[MUSIC]. Good afternoon, everyone. [SOUND]. My name is Vincent Racaniello. Welcome to virology.

We live and prosper in a world full of viruses. Earth is full of them. Viruses infect everything. All living things on earth have some kind of virus, and most of the time we haven't actually discovered it yet, but everything that we know of probably has a virus that infects it. We ingest. We ingest. We breathe in. We take up viruses by the billions on a regular basis. This room is teeming with viruses, especially at this time of year, when there are lot's of respiratory infections going around. If you happen to have one and at least one of you have some sort of upper respiratory infection, you are exhaling viruses. This room is full of them, and if we sampled the air we would be able to isolate them We carry viral genomes as part of our genetic material. We cannot escape viruses, and as you will see in this course, not only do they make you sick, but they probably are responsible for your health as well. The numbers, when we talk about viruses, this is one of the main things. I want you to appreciate through this course, the numbers of viruses on the planet are staggering. And this is one of the reasons why they are so successful. For example, bacteriophages, viruses that infect bacteria, there are more than 10 to the 30th of these viruses. In the oceans of the world. That's something like a couple of million virus particles per teaspoon. So every time you go into the ocean, and you take some water in your mouth and you spit it out playfully, you are aerosolizing many many millions of viruses. It's not harming you at all. We are all, we do that all the time and we're very healthy. Now, just to give you an example of what happens when you have numbers like this. If you calculate the total mass of just

these bacteriophages in the world's water, it exceeds the biomass of elephants, by more than 1000-fold. So, these are things you cannot see. Right? With the naked eye you cannot see them, they are so tiny. Yet, their biomass is incredible, simply because there are so many of them. If you line them up head to tail, these bacteriophages ten to the 30th of them, that would go. That line of them would stretch for 200 million light years. That's a long ways, and these again are things you can barely see, and someone actually did these calculations. You can go check out this. This website to see that. 200 million light years is pretty far. The closest galaxy, is two and a half million light years away. So that's remarkable. And those are just the bacteria phages, in the oceans. Whales are infected with small RNA viruses. Diagrammed here called Calisi viruses. And these are viruses that, are well known to cause disease in humans. They cause gastroenteritis. In whales, they can also cause disease. They can cause blisters and rashes. gastroenteritis and so forth. And sometimes the whale viruses actually infect people. This happens very often in the world of viruses; these are called zoonotic infections. Animal viruses infect people. In fact, most of the viruses, I would say all of the viruses, that we have right now came from animals. These whales excrete 10 to the 13th Virus particles every day in their feces. It's a huge number of virus particles. And every other living thing in the ocean also has its own viruses. All the other mammals and fishes as well have viruses of their own. If you look at the biomass in the world's oceans This is simply a pie chart showing the fraction that's prokaryotic. protists and viruses. We don't even show the eukaryotes here because they would be such a small sliver. So the prokaryotes by mass alone predominate in the oceans' waters, but by abundance, by shear numbers, you can see

the viruses predominate. There are just so many of them, and these viruses play really important roles. In the biology not only of the ocean, but of the whole planet. There are so many infections per second in the surface orders of the ocean, that turns over amazing amounts of carbon and contributes to geothermal cycles that are important for regulating the entire globe. So they really have an amazing effect on the planet At the moment, there are 10 to the 16th human immunodeficiency virus genomes on the planet. It's a calculation based on the number of infected individuals. And how many genomes we know to be in each person. That number is so big that it means that it is likely that there are already mutant viruses resistant. To every antiviral we have at the moment, and we currently have something like between 20 and 30 anti-HIV antivrials. So already out there, there's, there's resistance, it just hasn't shown up yet. In addition, that number is so big, that whatever drug we ever make for the foreseeable future, the resistant mutants are already out there. That's how big that number is. That we cannot combat the resistance in simple manners. So how infected in fact are we? Well each of you is infected, besides these respiratory viruses that may be bothering you, you're infected with at least two of these herpes viruses. We'll talk a bit about herpes viruses in this course, there are quite a few of them: herpes simplex virus types one and two, varicella zoster virus, human cytomegalovirus, Epstein-Barr, and then the human herpes viruses six, seven, and eight. So each of you has at least two of these, these are what they look like, And once you're infected with the herpes viruses, you're stuck with them for the rest of your life. They, remain with you and sometimes reactivate to cause infections. And this picture of eggs is here to remind me that on the average we all have about a dozen different viruses. In us at any given time in addition to these two herpes viruses, some have probably more, some have probably less. these viruses for the most part don't

bother us. They may initially cause disease when they infect [COUGH] us, but I think for the most part, they coexist peacefully with us, and this is an area that we know really little about. are these viruses of benefit to us. And we just, we simply don't know. Now, you all may be aware of efforts to determine the human microbiome. That is all the bacteria that inhabit on us and in us. There are many different microbes that we carry. And they're beneficial microbes of course, they do great things for us. And the NIH has been running a study for a number of years now to sequence and identify the microbiome at all these different body sites. So these are sites in all, all parts of the skin, the gastrointestinal tract as well. In other areas where we know bacteria live, and we'd like to know what they are because this simply hasn't been done. So that's the microbiome. There's also a virome, a human virome. That is all the viruses that live on and in us. For sure, these bacteria, these beneficial bacteria are infected with phages. That probably help them to carry out their functions that help us. But in addition, there are eukaryotic viruses. Viruses that infect our cells that probably are beneficial also. And there's no current plan to determine the human virome. It hasn't reached the prominence of the microbiome, but we do have viruses at all these sites and in our guts and in our lungs that have taken up residence there. And I think it's important to enumerate them and figure out what they're doing. Now, I mentioned earlier that we carry viruses as part of our genetic material. this is a pie chart. Which shows fractions of our genome. that is, that are dedicated to different purposes. So for example, introns. 25 percent of our genome consists of intervening sequences that are removed by splicing. and you can see a variety of other things here. What I want are, the protein coating

genes are, in fact, the minimum of our genome, amazingly. 8 percent of our genome, by sequence, consists of what are called LTR retro transposons. These are basically viral remnanats that are integrated into our genome. We'll talk a lot about that later on. They're derived from viruses called retroviruses. We carry them. And many animals do carry such, endogenous retro viral genomes. We don't make any infectious particles from these. But many other animals do. And they seem to have been with us for many many years. Perhaps from even before we became homo sapiens. >> And we don't know if they're of benefit or not. They, some people think they must be, because they've been maintained for so long. And there are some examples in animals where genes are expressed from these endogenous viral sequences, and they are of benefit. Yes. >> how do they figure out what [INAUDIBLE]. >> The question is: How do you figure out that these sequences are viral as opposed to something else? So, we have sequenced many viral genomes over the years. And so, when the human genome was sequenced And compared to all the known sequences, it became very evident that these were viral sequences. And you can even, you can identify sequences being viral even if they are 100 or 200 million years old. Because there's enough conservation. Now of course there are probably sequences that we dont' recognize that are viral. And there's not much we can do about that until we get some evidence that they are in fact from viruses. Anyway, you pass these on to your children and your children pass them on to them. They are hereditary, they are here-, they are inherited. And so what their doing is anyone's guess for now. Well, as I said, we'll be talking more about that later.

So, I've been telling you about all of these viruses that impinge on you. Constantly, but amazingly, for the most part, none of them really harm us, or very rarely do they harm us. We'll, we'll get a respiratory infection, we'll get gastroenteritis, but considering all the viruses that infect us or impinge on us on a daily basis, we're pretty healthy. And that's because we have this amazing immune system. Which is diagramed at the left here. And if some of you have taken Professor Mosowitz's immunologry course. I'm sure. How many of you have? Yeah, so you heard me talk about vaccines then. you know all about this. We'll talk a little bit of immunology in this course as it relates to virus infection. But for those of you with a great immune system, you're pretty healthy with repect to virus infections. But when your immune system is down, if you have AIDS for example, that's an immunosuppresive infection, measles is a immunosuppressant infection, or if you have an organ transplant and you are immunosuppressed because you are being given drugs that Prevent rejection of the transplant. Then even the most innocuous virus infection can kill you. So this immune system is incredibly important and we'll be talking a bit about that in this course as well. Not all viruses make you sick. In fact virology is tainted in a way because the field arose. To study virses that made humans sick. And it gets money and support for research to solve health problems. The National Institutes of Health, right, NIH, is aimed at keeping you healthy. But I think, and many others do There are plenty of viruses in us that don't make us sick and perhaps they even help us. And let me give you a couple of examples of that. So on the upper left here in this light is a polyoma virus. These are rather small viruses that have DNA genomes and there a variety of polyoma viruses that affect all sorts of animals. We have about a dozen different sorts of polyoma viruses that affect us.

I would say if we took blood from all of you and look for antibodies to these polyoma viruses, 95% of you would have antibodies. That means you were infected at one time with one of these polyoma viruses and we're not sure if they cause any disease at all. In fact, antibodies to these have been used to trace the migrations of peoples from their origins in Africa to Europe, and Asia, and the Americas. So you can distinguish the different polyomaviruses by serum antibodies. And then you can track those, the movement of those, in migration. It's really quite an interesting story. And on this slide what I am showing you is the predicted migration of homo sapiens from Africa to Europe, Asia and the Americas. The black line is what is known from our genome. If we compare the genomes of All the individuals on these different continents. This is the map of migration that was derived from that. The dotted line is a migratory map based on antibodies to these polyomaviruses, which again are in many, many people without apparent consequence, and you can see that this traces a slightly different path from Africa to Europe. to the northern parts of this continent. And this dotted line, this path which is traceable by, antibodies, by cyrology, cannot be detected in our genomes. So it's telling us something different. Here's a wonderful, one wonderful example. Of a good virus in nature. There are, there are dozens of these. We could spend an entire hour talking about them. They're fascinating. And this one is in a plant. this is called a panic grass. And it lives in environments where the temperature is over 50 degrees Celsius. So, you go by Yellowstone Park by the geysers and the hot springs, you will find these grasses growing right there. They can grow in very high temperatures. A number of years ago, it was found that in order for these grasses to grow at high temperatures, they have to be colonized by a fungus called Curvularia protuberata. So if you take the plant into the lab,

and you, you cure it of the fungus, it will now not be able to grow at 50 degrees. It turns out that the fungus, in an, in turn, is infected by a virus, and both the virus and the fungus are required in order for the plant to live at high temperatures. So the virus Is part of this symbiosis here. The, the fungus gets to grow on the plant, and the plant grows at high temperatures because of both the fungus and the virus, and again, there are many, many really neat examples of this kind, these kinds of symbiosis. So basically this was just a little. Tantalizing view of virology if any of you are thinking maybe this course isn't for you. Virology is just amazing. Viruses are amazing. And this course is going to teach you why we think they are, and how they are amazing. So that's our goal. And if you stick with us, by the end, you're going to know more than 99.99% of the world's population about viruses. because in fact. Most individuals know very little, and one of my goals is to impart that knowledge to you because you're going to go out into the world, and you're going to look at headlines and newscasts about viruses and I want you to be able to distinguish the ones that are. Completly wrong from the ones that are right. And I can tell you by having looked at the news media over the years, that most of the virus stories are reported incorecttly. For example, here is a shot from a CNN news program 2009, when we had a pandemic influenze virus. Emerge, and this, this person was saying this virus can ravage the lungs, spread through the respiratory system, causing lesions. It doesn't stay in the head like "seasonal flu." That isn't even right, because [LAUGH] seasonal flu moves into your lungs, for sure. That is influenza. It's not an upper tract infection, but these two Statements were based on a study done in ferrets. And it turned out that they were the complete opposite of what the virus did

in people. But what are they doing here on CNN? They're trying to scare everyone and get people to watch and go "Wow, that's amazing what they're doing." And this is completely wrong. So if you didn't know anything about virology, you'd watch this and "Oh my God, what's going to happen here?" I want you to go and be able to distinguish between all of these incorrect news reports. Now, it's not to say that all of them are wrong. But many of them are wrong, and I hope maybe some of you will be journalists some day. And you'll know to write the right stories. But if not, you can email me and ask me if that's correct or not. Here's another example. This is a story which we will dedicate a lecture to at the end of the course. Avian influenza virus, H5NY. At the begininng of 2012, the end of 2011 actually, a couple of investigators. modified these viruses so they could be transmitted by the, in the air by ferrets. Now these avian viruses kill birds but they're not very good at transmitting from person to person. In fact there's no evidence that they can do so and these investigators made a strain that could transmit in the air among ferrets. The New York Times Said they were making an, an engineered doomsday because they were afraid that the sequences of these viruses would get into the hands of bioterrorists and they would be used to make a weapon of mass destruction. The New York Times didn't even have the paper that described the results and they said the work should never have been done. Looks like the research should never have been done. It turned out that these viruses were not lethal in ferrets at all. They gained the ability to become aerosol transmitted. But they lost fitness as a consequence. And they were no longer virulent. The New York Times didn't know that. And even if they did, I'm not sure they would have understood it. So again, I want you to be able to read something like this and understand what's

right or wrong about it. So here's my overview of what I want you to learn. I want you to learn the big picture of virology. You noticed the syllabus, this is not a course where each lecture is on a different virus. [INAUDIBLE]. That is not the way to learn virology. That's a good way to investigate specific viruses later on. But for a first virology course, what you need is an integrated overview of the whole field. And the only way you can do that is to get away from the one lecture, one virus approach. Many people do that. I have lots of colleagues who I highly respect. And they say to me. Vinnie, I can't teach the way your book is written, I got to teach virus by virus. And I say, you're wrong I do it every year and it works. >> [LAUGH] So, you're not going to learn, for example, basic principles of pathogenesis by me teaching you how flu does it, how herpes does it, how ebola virus does it. So that's why we have lectures on attachment and entry, replication, packaging and so forth. So that's what I mean, we want you to think about virology as an integrated disipline. Not an isolated collection of viruses, diseases or genes. We're trying to give you the overview. Now once you've taken this course, That would be great for you to take another course where each lecture is a virus. because then you could go into it deeper. And I'm thinking of teaching that someday as well. That would be a fun course. But the prerequisite would be this one. And you're going to learn all about how these wizards amaze the informed, and frighten the uninformed. So that's it. If you don't know about viruses, you're scared. And there's no need to be most of the time, and I want you to go out into the world and be informed about viruses. [MUSIC].