This post is the third in a series of ‘meet the expert’ articles about worldwide investigators working in virology research. These posts are written by the CVR bloggers and are designed to educate, engage with, and inform the public and fellow scientists about who scientists are and what are our motivations. Joanna Morrell, Ph.D. student in the lab of Pablo Murcia, has a chat with Wendy Barclay when she was visiting the MRC-University of Glasgow Centre for Virus Research. Her research focuses on understanding influenza virus pathogenesis, host range restrictions and transmissibility. Wendy is the Chair in Influenza Virology at Imperial College London and the Chair of Virology for the Society of General Microbiology.
For the interests of the blog and people that might not know about your research, would you be able to sum it up in one or two sentences?
I will try! My lab work is on influenza viruses and we work on all types of flu, the main question is about influenza pandemics and host range. Why when there are so many viruses in birds do they not infect humans more frequently; and what does it take for a virus of birds to transform into one that can both infect people, and transmit amongst us?
Why are you so interested in respiratory viruses and have chosen that to be your field of study?
Well, you can have the answer that says, “Oh because they are really interesting and are the most important”, or you can have the answer that says, “That’s where I ended up after a few interesting choices in my career”.
I started out as a PhD student in this weird and wonderful place called the Common Cold Unit (CCU) in Salisbury, which doesn’t exist anymore, but which was set up just before World War II, to understand the transmission of disease between humans. They worked mainly with common colds as a model for looking at communicable disease. (Video showing day-to-day life in the CCU in 1958.) The reason they were worried about that was because of the air raid shelters that were going to be used in the War to protect people from the bombing, and the spread of disease through those. So they wanted to have testing centres where they could look at drugs and strategies for stopping the spread of disease. Then as the war went away and they carried on this research, it became more and more focused on the common cold.
So right from the beginning, I’d not done any virology before that, I had learnt all of my virology based on common colds. My PhD was inoculating people with Rhinoviruses, giving them colds, measuring their immune responses, and then inviting them back the following year and giving them the same cold again and asking – is there an immunity that lasts and what is the nature of that? So the sort of PhD that you don’t get to do so much anymore, and it was full of all kinds of interesting stories and interesting volunteers.
“I loved research in the lab, I loved the environment, I loved the people and after that I didn’t look back. I thought this is a good way of life and a good way to be.”
After that I was very interested in viruses, and the concept of viruses, but I wanted to learn more about molecular virology. Jeff Almond offered me a Postdoc, and he’d been decoding the basis of vaccine attenuation for the Sabin strains of poliovirus vaccine strain, Sabin strain, and that seemed the perfect opportunity to learn how to clone, how to manipulate viruses. I was just bowled over by the fact that you can make a virus de-novo, and I loved doing that – understanding the replication, the way that the cis-acting signals in the poliovirus genome controlled the packaging and the replication of the genome, the piece of RNA.
So I learnt how to do that with poliovirus, which people had been able to do for some years already, and then at a conference I met Peter Palese, and he had just discovered how to get that to work with negative-strand RNA viruses and flu, and he offered me a Postdoc. So I went off to New York and did that. It was funny because at that time I wasn’t even thinking of flu as a respiratory infection really, it was just another piece of RNA to manipulate and mess about with. Much of what we did in the flu lab with Peter at that time was not really designed thinking big picture, it was about what you could do with this new technique that nobody had been able to do before.
I guess over the years, having come back and set up my own lab, I’ve kind of combined that original interest in communicable disease by respiratory route with the ability to do molecular virology. I suppose now I bring those two sides together – about how a respiratory virus spreads, and what the routes of transmission and the molecular determinants of those are.
It is fascinating to hear how everyone first started on the path to becoming a scientist; can you pinpoint a time where you decided?
I think I really didn’t want to be a scientist at all when I was at school. I went to an all-girls school and there were only me and one other person who I suppose were good enough and could be persuaded to do Physics as an A-level. There was a similar situation with Chemistry; I think there were about five of us in the Chemistry class. I wasn’t very interested in Biology, lots of the other girls wanted to do Biology, but it seemed to me much more boring. So I did Maths and Physics and Chemistry, mainly because I could and because the school pushed me into doing it. I thought to myself I might become a Chemist, but I also at that time thought I might just earn loads of money by going into the pharmaceutical industry because I assumed that everyone that went into the pharmaceutical industry did earn loads of money. Actually I remember reading one of these books, I think by Arthur Hailey, some sort of novel about a female who worked in the pharmaceutical industry and became very powerful and I thought “oh yeah, I’ll do that”.
So I went to university with the full intention of doing some Maths and some Chemistry and carrying that on, but because of the way that the university was set up you had to choose different modules in the first year. By default I choose a few Physiology and Biochemistry-type modules and thought they were brilliant. It was nothing like the Biology I had done at school, it was much more in-depth and much more interesting. After all of that I ended up majoring in the biological side of the degree rather than the others. Even then I still wasn’t really sure I was going to stay and be a scientist, I tried and interviewed to be a patent lawyer, and failed miserably at that. I had an interview at a pharmaceutical company to be a marketing type person, and failed miserably at that too. I didn’t prepare for those interviews at all and I had no idea what the jobs really involved; I just thought they were what I wanted to do. Then finally you get to your undergraduate project so begrudgingly I went into the lab and did the project, and it was absolutely brilliant! I loved research in the lab, I loved the environment, I loved the people and after that I didn’t look back. I thought this is a good way of life and a good way to be.
You’re one of the founding members of Scientists for Science. Why do you think it is so important for the continuation of these so-called “gain of function” experiments?
I think the point about Scientists for Science is that it’s bigger than gain of function. It’s really important that everyone becomes engaged in this because it goes to the fundamentals of who should control the science that we do, and who should decide what knowledge we share, and all of those deep-rooted things that I do care very passionately about.
So right at the beginning with the H5N1 controversy, there was a discussion about not allowing the information to be shared. I felt really strongly about that and wrote several articles in newspapers and stuff. I always use Alexander Fleming and penicillin as the blue-sky illustration, but basically we just don’t know what we don’t know – that awful Donald Rumsfeld thing. To me knowledge is everything and you just don’t know what you’re going to discover tomorrow, and you don’t know who is going to discover it. So the American government should not be in control of who knows what, we should tell everybody and hope that collectively human beings make a better place. The reason that I’m in it is because of that, because it’s about knowledge and it’s about science.
“To me knowledge is everything and you just don’t know what you’re going to discover tomorrow, and you don’t know who is going to discover it. So the American government should not be in control of who knows what, we should tell everybody and hope that collectively human beings make a better place.”
I do accept that we have to at this stage sit, stop and think seriously about how we do these things. It’s tremendously unfortunate that there have been some accidents that have added weight to the argument from the other side, when anthrax is mislabeled or whatever it’s awful. That having said, all of those things have to be tidied up, there’s no doubt we all can do better than we do currently. The consequences of those accidents, actually they’re not accidents they are incidents, they are things that have been picked up; nobody has died as a result of these things and it’s ok.
The reason I’m trying to stir up debate in this is because I see that we’ve come to a point a little bit like the GM debate 20 years ago where, if we’re not careful, uninformed people will be making decisions about things which are really very important for us. Sometimes it’s very difficult for scientists to be trusted by the public, and it’s just becoming more and more important that scientists speak out and relate to the public, and seen to be open about this. We have to communicate clearly, we have to explain ourselves clearly, and we have to listen to what the public and other scientists are saying, and be grown up and reasonable about it.
Along your career, if you had to pick out one experiment you could point at and say, “that’s the experiment I’m most proud of”, is there one that springs to mind?
The one I love the very most is the experiment that I did with Jeff Almond in my Postdoc time, when I just learned how to make viruses from bits of synthetic DNA. We were looking at the way poliovirus controls it’s replication, and we knew there was a structure of RNA in the genome that must be important. We tried to disrupt that piece of RNA, and the way we would do that is we would synthesize a mutated piece of RNA, and with polio it’s so easy, you put all the RNA to cells and plaques come out because the RNA itself is infectious. We could do this, and overlay the cells having put different dilutions of RNA and do like a plaque assay almost on the RNA, and then about two days later you’d come and count the plaques and see what you’d got. The wild-type virus was giving plaques right out to 10-4/10-5 dilution, but this particular mutant. It rescued, it made a virus, but it only made plaques to a 10-2 dilution.
What we realized was that what we were rescuing was not what we had put in, the sequence had changed even in the rescuing of the virus. When we went and sequenced those plaques they had mutations that restored the structure of the RNA by base pairing in a different way than we had originally started with in the wild-type. That was brilliant, because it told us so many things at once. It said this is a combination of reverse genetics and forward genetics, we’ve tried to make the virus do one thing but it’s said, “no I’m not doing that but I’ll do this instead”. That told us how important that bit was and the difference in the numbers, because I’ve always quite liked maths, it was indicative that the virus had made the decision. The virus could only make that decision in every 103 times which was why we had 103 fewer plaques.
So I think that sums up everything that I like about doing virology – you test out your hypothesis, then the virus tells you what the answer is, and if you’re smart you can put the information together and learn from it.
Tons I suppose. It’s really tough these days. You’ve got to get published, and when I started doing my PhD the best advice that my PhD supervisor David Tyrrell gave me was – try to think about a paper as soon as you get your result, if not before. Young people need first author papers and so in your PhD when you’re doing your experiments can you see the paper in your head already? Do you know what the title is? Do you know what the figures are going to look like roughly? Are you doing experiments that are going to give you figures? That’s not to say that it’s all about publication, but if you ask yourself honestly, are you doing an experiment that you wouldn’t even publish then are you wasting your time or somebody else’s money doing it?
I see so many people be judged before they are even in the room based on their publications, and I get sent CV’s and you have to see that people can do some good science, finish it off and write it up, and get it through that stage. At this stage in your career I think papers are really important. I’m sorry if that’s a bit depressing, but remember it can be fun at the same time!
If you hadn’t been a scientist what career path could you see yourself doing instead?
I think I would have failed miserably at all of the things that I thought I would have done. My poor old Mum wanted me to be a doctor and I am so interested in all the biomedical; I would have been a proper doctor, not a PhD. I sort of wish that I had done medicine so that I would have the option of really helping people, and the whole Ebola thing where many of you young people are going out and helping, and some of my colleagues are as well, I have absolute admiration for them and many times think “shall I do that too?” I suspect if I were a medic I would feel even more compelled to go and help, and I think there is something wonderful about being able to go and really help people. So I wish that I had been a medic, and I wish that I’d helped more people than I have. I don’t know that I would have been very good at it, as I’m not very good with things like blood, and I would have fainted during practical classes. But I suppose if I started all over again I would probably make myself go to medical school like my Mum would have made me.
Background – Influenza virus
Influenza viruses come from the Orthomyxoviridae family of viruses, and have 8 negative-sense RNA segmented genomes. They cause a huge burden on healthcare as every year globally 5-10% of adults and 20-30% of children are infected, resulting in an estimate of about 250,000 to 500,000 deaths.
Therefore it is all the more remarkable that Influenza A viruses are not naturally human viruses but were in fact viruses that originated in birds. This means the influenza viruses that currently circulate seasonally (H1N1 and H3N2) have at some point in history been able to jump the host species barrier to infect humans, and have been circulating among us ever since. Now there are many different species that can be infected with influenza A viruses including pigs, horses, dogs, bats and even whales.
An Influenza A virus is made up of 8 negative-sense RNA segments; two of these encode the glycoproteins, the structures that are found on the surface of influenza A particles. These are called the haemagglutinin (HA) and neuraminidase (NA) proteins, and currently there are 18 and 11 subtypes known for each, consecutively. These subtypes can sometimes mutate or reassort creating a new virus that may have the potential to jump species barriers and infect new hosts. There are also 6 other segments that can also be involved, and scientists are currently trying to research if there are specific mutations that they can be on the lookout for, so as to predict a new influenza pandemic before it happens. Wendy Barclay is one such scientist trying to discover the answers to this fascinating question.
By Joanna Morrell, Ph.D student. @joanna_morrell
With thanks to the rest of the blog contributors for reading critically.
The MRC – University of Glasgow Centre for Virus Research has a range of research groups studying influenza – the structural biology of filamentous influenza particles (David Bhella and Frazer Rixon), understanding the molecular and evolutionary mechanisms of influenza emergence into new hosts (Pablo Murcia), and how influenza engages with ubiquitin and ubiquitin-like modification pathways during infection (Chris Boutell).