What is a virus?

 

EPISODE TRANSCRIPT

Welcome to What Do You Want To Know, the podcast that tries to find the answers to your questions. My name is Jenny and I'll be your host... although I might stop calling myself that by the time this particular episode is over...

We've all been impacted in some way by the Covid-19 outbreak, so I guess it was inevitable that we would have to do an episode like this one. As we're recording, Ireland is just a couple of days into the first phase of the plan to reopen the country. We've all heard a lot about viruses, vaccines, immunity, and reproductive rates over the last few months, and some of us have probably watched all of the pandemic movies on Netflix by now. There is a mountain of information out there, and it's often difficult to know what's reliable and what isn't. 

But how many of us actually know what a virus is? Or how they work? Have you ever asked yourself if a virus is alive? Or wondered how a virus is different from bacteria? Or why everyone is so obsessed with antibodies?

I asked Andrew Bowie to help me answer these questions. Andrew is a Professor of Innate Immunology at the School of Biochemistry and Immunology and the Trinity Biomedical Sciences Institute at Trinity College Dublin. Andrew is a global leader in the research fields of innate immunology and viral evasion, and he was one of the most highly-cited researchers in the world in 2018. His research looks at how human cells detect viruses, and some of his discoveries have redefined our understanding of how pathogens engage with human cells. 

I began by asking Andrew 'What is a virus?'

Andrew: Yeah, so viruses are very simple structures, so they're made of up of just a few very basic biological molecules. They have some genetic material, and that encodes their various proteins that they need to be a virus, to make a structure of a virus, and that genetic material can either be DNA or RNA. And apart from the genetic material, all they really have is then a coat of protein and lipids surrounding the genetic material. So they're very simple and very small particles.

They're incredibly abundant in nature, so for example in one drop of sea water there's probably about 10million viral particles, so really, really abundant. And new ones are being discovered all the time, so there are lots of viruses we still don't know about that exist out there. And obviously, particularly at the moment, the virus that's of interest to people is the virus that causes the disease of Covid-19. That virus isn't called Covid-19; it's called SARS-Cov-2, and that stands for Severe Acute Respiratory Syndrome Coronavirus 2. So it's a bit like the way the HIV virus causes AIDS. SARS-CoV-2 causes Covid-19.

Jenny: Ok, just to pick up on something there: a lot of us would have heard of DNA but might not be so familiar with RNA so what's the difference between the two of them?

Andrew: Yeah, so both are genetic material - in other words, that they have the ability to contain information. So in our own bodies, in fact, although people have heard a lot about DNA we also have a huge amount of RNA in our cells as well because RNA is the molecule that brings the information from the DNA to the machines in our cells that make proteins. So you can actually encode information either in DNA or RNA, and there's a huge amount of viruses actually that are RNA viruses and this virus we're talking about today – SARS-CoV-2 - it's an RNA virus.

Jenny: So what are some other viruses that we might have heard of? We'd all be familiar with colds and flus and different things like that, but...

Andrew: Yeah, absolutely. And again, colds and flus are diseases that are caused by specific viruses so there are some much milder coronaviruses that cause the common cold in humans. Flu is caused by influenza virus, so it's a virus that probably originally was in ducks and birds and different things and jumped to humans a long time ago. Another very commonly known about virus that's been in the news a lot is measles. Measles is a very common viral infection. People will have heard of herpes viruses as well. Hepatitis C virus, another one that's very commonly worked on, and then, you know, some more exotic ones that have been in the news in more recent years would be things like Ebola virus and Zika virus.

Jenny: So, in general, how do viruses work once they actually get inside our bodies?

Andrew: Viruses have to get inside our bodies because they need a cell to be able to replicate and to produce more virus particles, so viruses are a bit like I suppose you might call them molecular parasites. People might remember from their biology in school that a parasite is an organism that co-exists with another organism, and if it's an obligate parasite it means it needs that other organism to survive. And viruses need a cell to survive in. So once they're inside the body, they have to get inside a cell, and for some viruses that's very easy because they can just be sucked in by the cell in different ways.

For other viruses, they have to bind to a very specific receptor on a cell. This in fact is really interesting because this then defines why some viruses can infect certain people and certain animals, and so for example, again in the case of SARS-CoV-2, there's a protein on human cells called ACE2 that it binds to. That's the receptor it uses to get inside cells, so if SARS-CoV-2 was not able to bind to ACE2 on the surface of our cells it wouldn't be a problem at all. So this is an example of a virus that binds to a very specific protein on a human cell and gets in. And then, of course, the cells that actually have ACE2 on the surface are the ones that are susceptible to being infected. Even in terms of a whole population, one reason that some people might be more susceptible to this virus than others, for example children versus older people, might be to do with how much of that receptor they actually express on their cells.

So once the virus sticks to the outside of a cell, often by using one of these receptors, it then gets taken inside the cell, and then what it does is it hijacks the cell's machinery and uses the cell's machinery to replicate itself. So our cells have all sorts of proteins inside them that are used to replicate our own cells, and to produce new cells, and the virus hijacks all that machinery and uses it, and you know, we even talk about viral factories in the inside of our cells, if viral factories get produced and the virus can then very rapidly produce multiple copies of its genetic information and then it can assemble new viral capsids as they're called, and then the viral particles can pop out of infected cells, and that can all happen in a matter of days. In a matter of days, one cell can actually produce millions of viral particles.

Jenny: So, are viruses alive then, because they need to be in a body, or they need a host as such, could we consider them to be alive? Or are they only active when they're attached to something?

Andrew: Well, it's actually a very good question, and it doesn't have a clear answer. There are articles written over the years discussing even the philosophy behind this. How do we define life, and you know, are viruses actually alive? So one definition that I liked is someone said that viruses are 'organisms at the edge of life.' They're sort of alive, but you know, some people would define life as the ability to reproduce yourself, and viruses can only reproduce as I said if they're inside a host cell. So the host cell could be a human cell or if it's a virus that affects an animal, an animal cell, but they need to be inside a cell to replicate. So it depends on how you define life, but you know I like the idea that viruses are organisms at the edge of life.

Jenny: Sounds good. So what's the difference then between a virus and bacteria?

Andrew: So obviously viruses and bacteria both cause disease, so we call them pathogens, so people would often lump them in their minds as maybe very similar. And you might be familiar of course with the fact that sometimes you go to the doctor because we have an illness, and we're prescribed antibiotics and people will say 'well, it's a viral infection so there's no point taking antibiotics' so they are quite different, and how the body fights them can be quite different.

One big difference is size, so on average, you know an average virus - and the viruses vary a lot - but an average virus is maybe one hundredth the size of a bacterial cell so that's one difference. Another difference is cell structure, so as I described viruses are very simple. They've just got, you know, protein, lipids, genetic material. Bacteria are much more complicated. They're much more harder to understand actually. There's still huge research going on just to understand the basics of how bacteria grow and infect cells, so they're much more complicated. Bacterial cells look a lot more like our own cells, and in fact it's interesting because bacteria themselves can be infected by viruses. So there are viruses called phages which attack bacteria, and just like we have immune systems to combat viruses, bacteria actually have protective mechanisms as well to try to overcome phage infection.

Even more interesting is the fact that there is now a type of medicine called phage therapy, and that's where researchers are now starting to use viruses that target bacteria to kill bacteria and bacterial infections. So you know, antibiotic resistance is a big problem now, that some antibiotics we use aren't effective anymore against bacteria. But in phage therapy what we do is we take viruses that are known to attack a certain bacteria that causes a human disease, and you actually give those phages to people that have severe bacterial infections, and there's been great success stories in terms of how people have been brought back from the brink of death by using this phage therapy.

Jenny: That's really interesting! A word that we've heard a lot about recently, with everything that's been going on, is antibodies. What are antibodies?

Andrew: Yeah, there's lots of talk about antibodies at the moment, both in the context of maybe vaccines, and ways that our body can fight viruses. Also in terms of things like immunity passports so, you know, people have been discussing in the news I'm sure you've heard about the fact that if you have certain antibodies that might mean that it's an indication that you've had the virus, that you're now immune. So antibodies, they're proteins first of all, that's what their structured in. They're a key type of weapon that our immune system has to fight intruders and they bind very specifically and very tightly to their target molecule. The target molecule they bind to is usually a foreign molecule, so our immune system is able to discriminate between molecules it sees all the time, the normal molecules that circulate in our body, and molecules that shouldn't be there - foreign invaders such as viruses.

The immune system can generate antibodies to foreign material so that's why if you have certain antibodies in your system it actually is a sign that you've been exposed to that foreign material. So they bind, antibodies bind very tightly to their target molecules on viruses and there are different types of antibodies in the body. You know, some of them we know really well how they work, other ones it's a bit more obscure. Different places in our body, like tissues versus cells, express different types of antibodies. The ones that are probably most interesting currently are called neutralising antibodies, and they're called that because they can neutralise the pathogen or the invader, and so there's huge interest at the moment in trying to work out which are the neutralising antibodies that will neutralise this virus, because they're the ones that would be effective in a vaccine, or even in natural immunity.

So, antibodies, they can be generated in lots of different contexts, so they can come from natural immunity, so if you've been exposed to SARS-CoV-2 you will generate antibodies in your system and, we hope, that they would then protect you from a further infection. They can also come from being exposed to a very similar virus so, you know, there are some viruses that are very similar to this virus - things like MERS, actually, and SARS - and it's possible that if you've been exposed to those viruses in the past, your body has made antibodies that are also able to neutralise this virus.

They're the things that we try to elicit from the body during a vaccine, so one of the main ways that vaccines work against viruses is by generating antibodies that will neutralise the virus. And also, in fact, there's been interesting trials where people have taken serum from patients that have recovered from Covid-19, and given that serum to others that are very ill, and that's had a protective effect and that's because there are neutralising antibodies in that convalescent serum, as it's called, and that can actually protect people or help them to fight the virus when they're seriously ill.

Jenny: So, then, to follow on: what are vaccines and how do they work?

Andrew: Vaccines are always in the news, sometimes for good reasons, sometimes for bad. People have huge, strong opinions on vaccines. I mean, you know, my perspective is that vaccines are one of the greatest gifts that modern medicine has given us. I'd hate to live in a world where there were no vaccines, but they're really interesting. The first ever vaccine was where Edward Jenner vaccinated a child with cowpox and that protected that child against smallpox. And in fact that's where the name 'vaccine' comes from because vacca is Latin for cow, and so the reason we talk about vaccines is because of the fact that the first vaccine was in fact cowpox. Now it turns out that the first vaccine probably wasn't cowpox, it might have been horsepox - that's a different story - but the place that we get the name from is from that initial very famous experiment that many of us know about where Edward Jenner got protection from smallpox, which is caused by variola virus, by infecting this child with apparently cowpox.

So a vaccine is a safe part of a pathogen, or maybe part of a pathogen, or maybe a related pathogen that isn't dangerous to humans, that we give to somebody to try to elicit an immune response against a more dangerous, similar pathogen. Really, a vaccine is given to someone - to a person or an animal as well - to wake up their immune system to be able to subsequently attack the real virus or the real bacteria.

Jenny: So that's pretty much how they work, is that they're waking up our immune system?

Andrew: Yeah, so in terms of how they work then, as I said they wake up the immune system but they wake it up in a very specific way so most vaccines will be very specific to a certain pathogen. And that again comes down often to this idea of the specificity of the antibodies. So antibodies will target a very, very specific type of structure on a virus so that's why we give - like, there are many different ways to give a vaccine, many different types of vaccines. At the moment, I think - I checked yesterday - there are over 130 different vaccines in development for SARS-CoV-2 so lots and lots of possibilities that some hopefully will work. And if you look at those kind of vaccines they're a very good example of different strategies people use, because some of those vaccines are using the genetic material of the virus and giving that directly to people, and that genetic material will then produce a protein of the virus which will be seen by our immune system as foreign so our immune system will then mount a response to that protein which could be neutralising antibodies, which hopefully then would give those antibodies to people for when they encounter the real infection.

Another type of effective vaccine often, is to give people a dead virus so another vaccine is in fact to grow up lots of the virus to activate it, to kill it, but then to give that dead virus to our immune system and that has lots of things that look like the real virus that could wake up the immune system as well. Or often, in fact, what's used as well is if you take a safe virus and you add a bit of the virus to the safe virus, and then that virus is infected - someone's infected with that, and that can elicit an immune response as well. So the bit of the safe virus, or the similar virus, is called the antigen, and that's the thing the immune system recognises as foreign and will mount a response to, and as well as an antigen in a vaccine you often have an adjuvant as well. An adjuvant is something that generally just stirs up the immune system and wakes it up in a non-specific way. So you have the specific antigen and non-specific adjuvant and most vaccines have both of these components in them, as well as other things as well. As I mentioned, that is often to produce an antibody response.

Another response that can be protective is a T-cell response so you can also wake up very specific T-cells and prepare the body to have lots of T-cells to fight an infection. So if you've been given an effective vaccine, hopefully then when you're infected with the real infection, your immune system is already awake and primed to take on the invader and doesn't have to learn from scratch which can be devastating for some people. So because this is a new virus that's new to humans as far as we know, it means that our immune system has never seen it before so if you get infected your immune system is seeing it for the first time, takes a long time for your immune system to wake up. Some people's immune systems, you know, don't wake up as well as others and by that time it's too late so this is why we need a vaccine so we can actually prime all of our immune systems and have our immune system alert and ready to fight this virus if we get infected.

Jenny: How long does it typically take to develop an effective vaccine?

Andrew: Years and years! There's a huge amount of work that goes into it. Although as immunologists and virologists we know a lot about how the immune system works, and how viruses affect us, it's really only when you in fact start to make a vaccine that you start to understand exactly what type of very specific response will work for a certain pathogen. So that's why it takes years. There's all sorts of questions that have to be answered along the way. We just talked there about antigens and adjuvants so one question is what antigens and adjuvants do we use for a vaccine? Another question is what type of immune response would be effective? Like, will it be the neutralising antibodies, will it be the T-cells that will be protective? Maybe both, maybe neither. Will the vaccine give protection? A really important question is will it be safe to give to different groups of humans? Will a vaccine be safe to give to young people, to old people, to people of different ethnicities? Another really big question is can it be mass produced? So once you actually have an effective vaccine, do you have a mechanism to make what would be effectively billions of doses that would be needed in this case? So there's all sorts of things that need to happen, but the great news is that there's such a focusing of minds at the moment in terms of the Covid-19 disease, that it's quite possible that we might have the fastest ever vaccine development.

Now we still don't know for sure that a vaccine is going to be effective, but you know the science coming out already indicates lots of positive signs to that effect. So it's already known in fact that people do produce neutralising antibodies to the virus, and that those neutralising antibodies in experimental settings can be very good to give protection, so there is great hope there. But there are huge hurdles still to cross. So the big three to summarise are: does the [vaccine] work, is it safe, and can it be mass produced? And thankfully there's lots of government resources going into this as well, because in the past there are some viruses that we probably could have developed vaccines to like MERS and SARS that would have been really useful now for this pandemic, but there wasn't really the political will or the motivation so hopefully we will get a vaccine for this coronavirus and that will help us to be more prepared for the next pandemic whenever it might come.

Jenny: Another term that we've heard a lot about, and this is kind of following on from vaccines then, is herd immunity. What exactly is herd immunity?

Andrew: Yeah, so this has been a term that's been in the news a lot as well. It's quite a crude term, you know, as the phrase suggests - herd immunity - it was originally applied to livestock, to thinking about how you could get your whole herd of cattle to be resistant to certain infections, but then also applied to the vaccines and immunity in humans as well. So really it's about, herd immunity really refers to the indirect protection that susceptible individuals can have due to the fact that a whole population around those individuals are sufficiently immune. So in other words, with herd immunity what we're relying on is the fact that if you have a certain percentage of the population that are resistant to an infection - either because they've just been exposed to it and developed natural immunity, or because they've been vaccinated - that can also protect the smaller population that haven't been exposed or haven't been vaccinated.

It's not as clear cut as people might think, you know. One thing that is unclear in any situation is the strength and the duration of protection so even if herd immunity is achieved, and we can talk in a minute about how that might be achieved if you want - even if it's achieved, it's unclear how long that might last. It's different for different viruses we know already, so for example, for measles herd immunity, if it's reached, is very effective and lasts for a long time. For other diseases like pertussis or diseases caused by rotavirus, herd immunity wanes very quickly. It's not sort of the magic bullet, the golden answer to any kind of viral infection. It really depends on the virus and on the type of immunity that people develop.

Even when you have herd immunity as well, you can still have clusters of individuals that are susceptible, so you might have a whole group of people, for example you know in this case an elderly population, that would still be susceptible and you could have clusters and also on the way to herd immunity, especially with a disease like Covid-19, many people would be expected to die on the way to achieving herd immunity. I think it's actually quite, in terms of trying to reach herd immunity naturally that's a very dangerous idea I think. And it's an idea I think that people around the world have realised now that isn't going to work, even though some people are still proposing it.

Jenny: Yeah, and it kind of brings up a lot of very big questions... can you actually achieve it without vaccination though?

Andrew: The answer... I suppose the cold, calculated answer is yes. You can.

Jenny: But it's the cost of it...

Andrew: Exactly. But at a cost. So as I said, you could achieve it, and it mightn't be as strong and last for as long as you want. Really it depends on the Infection Fatality Rate. That's the number of people who die due to the disease of an infected population. And although for Covid-19 we know the Case Fatality Rate - that's the number of people that die from the people that we know are infected - but as you've heard there's probably lots of people are infected that don't know about it, so the Infection Fatality Rate is unclear. But, you know, some people estimate that the Infection Fatality Rate is somewhere less than one percent. But even at that, if you were to try to achieve herd immunity for Covid-19, at an Infection Fatality Rate of less than one percent, 30 million people would have to die to achieve herd immunity around the world.

And that doesn't take into account that there would be some populations like the elderly that are even more susceptible. That's an average number and of course, along the way as well, what would happen is that healthcare systems would be overwhelmed. So as well as those 30 million people that directly die on the way to herd immunity, you're going to have lots of people dying because healthcare systems can't cope and are overwhelmed and can't treat people that are less seriously ill. So, you can achieve herd immunity without vaccination, but at a huge, tremendous cost.

Jenny: I mean, you've already answered the question there I had about populations losing herd immunity so I mean you can kind of effectively wipe out the presence of a virus in the population but it can come back, then?

Andrew: Yeah, absolutely if it's still circulating. Herd immunity, I suppose, refers specifically to the immunity that the population has. The other factor there which you bring in which is an important one, is how much maybe the virus or a pathogen might still be circulating, how much it's still out in nature. So you know, a fantastic success story was eradicating smallpox, for example, and that happened in the 80s. It was the WHO declared that smallpox was eradicated. It's not a disease that we need to worry about any longer. Other diseases more recently that we've achieved herd immunity for, for example like measles virus in certain populations, what's happened is that when people have become suspicious about vaccines or worried about them, they haven't vaccinated their kids, and then there has been measles outbreaks in certain populations again. So that's an example of herd immunity not being effective because of people's particular choices and decisions they make.

So a population can lose herd immunity for all sorts of reasons, and again that's why it's really important to have a vaccine. If we have a vaccine on the shelf that we can take and use for people, we then, even if the immunity conferred by that vaccine doesn't last for life, we can then revaccinate people and hopefully that would work as well. So a lot of people I've talked to are wondering 'well, do we really need a vaccine or surely we could take Hydroxychloroquine or different things and that will be fine,’ and I think people sometimes get confused between three different things. Like, one thing we can do is we can do certain things to boost our immune system to make us more able to fight any kind of infection, including this one. And that is things like taking Vitamin D, taking other types of vitamins.

There's also some evidence, but not very strong, that other vaccinations can kind of wake up our immune system to give us an advantage over Covid-19 so some studies are looking at the BCG vaccine and seeing if people that have been BCG-vaccinated if they have maybe a head start in terms of their immune response. So there are things we can do to prepare our immune systems better for fighting any viruses, that's the first category. The second category is we need therapeutics that will work for people that have the virus to either slow down the infection or to prevent them dying, and there are over 200 different therapeutics that are being investigated at the moment around the world for that. And that's when people actually have it. And thirdly, we need vaccines to stop people getting the disease in the first place and therefore if they do come across, you know hopefully they're vaccinated, they come across the virus, it gets into their system, but because the vaccine has woken up their immune system they're resistant to it and they don't get it themselves and they don't pass it on.

Jenny: So what I'm getting from all of this is that is a very big challenge, but there's a good bit of hope there?

Andrew: Yeah, I think that's the case. I mean it is a very big challenge and there's probably never been a better time to have a pandemic because of what we know now about vaccines, because of the building political will. You know, lots of organisations are working well together - some aren't - but you know there are amazing examples of, for example, in America, the National Institute of Health and governments and pharma companies and academics all coming together to pool all their expertise and their resources to get ready to make vaccines once we find one that's safe and effective. There is still a chance that the vaccines won't work, but, as I said, so far the science is positive in suggesting that a vaccine will be effective and we'll still need therapies as well. We'll still need ways to make our immune systems more healthy. So we need all of this good stuff coming together.

But we need to really, I suppose, follow the science and follow the data, and not get swamped and misinformed by soundbites and by all sorts of false information that's out there as well. Obviously there's a viral pandemic at the moment; there's also a pandemic of information. Some of that's been good, some of that's been bad, and it's quite difficult for people that aren't informed to really be able to separate out the good stuff from the bad stuff.

Jenny: What would you recommend as a trusted source if people are looking for information about new treatments or to reduce risks?

Andrew: There are lots of trusted sources. I mean... the WHO, which again they've come in for a bit of flack but they're a trusted source. I think our own Department of Health, in the States the National Institute of Health. A lot of these agencies are just genuinely trying to do their best to sort out this whole situation and are providing really good information.

One thing I suppose that people probably worry about is can we trust scientists, or how can we trust scientists when one scientist says one thing and maybe another scientist says something else. And I won't mention names, but there are very specific examples currently of scientists that are wheeled out there by people with different agendas to say something, you know, quite controversial about this whole pandemic. And one thing I would say is there's always a body of scientific work that most scientists will stand with and stand behind, and if you hear something from one individual scientist you can check the body of scientific work and check what scientists are saying on average, and see if that matches up or not.

And also, you know, you probably want to be hearing about vaccines from immunologists, from virologists, not from maybe people that don't have any experience in those areas. So you know, you can check out someone's credentials. Sometimes people's credentials are wheeled out and they seem really impressive, but they may not actually have any experience in that particular area. So there is a body of scientific evidence and there are published scientific studies that are peer-reviewed, and then become accepted by the scientific community, and those are coming out at a phenomenal rate.

It's incredible how quick new information is coming out on this virus. You know, experiments that maybe in the past might have taken a couple of years to come to fruition and get published, are now taking weeks or months. So almost every day we're learning new information, which, a lot of that is really sound and believable information because it goes through the normal peer review process and is checked by the scientific community. So there's lots of reasons for hope.

Jenny: That's great. Thanks for talking to me today, Andrew! I'm going to finish with one question that I'm asking everyone: what is your favourite thing about being a researcher?

Andrew: There are huge pressures and challenges being a researcher, but most of us that are in it are in it because we find it tremendously exciting and a real privilege as well. I mean, I just think, you know, if you go out for a walk and you look at even the trees around you, and even if you're a botanist or someone who studies trees, when you look at that tree, there are so many things that you still don't know about how that tree actually even works, you know, what's going on in the cells and all that.

One thing that really excites me and motivates me about being a researcher is this privilege of finding out new things, even very small things that nobody's known before about the natural world, so discovering things for the first time. I can't remember who said it, but there was a quote a couple of years ago that really struck me where somebody said 'the universe is filled with things of unimaginable beauty just waiting to be discovered' and certainly, you know, even in biology and looking at individual cells, and proteins inside cells, you just find this unimaginable beauty within nature and these incredible things that are waiting to be discovered.

So, you know, it's intellectually very satisfying. I'm one of those people that likes to figure out how things work and, as well, the way research works where you're working with a research team, it's a wonderfully exciting journey of discovery where it's almost like you're on an adventure with a team of people, and you're applying all your different ideas and experiments to try to find the solution to really interesting questions. So being a researcher is fantastic... On a good day!

***

My thanks to Andrew for talking to me today, and I hope you found our chat helpful. If you want to find out more, go to tcd.ie/research/researchmatters where you'll be able to find a full transcript of this episode along with some links to the things that Andrew was talking about. You'll also be able to find the comment box where you can send us your suggestions for future episodes.

Thanks to Tim Nerney who composed our music, and Conor Reid and Paddy O'Leary at HeadStuff who help me with the production side of things. And thank you for listening! Tune in next time to find out more of what you never realised you wanted to know!