Episode 2 - Viruses

Episode 2: Viruses

https://youtu.be/rQusne-g_ac

Welcome to Untangling Science, a podcast about science that is for everyone, with me Darragh Ennis. You probably know me as The Menace from ITVs quiz show The Chase, but my day job is as a scientist at the University of Oxford. In this podcast I want to bring the world of science to people who think it’s too complicated to understand in a way that is fun and straightforward. We have a website, www.untanglingscience.com and you can follow us on Twitter @untanglings . I have a blog on the website that I leave useful information, links and diagrams from each episode in, so check that out. In the first episode I discussed the molecule at the heart of genetics, DNA. In this episode we will talk about something that people became a lot more aware of in the last couple of years, viruses. We might use some things from the DNA episode so it would be good to listen to that first if you haven’t already.

One of the main things about science is that it answers questions. Whenever we have to talk to people about our work, the head of our lab always insists that the first thing we do is tell the audience what question we are trying to answer. I guess it’s become second nature to me now, so in this podcast we will try to open episodes with some questions. Now, what questions could we have about viruses? What exactly is a virus? How did we discover them? How do they reproduce? How do they cause disease and how does our body fight them? How do vaccines work and how were they discovered? How on earth did the Covid19 pandemic happen? Over the next 30 minutes or so I will try to answer these questions in a clear way that makes sense. Then, as usual, we will end the episode with a little look into modern virus research too. I hope that sounds ok to everyone, and now on with the first question: what exactly is a virus?

I have a good friend, Alfredo, who is a world leading virologist and I asked him one day “Are viruses alive?” He responded by telling me how controversial a question this is. It is regularly argued about by senior virus scientists and there’s not really been a solid conclusion. So, if the people who know most about viruses can’t even agree if they’re alive or not, what exactly are they? The Nobel Prize winning immunologist, Peter Medawar, once described viruses as “bad news wrapped up in a protein,” and that’s a good place to start.

Viruses all consist of some genetic material, either DNA or RNA, wrapped up in some protein. The overall shape of the protein bit has 3 main types of shape, there are quite a few weird exceptions but the majority are mostly one of these shapes.The first are filaments, so basically cylinder shaped. The second is kind of like a leather football, but not as perfectly round. If you picture the different shaped leather patches that are all together to form the round shape of the football, it’s similar in viruses. The last type of virus shape is sort of a combination of these two and has one of the roundish shapes on top of the cylinder, and the cylinder has little leg like structures sticking out of the end. It really looks like a spaceship of some kind and is called a phage. Seriously, look it up P-H-A-G-E, that’s what they actually look like. But whatever shape they are, viruses are all largely genetic material wrapped up in protein. There are again a few exceptions to this, but they’re rare so we’ll ignore them for this episode. Some of them use part of their host cells membranes to make an outer wrapper but otherwise it’s still DNA or RNA covered in a protein wrapper. They also have a very wide range in size, though they are all extremely small. To understand how small they are I will use a unit of length called a nanometer, which is 1 billionth of a metre. So it’s really quite tiny, and the smallest viruses known are only around 20nm across. That’s far too small to see with a normal light microscope. Even the very biggest viruses are only around 1500nm in length but the vast majority are much smaller than this, in the range of about 100-200nm. Take home message here is that they are very, very small. So if they’re so unbelievably small, how did we ever discover them. Well, like a lot of scientific discoveries it took a lot of different people working at it, and building up evidence to get there but the first steps involved something very unlikely, tobacco.

Now that might seem like a bit of a leap, but if you want to talk about the history of viruses then really you first have to talk about tobacco. Towards the end of the 19^th century, tobacco was an absolutely gigantic industry, particularly in the United States. In the years following the American Civil War, tobacco accounted for over one quarter of the internal taxes raised in the USA and it was grown on a massive industrial scale. The advantages of growing crops like this due to efficiency and ease of harvesting and processing are massive, but there are some real drawbacks. Huge concentrations of one crop can lead to a concentration of problems, notably pests and diseases. Around this time a disease started to spread in tobacco and other related crops like peppers. The leaves started to show strange lighter coloured patches, and they became very susceptible to scorching in hot weather. This was a huge problem as tobacco is grown almost exclusively in hotter climates. Even if the leaves didn’t burn in the sun, the patches grew and spread with many leaves shrivelling up which greatly lowered the value of the crop. As this disease became widespread people wanted to know the cause. And seeing as we’re talking about viruses in this episode, the word disease should have got your attention. Maybe it did and you’re now asking yourself, “Hold on, do plants get viruses?” It may seem weird but the answer is absolutely yes.

This particular virus is called the Tobacco Mosaic virus, named after the mosaic pattern it made on tobacco leaves. The economic damage caused at the time was immense and this led to a large investment in finding the cause. In the 1880s, the Netherlands were a hugely important hub of global trading, with much of the tobacco shipped to Europe being traded in Amsterdam. The government agricultural scientists were tasked with studying the disease in order to find out the cause and to figure out ways to prevent it. It was here that it was first named Tobacco Mosaic Disease by the director of the Dutch Agriculture Experiment Station, Adolf Mayer. Mayer and his team carried out a range of experiments to try to find an animal or fungus that was causing the disease but they came up with nothing. He then found out that if he ground up a diseased plant and sprayed these extracts on healthy plants they would catch the disease. Thinking that it must be a bacteria, he grew up all the bacteria found in these plant extracts in the lab, but none were capable of causing the disease. When they did the same thing with bacteria from other sources such as soil and fertiliser he got the same result. So while Mayer and his team showed what wasn’t causing the disease they were still stumped as to what was.

In Russia, a young scientist named Dmitri Iwanowski took this one step further. He took the plant extracts from diseased plants and filtered them through the finest filters available at the time. These filters were so fine that they were able to filter out even bacteria. Despite this careful filtering, the extracts were still capable of causing the disease. Iwanowski could not figure out what could pass through these filters and still cause Tobacco Mosaic Disease. The man who found out was a scientist back in the Netherlands, Martinus Beijerink. He looked into how infectious these filtered extracts were, and concluded that they could keep infecting plants indefinitely, despite being bacteria free. It was clear to Beijerink that the extracts contained a disease causing agent smaller even than bacteria and he coined the word “virus” for this agent.

RECAP: To make it a bit easier to take in all of this information, I’m going to try out having little pauses in each episode to summarise what we’ve done so far. Let me know what you think and if people like them I’ll keep them in. Anyway, here’s the first. So far the main things we’ve learned are:

• Viruses are small! Most are about 10,000 times smaller than a millimetre.
• They can have different shapes; cylinders, roundish, even funky space-ship shaped. But regardless of their shape they are all pretty much some genetic material wrapped up in protein.
• They were initially discovered because of a disease that they caused in tobacco

So, we now had a name for this too-small-to-see agent that caused disease: virus. The word is derived from the Latin for a slimy liquid poison. But what is it that they do? How did they damage the tobacco? How do they cause Covid19, ebola, flu, common colds, HIV, polio, hepatitis, measles, mumps, chicken pox, small pox, western nile virus and even some cancers? And that is in no way the full list, the range of viral diseases is huge. If all we are talking about is something so small it makes bacteria look huge, and it only has some DNA or RNA wrapped in protein, how is it able to wreak such havoc with our complicated bodies with sophisticated immune systems? Well to understand that we need to talk a bit about how a virus does the one thing it needs to do above all else, make more viruses.

In episode 1, we talked about DNA and how our cell uses it’s machinery to use it’s DNA instructions to make proteins. And proteins are the things in our cells that get stuff done. Now if our DNA is a 30,000-page long instruction manual, a viruses genetic information is more like a pamphlet. For example, SARS Cov2, the virus that causes Covid19 only has instructions for making 27 proteins and the HIV book has only 15. How does the virus function with 2000 times fewer proteins than a human in its genetic code? Well the simple answer is, it steals what it needs from our cells by hijacking the cells machinery to do the work for it. So, to make this a bit easier to understand, we will follow a virus particle from being sneezed out by one host, through to making copies of itself in a new host. And for this virus we will pick one that pretty much all of us have had at some point in our lives, an adenovirus. Now our adenovirus particle is sort of blob-shaped and is 100nm across. This means about 10,000 of them would be about 1mm across, so again absolutely tiny. Adenoviruses are extremely common and cause a range of diseases including tonsillitis, conjunctivitis and the common cold. We’ll pretend this is a documentary and have a camera in our mind’s eye as our tiny blob is sneezed out into the world. It’s floating in the air before someone passes by and breathes it in. A new host! Exactly what our little virus needs to complete its mission. But being inside a host isn’t enough, our virus needs to get inside a cell quickly. If it hangs around for too long the human’s immune system might find it! The virus lands on a likely cell, but there’s a barrier called a cell membrane all the way around it. How will our virus get inside the cell’s membrane? Well, cells need to have things enter and leave them all the time. Raw materials for the cell to function, such as amino acids to build proteins, have to cross the membrane all the time and to help them do that there are gates made of special proteins. Our virus has been around humans so long that it has evolved a way to open these gates in our cell’s outer membrane. Essentially some of the protein that forms the outside of virus acts like a key to get through these gates in our cell membranes. It’s this part of the process that makes most viruses only able to infect one host species. It takes a fairly big change in the virus for it to be able to jump the species barrier and infect another host. And not only does it need the right species, for most viruses they need the right kind of cell inside their host, so they look for a very specific lock to find the perfect host cell and use their key to open it. The cell wraps the virus up in a piece of its membrane that then closes off inside the body of the cell, s the virus is inside the cell in a membrane bubble. The virus then uses one of it’s proteins to break this membrane bubble that it’s in and it’s now loose in the cell. I will post a picture on the the blog post for this episode www.untanglingscience.com so you can see what’s going on.

Now our virus is inside the cell it needs to get busy making lots of new viruses. The viruses own very limited genetic instructions now come into play. The really clever thing is that the virus not only turns the cell into a hijacked virus factory, it also stops the cell from triggering its defences. The way I like to think about this, being a child of the 80s, is comparing it to the A-Team. In the A-Team, the gang would always end up locked up somewhere like a garage and they’d use all of the equipment they find there to build some fantastic weapon so they can escape and beat the bad guy. The virus enters the cell and uses what it finds in there to build lots and lots of copies of itself. When you consider how simple viruses are, this is truly amazing. Now that our virus has produced thousands of copies of itself they now leave the cell and infect nearby cells, eventually producing vast numbers of adenovirus particles some of which are then coughed or sneezed out into the world to find new hosts.

RECAP:

• Viruses are actually really simple with very few genes in their genetic instructions
• We followed a virus particle on its trip into a human host. It first enters using a protein on the outside that acts like the key to our cell membranes
• Once inside the virus hijacks the cell to make its proteins, to provide proteins from our cells own DNA and the suppress the cells defences.
• Thousands of viruses are made and then they leave to infect other cells and eventually other hosts.

Viruses, despite being extremely simple, seem to have us figured out. They even have, sort of, the key to get into our cells whenever they want. The reason why are we not constantly ill is that our bodies have very sophisticated defences that are always battling these tiny foreign invaders, our immune system. Our immune system is truly amazing but for today I’ll keep it simple and stick to how it fights viruses and how it can be given a push with vaccines. When a virus enters our body, like our adenovirus example from a minute ago, it is entering an extremely hostile environment. The vast majority of viruses are destroyed before they can enter our cells to wreak havoc. And even those that do can be detected and the infected cell can be destroyed before it produces thousands of viruses to spread the infection. How this happens is usually separated into two different systems, the innate and the adapted. The innate immune system is always on and works by reacting to any foreign thing found in our system. It detects viruses and gets to work destroying them. This involves special cells in our body that swallow up things like viruses wherever they find them. We’ll think of them as security guards that move around our body looking for intruders. Cells in the area of an infection also start producing chemicals that attract more of these guards and can trigger our body to raise its temperature and increase blood flow to the area. This fever and inflammation are usually the first signs that we are fighting an infection at all. While it might make us feel rubbish, it makes our body a harder place for the virus to live while increasing our innate immune system’s ability to fight the infection. Infected cells that have turned into virus factories can also be found and our system destroys these cells to control the spread of the virus. The innate immune system response is extremely quick and acts against pretty much any foreign invader that makes it into our system. The other part of our immune response, the adaptive, is one that is adapted to specific invaders that the body has seen before. When we get a viral infection our body learns to recognise the virus and it builds up defences in case that virus ever comes back. So instead of security guards randomly wandering our body, this is like a surveillance system with photos of previous invaders so they can be recognised and dealt with. This adaptive response can take days or weeks to put in place, so while it won’t deal with the very start of infections, it can mean that we become immune to a particular virus and is the reason why we have some diseases you can’t catch twice. It is also the reason why vaccines work. Now I know the whole world has become much more interested in vaccines lately, but this episode is about viruses so I will stick to how vaccines prevent infections by viruses. How does that injection into your arm actually do anything? To keep it simple I’m going to continue with the security system analogy for our body’s immune response. So previously we had our security guards of the innate response, and our more sophisticated surveillance system of the adaptive response. The adaptive response is extremely effective, but it has the drawback in that the guards in that security team need a good idea of what the virus looks like and they need to be trained to recognise it. This is where vaccines come in. When you are vaccinated it’s like your body training up its adaptive surveillance team in advance. A tiny part of the virus is brought into the body and this is what your immune system recognises. Your innate system still kicks into gear with inflammation and slight fever, which is why you can feel a bit rubbish after a vaccination and your adaptive response trains its team to jump into action should the real virus ever come along. Within a couple of weeks of being vaccinated your immune system is ready to fight the virus much more effectively.

RECAP:

• Our body responds very quickly with our innate immune response to viral infection
• Special cells act like security guards and they detect foreign invaders like viruses and attack them
• Infected cells can be destroyed before they produce lots of viruses
• The immune system also causes things like swelling or fever to help fight the infection
• The adaptive immune response learns to recognise particular invaders but it takes a few days to get going
• Vaccines are like drills to train your immune system to respond much more quickly if the virus ever does invade.

In the last section of each podcast I like to talk a little about some aspect of research in our topic. For this one I’m first going to cheat a little and talk about some work my lab was involved in. It was led by two friends of mine Wael and Marko (and Marko has helpfully proofread this for me to make sure I didn’t say anything too stupid about viruses) and was published just a few weeks ago. We have already talked about how a virus uses the cells own machinery to make lots of proteins so that it can make lots more virus particles to go invade new cells. This work took the virus that causes Covid19 and got it to infect lots of lab-grown cells. They then studied the virus’s own genetic material, RNA instead of DNA in this case, and used a clever method to extract all of the proteins that were bound to it. All of these proteins that were stuck to virus RNA were then identified. It turned out that the virus needed over 100 different types of proteins from the host cell in order to function properly. They then studied another virus and found that it needed to hijack many of the same proteins during the course of their life cycle. This means there is a list of very strong targets for antiviral drugs, as if we can stop the virus using these proteins it could limit or event stop their ability to infect our cells. There is a youtube video of my explanation of this on the blog post of this episode, as well as a more scientific explanation from Marko and Wael and a link to the paper. The next thing I’d like to talk about is virus research that doesn’t aim to kill the virus or prevent it causing disease, instead its using viruses to treat diseases. I know, you’re thinking I’ve finally lost my mind but it’s true and to talk about this I need to go back to the beginning of this episode. Remember I was talking about the different shapes viruses have, and one of them looks like a spaceship? These are called phages or bacteriophages. Now I know that sounds complicated but phage is derived from the Greek word to devour or to eat, so these phages destroy bacteria and can be used to treat bacterial infections. This idea is not a new one and was first proposed more than 100 years ago. The advent of antibiotics meant that phage therapy research was very slow in the West but it was widely used in Eastern Europe. In recent years more attention has been paid to phage therapy due to the massive problem of antibiotic resistance. Antibiotic resistance occurs when bacteria evolve defences against these drugs. Phage therapy has the added advantage of the viruses being able to evolve alongside the bacteria. So while it takes years of research and testing to make new antibiotics and millions of dollars to bring them to market, phages can evolve ways past new bacterial defences themselves in a very short time. Considering the rapid onset of new antibiotic resistant bacterial strains, it might be that viruses could be our greatest weapon against some diseases.  They are also very specific to one species of bacteria, so they don’t wipe out the useful bacteria in your body like so many antibiotics do.

The final thing I’d like to talk about in this episode, and I will keep it brief as everyone is pretty much exhausted with it, is Covid19. Now, I won’t go into too fine detail but we’ll ask a simple question, how did this pandemic happen? Well the answer really should be, why did it not happen sooner? Throughout history, outbreaks of disease would be contained locally or would spread slowly as people didn’t move around all that much. If disease did spread it would do so very slowly and take years or even decades to make it around the world. But in a global economy with vast numbers of people travelling long distance and a growing population living in crowded urban environments its actually surprising it hasn’t happened more often. We have unintentionally created a near perfect environment for spreading disease over long distances. This is well illustrated with the Spanish Flu pandemic at the end of the first world war. Crowded conditions in trenches and barracks were the perfect incubator, followed by millions of soldiers going home to spread the virus. There have been some near misses in recent decades, with the likes of SARS and Ebola being contained before they could go global. Viruses evolve extremely quickly, as we’ve seen with new strains of Covid, so new more infectious strains of viruses will always happen. It’s very clear to epidemiologists that other outbreaks are inevitable, so the world needs to invest in research and disease control systems so that the last two years stay a once in a century problem rather than a regular occurrence.  

And on that cheerful note we will end. But first a final recap of what we’ve covered so far:

• Viruses are ridiculously small, have different shapes and sizes, but all of them are pretty much just genetic material wrapped in protein.
• Despite having very short genetic instructions they are able to enter our cells and hijack the cells machinery to make what they need to reproduce
• Our body has defences, some that react quickly and others that take time to learn what the virus looks like so it can attack it very efficiently
• Vaccines make our defences way more efficient by training our immune system to recognise the virus and attack it straight away.
• Virologists are researching new ways to target viruses by finding new drug targets and using viruses themselves to cure bacterial infections
• We’ve created a world that is perfect for spreading diseases, so a lot of work and investment is needed to prevent future pandemics happening more regularly

I hope you found that interesting. Comments and suggestions are welcome, so please contact me on twitter @Untanglings or on the website www.untanglingscience.com. Also please subscribe to the podcast and spread the word. I will keep doing these as long as enough people are interested, so if you want more get your friends to listen. I’ll update the blog post for this episode with some links and pictures to help you go along with the episode. For the next episode we will leave my comfort zone of biology and move into chemistry. We will start with the basics and talk about Atoms and the Periodic Table. Thanks for listening and I’ll talk to you soon.

Viral entry image: By Nossedotti (Anderson Brito) - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=14114788