood from various people and see what kind of polyoma virus infection they had we can trace migration and you can see it follows the genome but it's even more detailed you can see movement into australasia and South America as well so it's a virus that doesn't make us sick but it can give us interesting information now viruses also shape populations obviously if the viruses are killing cells or animals they can do that and a great example which we'll talk about more are viruses that infect eukaryotic phytoplankton so this is a bloom this is an algal bloom in the ocean it's a satellite photograph under certain conditions they get huge and you can see them from outer space it's an organism called emiliana Huxley eye and so when the sun comes out the blooms increase and then there are always some viruses around that will infect this organism the viruses collapse the bloom and it goes away so the viruses are shaping these populations and if you've seen green or blue or brown algal blooms in various Waters they're usually collapsed by virus infections so this is a little introduction to why I think viruses are amazing and we're going to explore all of these points in this course but maybe the most important thing to say at the onset is that virology is an integrative science it is not just one science it's not chemistry and I don't mean to denigrate chemistry chemistry is wonderful but it's chemistry and then there's biochemistry and there's other Sciences but virology takes all of them to understand how viruses work you need to know cell biology biochemistry organic chemistry you need to know sociology to see how people interact with each other psychology all sorts of fields need to be understood in order to understand virology and that's what I mean by it being an integrated science now we're going to talk mainly about the viruses themselves in this course but you'll get a sense for how you would need to know other things to understand them so my goals for this course are to give you the big picture of virology and I want you to think about it as an integrative science not a collection of viruses I don't want to teach you about influenza and herpes and polio you will learn about some viruses but you know a virus course is a separate course and maybe one day I will teach that but that's not what this is I want you to get the principles here you're going to learn fundamentals and you know people are afraid of things that they don't understand so all the misinformation in our society and and relating to viruses that would be misinformation about vaccines about Mass use about all sorts of issues surrounding covet all the misinformation comes from people being scared they don't know where to get their information they turn to the wrong Source but you're going to get the fundamentals here you're going to be able to understand and no longer be afraid because you won't be uninformed and hopefully you can pass the information on to others and help inform them about it as well now one of my one of my pet peeves that you will hear me I do some ranting in this course I figure it's my pulpit and I can rant but I have good bass strands and one of them is all about mutation we're going to talk a lot about this in the course and the covid pandemic has given me lots of raw material to complain about so let me just give you a little example these are various headlines from the very beginning of the pandemic January 2020 December and it's all about mutation um coronavirus could mutate China warns virus could mutate there is the possibility of viral mutation the coronavirus is mutating these are like headlines saying the Earth is round this is these are the dumbest headlines you could write because viruses are always mutating every time a virus multiplies you get mutations so these headline and you know when you talk to the the authors of these articles they say oh but the headline writers did it I didn't do it they always passed the buck to the headline guys well maybe some of you will be headline writers someday and so you will know what kind of headlines not to make and I'm not explaining this right now I'm going to go into it later why it makes no sense to write that viruses are mutating there's something else that you should be saying what is a virus anyway so here we are 40 minutes in what's a virus so this is my definition and by the way you guys know chat GPT right is that what it's called Chad GPA yeah so I asked it what is a virus and it gave a pretty good definition actually it's the mind is better because it's sure it's short and infectious obligate intracellular parasite with genetic material could be DNA or RNA got a protein coat and sometimes a membrane so chat GPT didn't have some of these complicated words didn't say infectious obligate intracellular parasite so what does that mean infectious of course means the virus can enter a cell or a host and reproduce and then spread to another one obligate intracellular parasite means the virus has to get inside of a cell in order to reproduce and being a parasite means you take something from The Host you take something away from the host so viruses take all sorts of materials in order to reproduce themselves sometimes they kill the host which is the ultimate parasite right but you can have different levels of parasitism then we can have DNA or RNA you have to have at minimum of protein coat so some of these viruses here have just a protein coat so here on the lower left is poliovirus which just has a protein coat surrounding an RNA genome this is adenovirus with the little Sputnik looking things there's DNA inside of that protein coat but many viruses also have a membrane around that as well so here's a coronavirus where we have a membrane around the nucleic acid which has got protein on it as well and many of these other viruses which we'll encounter in this course have membranes as well so this is a one sentence definition of what is a virus or that the chat GPT was like three paragraphs a little too verbose you get lost because viruses are obligate intracellular parasites or molecular parasites that studying them tells you a lot about the host and we've discovered many host functions by studying viruses like splicing of mRNA was that was discovered in a virus infected cell and many others as well and so whatever hosts you study whether it's a mosquito or a eukaryotic flagellate or humans or plants you can learn something about the host which is a nice benefit and now the question comes are viruses alive are they living so for a while I had a poll on my blog it disappeared but after so many 6 000 or so answers this is what we got two thousand voted yes 2200 no and then 2 000 something in between I mean I put these these answers in myself I don't think I should have put something in between and I I don't know what's in between right so but it was a long time ago and then a few people don't know so are they alive or not so I thought about this a long time and here's my take on it you don't have to agree um I think a virus is an organism with two phases the one phase is the particle so on the left here this is a polyama virus that's the virus particle so when I say particle I mean the virus itself some people are confused by me using the word particle but what I mean is the intact virus infectious particle all right that is not living it can't do anything if I had a tube of virus here it would just sit there it would never reproduce it would never evolve it would never mutate because it needs a cell so how can you say a virus is living if you're referring to the virus particle and most people when they say virus they usually refer to that however when that virus infects a cell it transforms the cell into a virus making factory and the infected cell is certainly alive it's the other phase of a virus it's the living infected cell so that's why I say two phases the virus particle not living the infected cell is living it's the embodiment of the virus because it's making more viruses the virus has completely reprogrammed the cell to make more viruses so it's certainly part of this organism called the virus so that's what I think and makes it perfect sense but I think it's very difficult for many people to grasp and um still even my colleagues my science colleagues talk about viruses being alive and if you mean the particle that cannot be now I want to warn you that when we talk about viruses don't make them human please don't anthropomorphize them right they don't think if you read popular science articles they often do this to make it easier for you to grasp a virus's goal is to do this no a virus doesn't have any gold it's not alive it is a chemical that is reacting to its environment you can't say viruses think employee ensure exhibit display because they're passive agents now why do I say this am I just being a pain in the butt no there's a reason there's a reason for this is because if you start giving human qualities to a virus you're going to get it wrong at some point because you have no idea what is driving the virus you're putting human qualities on it and that is almost certain to be wrong so you could say the virus mutated because it wanted to do this but you'd be making an assumption that isn't tested so that's why I say don't give viruses human qualities it'll Cloud your understanding of their evolution they're better ways to express what's happening if we would like to know why a certain mutation is selected for we we talk about it in those terms we don't say a virus wanted to do this we don't say a virus wants to transmit to a new host there simply is no desire on the part of a virus it is passively moving from host to host if it happens to encounter the right host it'll multiply and move on if it doesn't becomes extinct and certainly many viruses have done that over time all right try and be aware of that it's really important now viruses are small part of the original definition I used to give in this course is viruses are very small so here's a slide that kind of illustrates that we have E coli 100 000 X and there's a bacteriophage attached to the E coli and then above the bacteria the E coli is a rod-shaped virus that's tobacco mosaic virus the first virus discovered that's C and then above that D is HIV one so you can see they're smaller than E coli and then that little panel in a we magnify that a million times and then on the right you can see another virus H is actually poliovirus and G is a ribosome so polio virus about the size of a ribosome and then above it we have f is an antibody C is a TRNA I believe and and these are all various molecules inside of a cell so they can they can be quite small however they are actually bigger than we thought they were here's a nice scale to give you a sense of this so here we have a range from plant cells and this is the size here animal cells bacteria viruses ribosomes proteins small molecules and atoms so viruses somewhere in the middle here and the various techniques that you need to see viruses you can see most viruses you can't see an electron microscope you need a in a light microscope you need an electron microscope or you can do cryo em or x-ray crystallography things that we're going to talk about later and here on the bottom is a picture of a cell to give you again more sense of scale here's a cell with its nucleus and there on the surface of some virus particles and they include poliovirus again about the size of ribosomes ribosomes are 20 nanometers polio about 30 and there's the herpes virus which is substantially bigger so in the early days of this course I used to say a virus is a small intracellular obligate parasite but then we discovered giant viruses so if you're interested in how many viruses can fit on the head of a pin by the way there's there's a website from which I took this there's the head of a pin uh that is a hair laid on top of it there's a dust mite and in this boxed area or a variety of organisms we have red blood cells we have bacteria yeast pollen and in there are some viruses that's actually Ebola virus which is quite large so if it were rhinovirus which is about the size of polio you could put 500 million rhinoviruses on the head of this pin huge numbers and when you sneeze you are firing out droplets that contain many many different viruses that can infect many people now about 15 years ago we discovered really big viruses bigger than any we had seen before and those are the Mimi viruses shown here and in comparison we have rhinovirus HIV which was considered quite large here's a Mimi virus which was even bigger and here's a cell infected with Mimi viruses which I think is kind of cute looks like it's looking at you subsequently we found even bigger viruses and now we have a whole collection of viruses that we call Giant viruses where the particles can be seen in a light microscope this is Pandora virus and these are Pandora virus particles photographed in a light microscope they're one and a half microns in length so very few viruses are visible in the light microscope this is one of them why is it called Pandora virus well when the genome was sequenced which was about two and a half million base pairs of double-stranded DNA ninety percent of the genes didn't look like anything we'd ever seen no no protein looked like any of them so they called it Pandora virus because we didn't know what was inside the Box so we now have very very big viruses now the way viruses reproduce is important to understand they're very different from our cells and from bacteria viruses reproduce by making the parts and assembling them in cells they don't reproduce by binary fission so binary fission is when you take a single cell like this single bacterium you put it in broth and it doubles it becomes two and four and eight and sixteen and so forth that's binary Division and so the number of cells increases logarithmically with time but cells don't do that they don't divide they go into a cell they make parts to make new virus particles and then the new virus particles are assembled so here is this an experiment where we infect cells and then we ask is there infectious virus present at different times after infection and you can see there's a period of time when we don't see any viruses that's because the nucleic acid comes out of the viruses that we put into the cells and it directs the synthesis of proteins and eventually those proteins assemble into new virus particles and then we can see new infectious particles being made so this Eclipse period is key to distinguishing viruses from bacteria because there's no Eclipse when we put bacteria into broth they begin to divide relatively quickly so an essential difference between viruses and bacteria okay how old are viruses they're very old we will learn in a different lecture how you can date viruses but the best estimate so far we have is that some of them arose in the sea about 450 million years ago that would put them in the ordovician period there where the first land plants were appearing and that's those are the kinds of organisms that lived in the oceans at that time but in fact I will tell you when we talk about Evolution that viruses probably existed before cells arose on the planet and I'm sure you're thinking wait a minute you just said viruses were obligate intracellular parasites what are you talking about well we think before cells right there we're kind of an organic soup forming on the planet and we believe that self-replicating nucleic acids arose that could propagate on their own it was probably RNA and those were the precursors of viruses and we will talk about that later on and that's billions of years ago when the planet cooled and it was possible for these chemicals to form more recently though we see references in the historical literature to viruses that that uh vase there or from 700 BCE talks about a rabid Hector which rabies of course caused by a virus and this uh carving on the right from 1500 BCE is an Egyptian priest with a withered leg that looks like he had polio so we can find lots of references to what look like viral diseases of course no one knew what viruses were at these times no one knew what infections were we did start to vaccinate though in the 11th century in China they realized that people who recovered from certain diseases never got them again so they said let's give people the diseases on purpose so that was called variation it was done with smallpox and it made its way to Europe and Lady Montague was the British ambassador to Turkey and she saw this being done in Turkey so she brought it back to the UK we had no idea what was going on we just knew that people who got it got some kind of disease never got it again so in the case of smallpox they would take the pustules and blow them into the nose of someone you can see there or rub them on the skin and unfortunately that had you know a 10 to 20 percent fatality rate would not be approved by the FDA these days but they thought it was better than taking your chance now in the 1790s Edward Jenner in the UK did experiments to establish vaccination and we're going to talk about those when we talk about vaccines but again Jenner had no idea what was going on we didn't know anything about any kind of infectious agent no bacteria no viruses at the time concept of microorganisms took some time to be established we had live and hook in the 16 1700s who made the microscope the first microscope and that's important because people up until then thought everything they saw was all that there was on Earth there's nothing smaller and he showed that there were tiny things that existed in fluids including bacteria Pasteur in the middle there said found that bacteria could do various things they could ferment wine and cheese and then Edward cook in Germany found that some bacteria could cause disease so this established this concept that bacteria at least could cause disease and even had beneficial properties as well so then where does virus come in if you take a look at the Historical literature you can find virus as early as 1728 and it's used in a different way from what we'd use it today it was used to describe something that causes an infectious disease so by this time it's recognized that people give diseases to one another and they were called infectious diseases and they were called viruses virus means liquid or poison in Latin so viruses were thought to be liquids and passed from one person to another and in fact Pasteur said famously that every virus is a microbe but he wasn't talking about the viruses that we are going to talk about in this course he was talking about any anything that made you sick any infectious agent and he knew about bacteria at that point so here you're saying basically bacteria or or microbes our viruses [Applause] a key event in our understanding of viruses came from this guy Chamberlain he used to work for pastor in Paris and he he found that the water that he used for his experiments you know the water coming out of the tap was really dirty so he wanted to clean it up so he made this filter it was a porcelain filter and he used it to filter the water to remove bacteria to use in his experiments and Pasteur was doing experiments on rabies he we knew that dogs got rabies and he found that whatever was causing rabies and dogs was passing through these filters so he said oh it's a small bacterium causing rabies right okay then at the end of the 1800s you know by then tobacco is a big deal people are smoking cigarettes and pipes and cigars and so forth huge industry and tobacco develops this disease called tobacco Mosaic disease where the leaves are have this mottled look to them and so scientists want to figure out what it is and maybe get rid of it and so they do some experiments and they use this filter of Chamberlain they grind up the leaves in a buffer and they ask does the agent go through or is it retained on the filter if it's retained it would be a big bacterium different groups did this ivanovsky at Bayer Inc and they found that the agent passes through filters that retain bacteria so some people thought well it's a small bacterium but others said oh it's something different because it doesn't multiply in broth so the agent goes through this filter today we have similar filters which you can buy they have about a 0.2 Micron pore size it's roughly what the porcelain filter was viruses will go through them bacteria are retained so the tobacco Mosaic agent is going through the filter and the key was it didn't multiply if you just put it in broth it would only multiply if you put it on leaves and that was the difference between it and bacteria in 1898 the foot and mouth disease agent was shown to be filterable filter foot and mouth disease is a virus that causes disease in cattle you can see mouth lesions here this is agriculturally very important you don't want this in your cattle farm if you're if you're selling cows that agent goes through the filter and the key again is not just small but it doesn't reproduce if you put this agent in broth it doesn't multiply you have to put it in the cow or in the leaf the tobacco leaf so we have something small going through a filter it doesn't reproduce except in the host and this is used as an operational definition for viruses for some time they're called filterable viruses because there's some people still think they're small bacteria so they call them filterable they just go through the filter so they're filterable viruses and these are this is a list of discovery of some of these viruses you can see all viruses causing human diseases yellow fever rabies smallpox is variola a polio virus two viruses of chickens in 1908 and 11 which will come back to bacteriophages influenza virus now after 1933 something changes this by the way is the the timeline of discovery of bacteria so as soon as Coke developed bacteriological methods explosion in their Discovery discovery of tobacco mosaic virus and read lots of viruses are discovered over the years but in 1939 a key Discovery was made by the electron microscope so Helmut ruska had made the first electron microscope in Germany in 1933 and the first electron micrographs of bacteria were made this is one of the first ones and lo and behold they're particles they're not liquids this blew people away and they're not bacteria either this is the bacteria here they're obviously something much smaller so not until 1939 do we stop calling them filterable viruses now they're their own thing they're just viruses and then in this experiment which we've already encountered prove that they're not simply small bacteria so bacteria you put them in a broth they begin to divide right away viruses you infect the host there's an eclipse period because the viruses need to get in start making the parts and assemble new virus particles so now we just call them viruses they're not filterable viruses now we have pictures of lots of viruses showing their particulate bacteriophage tobacco Mosaic rabies poliovirus it's quite clear that they're different from from bacteria we can solve structures now of viruses this is polio viruses at two different resolutions very high resolution where you can see all the atoms and a much lower resolution where you can only see the surface and we'll talk about how these are done in a subsequent lecture and we now classify viruses because we discover so many of them and we typically just nowadays just sequence The genome and we can immediately classify it into all the existing viruses that we had in the old days we used to use other criteria like the kind of shell whether it had a lipid the dimensions but we don't use any of them SARS cov2 first sequenced immediately it's a coronavirus that's it you don't have to do anything else and we'll talk a little bit about that as well we use the line system for classifying and for viruses we typically talk about families so filoviridi we talk about Genera that would be Ebola virus and then species Zaire or Reston or Sudan Ebola virus these would be species as I told you at the beginning of the 1900s virus Discovery is driven by disease now we just want to see what's out there and we get samples and we sequence and we look for viruses so here's a cool study done in China a number of years ago where they got 220 invertebrates insects crustacea nematodes Etc they ground them up and they did the sequence we can do very very rapid genome sequencing nowadays that we can discover many many new viruses this way and these 220 invertebrates they found 1400 new viruses that we hadn't seen before so you can do this with soil you can do it with water with your blood it's just amazing what we can discover so why do we care about any of this well viruses outnumber cellular Life by ten to one on earth they're the greatest biodiversity on the planet they they drive Biogen chemical Cycles as I told you they shape host populations they're likely to be beneficial and of course all those viruses out there are potential sources of new pathogens so this sounds complicated but in fact as we move into this course there are two facts that are going to help sort all this out first of all all viruses are parasites they need to get into a cell in order to replicate and all viruses need to make mRNA that can be translated by the host cell no virus encodes a translation system so the MRNA that viruses need make need to be translated by the host cell so we'll see over the next couple of sessions how you can use that to simplify all those billions and billions of viruses out there so next time we're going to talk about the Infectious cycle that is what happens when a virus gets into a cell and then new virus particles are made [Music] thank you [Music]